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\begin{document}

\title{Plant-based anticancer compounds with a focus on breast cancer}



\author[1]{Amin  Moradi Hasan-Abad}%
\author[1]{Ali Sobhani-Nasab}%
\author[2]{Amir  Atapour}%
\author[1]{Hossein Motedayyen}%
\author[2]{Reza  ArefNezhad}%
\affil[1]{Kashan University of Medical Sciences}%
\affil[2]{Shiraz University of Medical Sciences}%


\vspace{-1em}



  
  \date{May 26, 2024}


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\selectlanguage{english}
\begin{abstract}
Cancer as a terrible disease ranks among the most important healthcare
issues confronting humanity, necessitating a proactive approach to
treatment. Numerous signaling cascades are involved in the complex
process of carcinogenesis. Despite its success, chemotherapy has had
some undesirable side effects. Plants offer a rich source of novel
substances and represent an exciting new option for cancer research.
Plants and plant-derived products are revolutionizing themselves because
they are less poisonous, quicker, cheaper, safer, and simpler than
standard treatment procedures. Natural products are viewed as viable
candidates for the creation of anticancer medicines because of their
pleiotropic effects on target events in a variety of ways. The actions
of plant-derived products are selective; they damage cancer cells and
have no significant effect on healthy cells. Several researches are
being conducted on the production of potential candidates from these
plant-derived products that can stop or inhibit cancer cell
proliferation without causing adverse effects. Numerous plant-derived
products and the analogs from which they were derived have been
identified as potential anticancer therapeutic possibilities. In this
review, we summarize research on botanical products with significant and
active anticancer activity and their anticancer constituents, with a
focus on breast cancer. This review sought to highlight the most recent
advances and key successes in plant-derived products and cancer
therapies focusing on nuclear and cellular structures. Furthermore,
cancer drugs and their problems are discussed.%
\end{abstract}%



\sloppy


\textbf{Introduction}

\textbf{Cancer and tumorigenesis}

A set of illnesses known as cancer involve abnormal cell proliferation
and can infiltrate or spread to other regions of the body. In 2020, 18.1
million new cases of cancer occurred, which were 9.3 million male cases
and 8.8 million female cases (1). Its etiology is largely related to
genetic, immunological, and environmental factors. Defects in immune
responses, cell apoptosis, and DNA repair functions have fundamental
role in its development and progression (2, 3). Oncogenes, as important
genes involved in cell cycle regulation and apoptosis, can undergo
genetic or epigenetically driven alterations that lead to cancer (4, 5).
The information required to determine cancer risk factors is provided by
epidemiological studies (\textbf{figure.1} ). Random mistakes in DNA
replication occur at varying rates in various organisms are among the
risk factors for developing cancer. Ionizing radiation, carcinogens,
bacteria, fungi, or viruses, DNA damage response, metabolism,
xenobiotic, immune system, hormone levels, and lifestyle elements such
as smoking, hormone therapy, dietary consumption, and physical activity
are considered as some environmental risk factors (6, 7).

The biological reactions to ionizing radiation are influenced by several
factors including the type and energy of the radiation particle, the
dosage rate, the types of DNA damage, the cell type, etc. Ionizing
radiation has the ability to damage nucleic acids, which could lead to
alter the regulation of ordinarily expressed DNA (8, 9). Some types of
cancer have been linked to infections caused by specific organisms. For
instance, stomach cancer correlated to Helycobacter pylori bacterial
infections, gallbladder or colon cancer to Salmonella, hepatitis C and B
to liver cancer, Kaposi sarcoma to the herpes virus, and cervical cancer
to the human papillomavirus infections (10, 11).

Toll-like receptor pathways (TLR), nuclear factor-kappa \selectlanguage{greek}β \selectlanguage{english}(NF-k\selectlanguage{greek}β\selectlanguage{english}),
cGAS/STING, Janus kinase/signal transducers and activators of
transcription (JAK-STAT), inflammation, and mitogen-activated protein
kinase (MAPK) have reported as the important factors related to the
occurrence of cancer. Interferon (IFN), Interleukins (ILs), and tumor
necrosis factor (TNF)-like cytokines, chemokines, growth factors such as
transforming growth factor (TGF), and vascular endothelial growth factor
(VEGF) play key roles in cancer development. Some inflammatory
metabolites, such as thromboxane, leukotrienes, prostaglandins, and
specific proresolving mediators (SPM), serve as significant regulators
in the initiation and resolution of inflammation in cancer (12, 13).

\textbf{Breast cancer}

Breast cancer, one of the most prevalent malignancies and the primary
cause of cancer-related death in women worldwide, disrupts the lives of
millions of women (14, 15). For many years, breast cancer has
consistently been ranked among the most lethal cancers in terms of
incidence and mortality (16-18). Similar to other cancers, it is
influenced by a person's lifestyle, environmental circumstances, and
genetic predisposition. Age and breast density are two examples of
natural characteristics that can increase the risk of breast cancer. In
addition, alterations in circadian rhythm, alcohol consumption, and
tobacco chewing or smoking are associated with the increased risk of
breast cancer (19). These circumstances can result in cellular stress,
the increased production of free radical oxygen species, and changes in
progesterone and estrogen hormones, all of which enhance tumor
aggression (20, 21). Common therapies for breast cancer include
chemotherapy, radiation therapy, and surgery, however these methods have
a poor prognosis and long-term negative effects. Breast cancer therapy
is impeded through metastasis, recurrence, and drug resistance, like
treatment for other cancers (22, 23). Scientists are focusing on
nutraceuticals as an emerging medicine with less side effects to address
the issue with breast cancer treatment. Due to lower drug-related
adverse effects and resistance phenomena, nutraceuticals can also be
used as an adjuvant therapy with currently available chemotherapeutic
medicines (24, 25). Since ancient times, people have used natural
remedies made from various plants or non herbal sources to treat a
variety of ailments, with many encouraging results. The need for
developing various herbal and non herbal drugs with therapeutic
potential is growing as a science and technology advance. As a result,
there is plenty of room for innovative, healthy nutrition substrates. In
2017, it was estimated that the global market for nutraceuticals would
reach 734 billion US dollars by 2026 (26, 27). Therapeutic compounds
known as nutraceuticals have drug-like qualities and are used to treat
serious illnesses like cancer, diabetes, atherosclerosis, neurological
diseases, and hematological disorders. According to study, health food
products contain polyphenols, terpenoids, tannins, alkaloids, and
flavonoids, which have a significant potential to combat these fatal
diseases (25, 28, 29). In this review, specific important and pertinent
breast cancer processes are highlighted, and nutraceuticals are assessed
along with their processes and potential in breast cancer prevention.

\textbf{Breast cancer pathophysiology}

Breast cancer typically starts as ductal hyperplasia and progresses
through benign tumors and even metastatic cancer because of numerous
toxins stimulating it. The effect of stroma and tumor microenvironment,
including macrophages, play a critical role in the onset and progression
of the cancer. Macrophages have the ability to create an immune
system-rejecting and mutagenic milieu that promote angiogenesis and
permits cancerous cells to spread (30). The cancer stem cell and the
stochastic theories are two hypotheses that may help to explain the
development and spread of breast cancer. The stochastic hypothesis
postulates that each tumor subtype is derived from a single cell type,
differentiated progenitor, or stem cell. Any breast cell can get random
mutations over time, and when enough mutations have accumulated, the
cell is eventually become a tumor cell. Based on the cancer stem cell
theory, various tumor subtypes develop via identical progenitor cells or
stem cells. Epigenetic and genetic alterations in precursor cells or
stem cells have fundamental role in determining different tumor features
(31).

\textbf{Limitations of cancer treatments and anticancer drugs}

A growing body of studies has performed to develop novel drug delivery
and targeting methods, enhance drug accumulation and its efficacy, and
minimize the negative side effects of medications during the course of
cancer therapy (32). The most current approaches to cancer treatment
include surgery, radiotherapy, chemotherapy, immunotherapy, cancer
vaccines, photodynamic therapy, stem cell transformation, and/or
combinations of these options. These methods are largely related to
serious side effects, including restricted metastasis, toxicity,
nonspecificity, and reduced bioavailability (33-35). Cancer treatments
are dependent on the type, stage, and site of cancer. Cytotoxic and
cytostatic drugs used in chemotherapy can exert their potential impacts
alone and/or in combination with other forms of cancer therapy.
Alkylating compounds, such as carboplatin, cisphamide, oxaliplatin, and
melphalan, may lead to cardiovascular, gastrointestinal, hematologic,
pulmonary toxicities, diarrhea, sensory neuropathy, and neutropenia
(36-38). These compounds are highly successful in treating numerous
malignancies, but they have serious side effects, are expensive,
complex, toxic, and unfriendly to the environment. Some cells, such as
those located in the gastrointestinal tract, bone marrow, and hair
follicles, develop quickly under usual physiological conditions. The
contemporary anticancer medications also target these rapidly growing
healthy cells. These anticancer drugs can lead to GIT inflammation, hair
loss, immunosuppression, cardiac conditions, reduction in blood
production, and neurological issues (\textbf{Table 1} ).

It is reported that genetic conditions participate in the development of
drug resistance in the cancer cells. \emph{ABCA4} and \emph{ABCA12} are
mentioned as drug resistance genes related to breast cancer. Previous
studies have indicated overexpression of these genes in human MCF-7
cells after docetaxel treatment. However, their expressions were
downregulated when the phytochemical curcumin was combined with
docetaxel (39). These observations suggest that cancer treatments need a
combination of current therapeutic approaches. Consequently,
plant-derived compounds and related products may provide the most
effective and safest methods for treating different cancers, based on
the findings of many studies (40) .

\textbf{Plant-derived anticancer compounds}

Newman and Cragg provide a full explanation of the functions of natural
chemicals as medications or a foundation for the creation of new
medications (5). They found that 929 new drugs (antiviral, antifungal,
antiparasitic, antibacterial, antitumor, etc.), approved in the last
forty years, had a natural origin. Approximately 29 of the 240
anticancer medications are purely synthetic, which may be due to natural
compounds' benefits such as fewer side effects and the capacity to
activate a variety of signaling mechanisms involved in cancer
development. Additionally, during the preceding 10 years, synthetic
compounds with natural pharmacological agents that mimic the actions of
natural chemicals have been approved as anticancer medications (41).

In the realm of oncology, the use of herbal remedies has been
extensively accepted as a supplemental or alternative treatment (42,
43). Numerous new cytotoxic chemicals have been discovered from plants
each year, opening up fresh avenues for the treatment of cancer. The
study of naturally occurring molecular entities which could be helpful
to the pharmaceutical business is a focus for many academics (44). When
substances are found to have anticancer effects in preclinical research,
researchers are often looking for a way to confirm their clinical
efficacy. This review has a specific focus on breast cancer and
describes the research on herbal remedies with considerable and active
anticancer activities as well as the anticancer ingredients discovered
in such herbal treatments.

\textbf{Breast cancer treatment with plant-derived anticancer compounds}

Nature provides various medicinal plants for humans to combat different
diseases and improve public health. Since ancient times, people have
used plants and their bioactive substances as medicines. It is reported
that numerous types of medicinal plants and their phytochemicals avoid
the spread and development of cancer (39). There are over 250 000 plant
species in the plant kingdom, but only about 10\% of those have been
studied for potential treatments of different diseases. Plant elements
such as the flower, flower stigmas, pericarp, sprouts, fruits, seeds,
roots, rhizomes, stem, leaf, embryo, and bark contain phytochemicals and
their derived counterparts, which have a variety of therapeutic uses.
Several primary and secondary metabolites play important roles in
hindering cancer cell activating proteins, enzymes, and signaling
systems or in activating DNA repair processes, promoting the formation
of protective enzymes, and triggering antioxidant activity, resulting in
potent anticancer effects, including Lignans, flavonoids, alkaloids,
vitamins, terpenes, taxanes, saponins, mineral substances, oily
substances, gums, glycosides, biological molecules (45, 46) . Table 2
provides detailed information on some medicinal plants on cell lines of
breast cancer. Additionally, Figure 2 shows the generalized concept of
carcinogenesis, immune responses, and the efficiency of natural
phytochemicals against cancer.

\textbf{Different strategies for the development of plant-derived
anticancer substances}

The potency of medicinal plants as therapeutic agents depends on the
type and quantity of their active compounds, which vary from species to
species depending on latitude, longitude, altitude, age, climate, and
season. Different parts of the plant may have various pharmaceutical
effects, which propose them as bioactive compounds in anticancer
treatments. Several techniques are used to purify active compounds
including combinatorial chemistry, isolation tests, and bioassay-guided
fractionation. The purification of these compounds are carried out in
several steps. Firstly, natural extracts (from dry or wet plant
materials) with known biological activities are evaluated. Appropriate
matrices, such as Superdex, Sephadex, and Silica, are then employed for
the fractionation of natural extracts. The fractionated extracts are
tested for bioactivity, and then the active fractions are separated
using a variety of analytical techniques such as thin layer
chromatography (TLC), high performance liquid chromatography (HPLC),
fourier-transform infrared spectroscopy (FTIR), mass spectroscopy (MS),
and nuclear magnetic resonance (NMR). Although these steps are flexible,
it is important that the bioactive chemicals have the highest purity,
quality, and quantity. This can be achieved by utilizing high-quality
solvents and matrices as well as careful handling. The extracted
compounds must be purified before evaluating \emph{in vitro} or \emph{in
vivo} anticancer effects. Furthermore, it is necessary that more studies
are performed on some characteristics of the extracted bioactive
compounds such as pharmacokinetics, pharmacodynamics, immunogenicity,
metabolic fate, biosafety and side effects, drug interactions, and dose
concentration. Figure. 3 depicts a thorough planning for the synthesis,
characterization, testing, and prospective use of a bioactive chemical
as a cancer treatment agent.

\textbf{Current challenges of plant-derived anticancer compounds}

Although bioactive compounds have potent anticancer properties, they
also have drawbacks that need to be resolved before their application in
clinical trials and improved for the approved drugs. The main concerns
in regard to the use of these compounds are their poor aqueous
solubility, poor penetration into tumors, absorption by normal cells,
limited therapeutic activities, and harmful side effects (47, 48).
Today, the uses of colchicine, camptothecin, and derivatives of
podophyllotoxin side are limited due to their adverse events. In
addition, some anticancer compounds like vinca alkaloids have a limited
impact and are usually employed in conjunction with other medications
(49). Further challenges in the discovery and development of new
anticancer agents are associated with their extraction, synthesis,
optimization, and characterization. New developments in analytical
technology and computational methodologies are anticipated to facilitate
the identification of new compounds, improve their extraction, and/or
decide on their chemical synthesis or modifications.

\textbf{Conclusions}

In addition to the role of herbal products in treatment of a variety of
human diseases, natural chemicals are still considered as an
inexhaustible source for the development of new active chemotherapeutic
agents. Although a great number of natural substances demonstrate
therapeutic value in preclinical investigations, their quantity
dramatically decreases when they enter the clinical trial stage. It is
still difficult for researchers to choose the best \emph{in vitro} and
\emph{in vivo} models demonstrating the efficacy of natural substances
and confirming their inclusion in clinical trials. Alternative in silico
and in vitro methods that can considerably reduce the time and expense
needed for \emph{in vivo} studies should be proposed to address these
liabilities. The low bioavailability of natural substances usually
limits their efficacy. As a result, in addition to the compound's
effectiveness, which should be of great interest, researchers must focus
on drug delivery systems that can resolve the compound's pharmacokinetic
problems and the investigation of suitable derivatives offering a number
of advantages in terms of biological availability and efficacy.

\textbf{Acknowledgment}

This study was no financially supported and was performed by personal
capacity.

\textbf{Funding} The authors declare that no funds, grants, or other
support were received during the preparation of this manuscript.

\textbf{Potential conflict of interest}

The authors have no conflicting financial interest.

\textbf{Availability of data and materials}

All data generated or analyzed during this study are included in this
published article.

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50. Zan L, Chen Q, Zhang L, Li X. Epigallocatechin gallate (EGCG)
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52. Garvin S, Ollinger K, Dabrosin C. Resveratrol induces apoptosis and
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53. Lai H-W, Chien S-Y, Kuo S-J, Tseng L-M, Lin H-Y, Chi C-W, et al. The
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vitro and in vivo. Molecular medicine reports. 2014;9(6):2447-52.

\textbf{Table 1. List of the anticancer drug classes and active
compounds in each class and} \textbf{common side effects.}\selectlanguage{english}
\begin{longtable}[]{@{}lll@{}}
\toprule
\begin{minipage}[b]{0.30\columnwidth}\raggedright\strut
\textbf{Drug Classes}\strut
\end{minipage} & \begin{minipage}[b]{0.30\columnwidth}\raggedright\strut
\textbf{Active Compounds}\strut
\end{minipage} & \begin{minipage}[b]{0.30\columnwidth}\raggedright\strut
\textbf{Common side effects*}\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\textbf{Antimetabolites}\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
5'-triphosphate, 5-Fluorouracil, Deoxyadenosine,
1-\selectlanguage{greek}β-\selectlanguage{english}D-arabinofuranoside, Mercaptopurine, Gemcitabine diphosphate and
triphosphate, 5-Fluorouracil, 9-beta-D-arabinosyl-2-fluoroadenine,
6-Mercaptopurine, Methotrexate, 6-Thioguanosine, 5-Fluorouracil,
Methyl-tetrahydrofolate Leucovorin\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Bleeding and Bruising (Thrombocytopenia), Anemia, Delirium loss,
Constipation, Appetite, Diarrhea, Fatigue (Swelling), Edema\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\textbf{Alkylating agents}\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Busulfan, Carmustine, Acrolein and phosphoramide mustard,
5-aminoimidazole-4-carboxamide, Lomustine, Mechlorethamine, Melphalan,
Azo-Procarbazine, Triethylenethio-phosphoramide, Semustine\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Nausea and vomiting\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\textbf{Anthracyclines}\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, Mitoxantrone\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Severe cough allergic, Photosensitivity, Hoarseness of voice, Skin and
nail hyperpigmentation, Flushing of the face, Allergic reactions
(anaphylaxis), Fatigue, Joint pain\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\textbf{Antitumor antibiotic}\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Bleomycin, Dactinomicyn, Mitomycin, Plicamycin\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Feeling of unwellness (malaise) rash, Fatigue, Fever and chills, Hair
loss, Diarrhea, Nausea or vomiting, Loss of appetite\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\textbf{Epipodophyllotoxins}\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Etoposide, Teniposide\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Nausea, Unusual tiredness or weakness, Constipation, Stomach pain,
Diarrhea, Sores in the mouth and throat, Loss of appetite or weight,
Vomiting\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\textbf{Taxanes}\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Cabazitaxel, Docetaxel, Paclitaxel\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Fatigue at the IV site, Muscle aches and pains, Called myalgia, which
can be extreme. Redness or swelling, Skin rashes, Nausea and vomiting,
Hair loss, Mouth sores. Joint or bone pain\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\textbf{Vinca alkaloids}\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Vinblastine, Vincristine, Vinorelbine\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Nausea, Diarrhea, Constipation, Tiredness/weakness, Abdominal pain,
Headache, Mouth sores, Vomiting\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\textbf{Campotothecins}\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
SN-38 (7-ethyl-10-hydroxycamptothecin), Topotecan\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Diarrhea, Constipation, Back pain, Tiredness/weakness, Headache, Nausea,
Vomiting, Abdominal pain\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\textbf{Platinum analogs}\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Carboplatin, Cisplatin, Oxaliplatin\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Headache, Vomiting, Constipation, Nausea, Mouth sores, Altered taste
sensation, Abdominal pain, Diarrhea.\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\textbf{Monoclonal antibody}\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Bevacizumab, Cetuximab, Rituximab, Trastuzumab\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Nausea, Allergic reactions such as hives or itching, Diarrhea, including
chills, Fatigue, Fever, Muscle aches and pains, Allergic reactions,
Vomiting, Low blood pressure, Skin rashes, Flu-like signs and
symptoms\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
\textbf{Growth inhibitor}\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
Axitinib, Bortezomib, Sunitinib, Crizotinib, Lapatinib, Dasatinib,
Imatinib, Dabrafenib, Nilotinib, Bosutinib, Sorafenib, Pazopanib,
Trametinib, Vandetanib, Vemurafenib\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
Coughing up blood, Depressed mood, Chest tightness. Clay colored stools,
Cloudy urine, Bleeding gums, Decreased urination, Bloody nose\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

*https://www.drugs.com/professionals.html

\textbf{Table 2. plant-derived anticancer compounds in cell lines of
breast cancer.}\selectlanguage{english}
\begin{longtable}[]{@{}llllll@{}}
\toprule
\begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
\textbf{Natural compounds}\strut
\end{minipage} & \begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
\textbf{Source extractions}\strut
\end{minipage} & \begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
\textbf{Cell lines}\strut
\end{minipage} & \begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
\textbf{Active concentrations}\strut
\end{minipage} & \begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
\textbf{Findings}\strut
\end{minipage} & \begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
\textbf{Ref}\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{Nobiletin}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Citrus depressa\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
MCF-7\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
500 ml\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Reduces ERK1/2, cyclin-D1, p21 upregulation, mTOR and AKT
inhibition\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
(50)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{Resveratrol}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Vitis vinifera\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
4T1\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
IC50 = 93 \selectlanguage{greek}µ\selectlanguage{english}M (72 h)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
S-phase slowdown Cell cycle suppression, higher levels of
apoptosis\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
(51)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
\textbf{Resveratrol}\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Vitis vinifera\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
SUM159/MCF10A/ MCF-7\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
100 mg/ kg/d)\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Through inhibition of Wnt \selectlanguage{greek}β -\selectlanguage{english}catenin pathway\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
(52)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
\textbf{Resveratrol}\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Vitis vinifera\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
/ MDA-MB- 231/ MCF-7\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
10, 25, and 50 \selectlanguage{greek}μ\selectlanguage{english}M\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Decrease in MMP-9, MMP-2, c-Myc, and Cyclin D1 expression, decrease in
Sox2 translation and stimulation of STAT3 and Akt\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
(53)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{Curcumin}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Curcuma longa\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
BT-474/ MDA-MB-231\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
1--25 \selectlanguage{greek}µ\selectlanguage{english}g/mL (72 h)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Akt phosphorylation and MAPK stimulation, Decrease HER-2 oncoprotein,
and Decrease NF-B\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
(54)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
\textbf{Curcumin}\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Curcuma longa\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
MDA-MB- 231\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
10, 20 and 30 \selectlanguage{greek}μ\selectlanguage{english}m/ml\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Expression of EGFR and Induction of cell death\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
(55)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{Curcumin}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Curcuma longa\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
MCF-7\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
1, 5, 10, 30 and 50 M\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
By suppressing NF-B/ AP-1, MAPK, and PKC signaling, TPA causes MMP-9
overexpression\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
(56)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
\textbf{Curcumin}\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Curcuma longa\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
MDA-MB- 231/MCF-10F/ Tumor2\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
30 \selectlanguage{greek}μ\selectlanguage{english}M\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Reduced expression of EMT-associated, Fibronectin, Slug, N-cadherin,
Twist1, Vimentin, AXL, and. E-cadherin/ proteins -catenin\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
(57)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{EGCG}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Epigallocatechin gallate\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
MDA-MB-231\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
[?] 75 \selectlanguage{greek}µ\selectlanguage{english}M (24 h)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Reduce expression of -catenin, p-Akt, and cyclin D1, inactivate the
catenin signaling mechanism, Reduced proliferation of cells and
disruption of adhesion junction formation\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
(58)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
\textbf{Eugenol}\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Syzygium aromaticum\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
, 0.25, 0.50, 0.75, 1.0 and 1.5 \selectlanguage{greek}μ\selectlanguage{english}M,\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
BT-20/ MDA-MB-231/ MDA-MB- 468\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Inhibits NF-B signaling, thereby decreasing IL-8 and IL-6
production.\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
(59)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
\textbf{Baicalin}\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Scutellaria baicalensis\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
MCF-7/ MDA-MB-231\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
0, 20 or 30 \selectlanguage{greek}μ\selectlanguage{english}M\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Reduces NF-B- p65 protein synthesis and NF-B- elicited upregulation of
BCL2, BIRC3, BIRC2, and CCND1 expression\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
(60)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
\textbf{Artemisinin} \textbf{(Artesunate)}\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Artemisia annua\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
MDA-MB-231\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
25, 50 and 100 \selectlanguage{greek}µ\selectlanguage{english}M (48 h)\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Reduce Bcl-2, enhance Bax, G2/M-phase arrest Reduce Cyclin-B1 and
Cyclin-D1, heterochromatin agglutination, degeneration of mitochondrial
vacuoles; nuclear enlargement, Reduce the amount of organelles within
cells\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
(61)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
\textbf{Ellagic acid}\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Juglans regia\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
MCF-7 cells;\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
0, 10, 20 and 30 \selectlanguage{greek}μ\selectlanguage{english}g/mL\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Reduces signaling of TGF-/Smads\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
(62)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{Ginseng extract}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Ginseng\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
MCF-7\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
100--400 \selectlanguage{greek}µ\selectlanguage{english}M (24 h)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Reduce Bcl-2, augment Bax, cytochrome c, and activated caspase-3,augment
ROS production\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
(63)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{Oleuropein}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Olea europaea\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
1.7 mg/day\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
MCF-7\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Blocking the growth and proliferation of MCF-7 cell xenografts\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
(64)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
\textbf{Eupatorin}\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Eupatorium semiserratum\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
MCF-7/MDA-MB- 231\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
20 \selectlanguage{greek}μ\selectlanguage{english}g/ml\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
By inhibiting the p-Akt pathway, and boosting the production of
SMAC/Diablo, cytochrome c, Bax, Bak1, Bad, and HIF1A\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
(65)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{Emodin}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Aloe vera\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
IC50 = 8.6 \selectlanguage{greek}µ\selectlanguage{english}M\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Unique energy-dependent pathway of drug uptake inducing apoptosis\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
(66)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
\textbf{Genistein}\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Glycine max\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
MCF-7\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
10 nM--10 \selectlanguage{greek}μ\selectlanguage{english}M\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Through the downregulation of the Hedgehog-Gli1 Signaling\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
(67)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
\textbf{Genistein}\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Glycine max\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
MCF-7/MDA-MB 231/ MCF10a\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
18.5 \selectlanguage{greek}μ\selectlanguage{english}M\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Elevated levels of BRCA2 and BRCA1 protein\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
(68)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
\textbf{Artesunate}\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Artemisia annua\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
IC50 = 2.3 \selectlanguage{greek}µ\selectlanguage{english}M\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
VEGF expression reduction\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
(69)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{Kaempferol}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Moringa oleifera\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
MDA-MB231\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
50 \selectlanguage{greek}μ\selectlanguage{english}M\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Increase the production of NRF2 and its enzyme NQO1 in MCF-7 cells,
thereby preventing oncogenesis\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
(70)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{Kaempferol}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Moringa oleifera\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
MCF-7\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
10 \selectlanguage{greek}μ\selectlanguage{english}M\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
halts cell cycle progression at the G2/M phase by inhibiting CDK1\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
(71)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{Betulinic acid}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Betula sp.\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
IC50 = 13.5 \selectlanguage{greek}µ\selectlanguage{english}M\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Induction of the extrinsic apoptosis mechanism through increased levels
of DR4, DR5, and PARP cleavage\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
(72)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
\textbf{Icariin}\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Epimedium sagitatum\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
MDA-MB-231 /4 T1\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
10 or 20 \selectlanguage{greek}μ\selectlanguage{english}M\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Reduces the signaling cascade of NF-B and SIRT6\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
(73)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{Betulin}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Betula sp.\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
IC50 = 30.7 \selectlanguage{greek}µ\selectlanguage{english}M\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Induction of the extrinsic apoptosis cascade through increased levels of
DR4, DR5, and PARP cleavage\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
(74)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
\textbf{Isoliquiritigenin}\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Spatholobus suberectus\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
MCF-7/ MDA-MB-231 /BT-549\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
10 \selectlanguage{greek}μ\selectlanguage{english}g/ml\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
By blocking \selectlanguage{greek}β-\selectlanguage{english}catenin/ ABCG2 signaling.\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
(75)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
\textbf{Berberine}\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Berberis vulgaris\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
IC50 = 25 \selectlanguage{greek}µ\selectlanguage{english}M\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Activation of cell cycle arrest, a combined effect with
drugs/dose-dependent decrease in tumor volume and angiogenesis\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
(76)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
\textbf{Epicatechin} \textbf{gallate}\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Camellia sinensis\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
IC50 = 350 \selectlanguage{greek}µ\selectlanguage{english}M\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Promote apoptosis in various types of cells of cancer\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
(77)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
\textbf{Morusin}\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Ramulus mori\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
MCF-10A/ MDA-MB-231/4 T1 /EMT6 and MCF-7\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
1, 2, 4, 6 and 8 \selectlanguage{greek}μ\selectlanguage{english}g/ml\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Lipoapoptosis and adipogenic transformation are mediated by PPAR and
C/EBP\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
(78)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
\textbf{Epigallocatechin}\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Camellia sinensis\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
IC50 = 22 \selectlanguage{greek}µ\selectlanguage{english}M\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Growth restriction\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
(79)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
\textbf{D Rhamnose} \selectlanguage{greek}\textbf{β-hederin}\selectlanguage{english}\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Clematis ganpiniana\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
MCF-7/ SUM1315/ MDA-MB-231/ BT474\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
5, 10, 20, 40 and 80 \selectlanguage{greek}μ\selectlanguage{english}g/ml\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
via inhibiting the pathway of PI3K and AKT and enhancing the ERK
pathway\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
(80)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{Myricetin}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Camellia sinensis\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
MDA-Mb-231\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
50 mg/kg\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
By suppressing the expression of MMP2/9 as well as ST6GALNAC5
proteins\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
(81)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
\textbf{Ingenol} \textbf{mebutate}\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Euphorbia peplus\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
IC50 = 23.9 \selectlanguage{greek}µ\selectlanguage{english}M\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Necrotic mechanism\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
(82)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
\selectlanguage{greek}\textbf{β-Elemene}\selectlanguage{english}\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Rhizoma Zedoariae\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
MDA-MB-231 / MCF-7\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
0--320 \selectlanguage{greek}μ\selectlanguage{english}mol/L\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
inhibiting the aerobic glycolysis triggered by dimer formation of PKM2
and nuclear transfer\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
(83)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{Dehydrocorydaline}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Corydali syanhusuo\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
MDA-MB-231\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
20,30, 40, 50 or 100 \selectlanguage{greek}μ\selectlanguage{english}M\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
By reducing BCL 2, CCND 1, BCL 3, and CDK1 and enhancing the generation
of pro-apoptotic proteins caspase9/3/8\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
(84)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
\textbf{Theacrine}\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Theobroma grandiflorum\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
MDA-MB-231\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
10--100 \selectlanguage{greek}μ\selectlanguage{english}M\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
EMT induced by TGF is inhibited\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
(85)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{Bilobetin}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Ginkgo biloba\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
IC50 = 57.6 \selectlanguage{greek}µ\selectlanguage{english}M\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Stopping the cell cycle at the G2/M phase\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
(86)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
\textbf{Harmine}\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Peganum harmala\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
MDA-MB-231 and MCF-7\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
50, 100 or 150 \selectlanguage{greek}μ\selectlanguage{english}M\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
By decreasing pErk, Bcl2, pAkt, and TAZ expression\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
(87)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{Isoginkgetin}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Ginkgo biloba\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
IC50 = 92.1 \selectlanguage{greek}µ\selectlanguage{english}M\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Stopping the cell cycle at the G2/M phase\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
(86)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
\selectlanguage{greek}\textbf{α-santalol}\selectlanguage{english}\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Santalum album\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
20, 40 \selectlanguage{greek}μ\selectlanguage{english}M\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
MDA-MB 231/ MCF-7\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
via suppressing the Wnt/-catenin signaling pathway\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
(88)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
\textbf{Licoagrochalcone}\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Glycyrrhiza glabra\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
IC50 = 28.6 \selectlanguage{greek}µ\selectlanguage{english}M\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Promotion of apoptosis and suppression of cell division\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
(89)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
\textbf{Astragaloside IV}\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Astragalus membranaceus\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
MCF-7/MDA-MB- 231/ / MDA-MB-468\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
40 and 80 \selectlanguage{greek}μ\selectlanguage{english}g/ml\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
prevent BC cell proliferation and metastasis via inducing expression of
TRHDE-AS1\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
(90)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
\textbf{Apigenin}\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Matricaria chamomilla\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
IC50 = 100 \selectlanguage{greek}µ\selectlanguage{english}M\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
augmentation of the DR5 mechanism\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
(91)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
\textbf{Betulinic acid}\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Castanopsis acuminatissima\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
MCF-7\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
50 \selectlanguage{greek}μ\selectlanguage{english}M\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
via reducing topoisomerase or cyclin, suppressing VEGF signaling,
decreasing SP and NF-B stimulation, and downregulating matrix
metalloprotease production\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
(92)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
\textbf{Chamomillol}\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Matricaria chamomilla\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
IC50 = 300 \selectlanguage{greek}µ\selectlanguage{english}M\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Repress angiogenesis by repressing expression proteins.\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
(93)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
\textbf{Cucurbitacin B}\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Cucurbeta pepo\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
MDA-MB-231\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
0.5 and 1 mg/kg\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Reduce NF-B and STAT3\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
(94)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
\textbf{Lycorine}\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Narcissus pseudonarcissus\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
MCF-7/T47D/ MDA-MB- 231\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
5 or 10 mg/kg\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
via interfering with the Src/FAK pathway\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
(95)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{Ginsenoside}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Panax ginseng\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
IC50 = 30 \selectlanguage{greek}µ\selectlanguage{english}M\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Activation of apoptosis and suppression of cell division\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
(96)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
\textbf{Citral}\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Cymbopogon citratus\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
MDA-MB-231\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
2.5, 5.0 and 10.0 \selectlanguage{greek}μ\selectlanguage{english}g/ml\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Reducing the expression of aldehyde dehydrogenase 1A3\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
(97)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
\textbf{Borbonol}\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Persea americana\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
IC50 = 20.5 \selectlanguage{greek}µ\selectlanguage{english}M\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Inhibition of proliferation\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
(98)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
\textbf{Matrine}\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Sophora flavescens\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
MCF-7\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
2, 4, 8 and 10 mM\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
through the aggregation of light chain 3 II and reduced levels of p62,
phosphorylation of mTOR and AKT was suppressed\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
(99)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{Germacrone}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Rhizoma curcumae\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
MCF-7\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
100 or 200 \selectlanguage{greek}μ\selectlanguage{english}M\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
via inhibiting ER-driven gene expression\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
(100)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{Salvicine}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Salvia prionitis\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
IC50 = 1.4 \selectlanguage{greek}µ\selectlanguage{english}M\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Breaks two strands of DNA through increasing TOP2 activity; prevents
re-ligation\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
(101)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
\textbf{Noscapine}\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Papaver somniferum\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
MCF-10/ MCF-7/ MDA-MB-231\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
20, 40, 60, 80 and 100 \selectlanguage{greek}μ\selectlanguage{english}M\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
A decrease in the expression of the NF-B gene and protein, along with an
increase in the expression of the IB gene\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
(102)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
\textbf{Cepharanthine}\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Stephania cepharantha\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
MDA-MB-231 and MCF-7\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
5 \selectlanguage{greek}μ\selectlanguage{english}M for MCF-7,4 \selectlanguage{greek}μ\selectlanguage{english}M for MDA-MB-231\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
By disrupting AKT/mTOR signaling system\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
(103)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
\textbf{Ursolic acid}\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Ocimum tenuiflorum\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
MDA-MB-231\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
10.0 \selectlanguage{greek}μ\selectlanguage{english}g/ ml\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Reduced EGFR, PI3K/Akt/mTOR, and ERK activity\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
(104)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
\textbf{Protocatechu} \textbf{aldehyde}\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Salvia miltiorrhiza\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
MCF-7 and MDA-MB-231\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
0, 5,10, 25, 50, or 100 lM\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
inhibits the expression of -catenin and cyclin D1\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
(105)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
\textbf{Silibinin}\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Silybum marianum\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
IC50 = 24 \selectlanguage{greek}µ\selectlanguage{english}M\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Apoptosis induction and cell cycle arrest\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
(106)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{Piperlongumine}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Piper longum\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
MCF-7/MDA-MB-231/MDA-MB-453 And BT-549\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
6.25,12.5, 25, 50 and 100 lM\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Through decreasing Bcl-2, cyclin D1, p-Akt, p53, p70S6K1, and 4E-BP1
expression and increasing cytochrome c and Bax expression; by inhibiting
the PI3K/Akt/mTOR signaling axis.\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
(107)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
\textbf{Gossypol}\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Gossypium hirsutum\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
MDA-MB-231 / MDA-MB-468 MM-231 / MM-468\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
0--100 \selectlanguage{greek}μ\selectlanguage{english}M 0--50 \selectlanguage{greek}μ\selectlanguage{english}M\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Increases the expression of BNIP3, TNFRSF9, and GADD45A\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
(108)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
\textbf{Silymarin}\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Silybum marianum\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
IC50 = 75 \selectlanguage{greek}µ\selectlanguage{english}M\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Interaction with the production of cell cycle regulators and apoptotic
proteins; activation of cell cycle arrest\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
(109)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{Pterostilbene}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Cyanococcus\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
MDA-MB-468\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Dose:50 \selectlanguage{greek}μ\selectlanguage{english}M\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Reduces phosphorylation of mTOR and AKT and decreases cyclin D1
expression\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
(110)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
\textbf{Paradol}\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Zingiber officinale\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
IC50 = 20.4\selectlanguage{greek}µ\selectlanguage{english}M\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Reduced cellular viability\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
(111)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{Colchicine}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Colchicum autumnale\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
MCF-7\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
0.3125, 0.625, 1.25, 2.5, 5, 10, 20 and 40 \selectlanguage{greek}μ\selectlanguage{english}g/ml\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
through cells unable to exit the G2/M phase.\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
(112)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{Tanshinone-IIA}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Salvia miltiorrhiza\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
MDA-MB-231\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
0, 3 and 6 \selectlanguage{greek}μ\selectlanguage{english}M\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Through inducing S-phase cell cycle arrest and boosting GSK3 expression,
MMP expression is inhibited.\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
(113)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
\textbf{Shogaol}\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Zingiber officinale\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
IC50 = 24.4 \selectlanguage{greek}µ\selectlanguage{english}M\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Inhibitory activity\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
(114)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
\selectlanguage{greek}\textbf{β-caryophyllene}\selectlanguage{english} \textbf{oxide}\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Myrica rubra\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
MDA-MB-231 and MCF7\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
5--500 \selectlanguage{greek}μ\selectlanguage{english}M\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Inhibition of NF-B\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
(115)\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

\textbf{Table 3. plant-derived anticancer compounds in animal model of
breast cancer}\selectlanguage{english}
\begin{longtable}[]{@{}llllll@{}}
\toprule
\begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
\textbf{Natural compounds}\strut
\end{minipage} & \begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
\textbf{Source extractions}\strut
\end{minipage} & \begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
\textbf{Animal models}\strut
\end{minipage} & \begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
\textbf{Dose/administrations}\strut
\end{minipage} & \begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
\textbf{Therapeutic effects}\strut
\end{minipage} & \begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
\textbf{Ref}\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{EGCG}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Epigallocatechin gallate\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
CB-17 rodents with severe combined immunodeficiency\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
100 mg/kg of EGCG dissolved into 100 L of water is administered orally
every two days.\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Reduce tumor proliferation; reduce miR-25 expression; reduce Ki-67; and
enhance pro-apoptotic PARP expression\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
(50)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
\textbf{Artemisinin} \textbf{(Artesunate)}\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Artemisia annua\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Xenograft model of 4T1 cells in female BALB/c mice\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Every day intraperitoneal injection of 100 mg/kg artemisinin dissolved
in 0.2\% DMSO for twenty days\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Reduced splenic and tumor Treg and MDSC growth; enhanced percentages of
CD4 + IFN- + T cells; elevated FN- and TNF-\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{Ginseng}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Ginseng\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Xenograft model of MCF-7 cells in female BALB/c athymic nude mice\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Ginseng extract (50 or 100 mg/kg) was given intravenously once a day for
four weeks\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Increase Bax, activated caspase-3, and activated PARP; reduced Bcl-2;
reduced tumor weight\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
(51)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{Resveratrol}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
skin of grapes, blueberries, raspberries, mulberries, and peanuts\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Xenograft model of MDA-MB-231 cells in female athymic mice\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
resveratrol (ethanolic solution) 25 mg/kg/day intraperitoneally for
three weeks\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
reduce tumor size, boost apoptotic index, and stop angiogenesis\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
(52)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{Curcumin}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Turmeric or Curcuma longa\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Female athymic nude mice with BT-474 xenograft mod-el overexpressing
HER-2\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Curcumin was administered intraperitoneally twice weekly for a period of
four weeks at a dose of 45 mg/kg, dissolved in 0.1\% DMSO\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Tumor volume reduction\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
(53)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
\textbf{Berberine}\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Berberis vulgaris\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
IC50 = 25 \selectlanguage{greek}µ\selectlanguage{english}M\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Cell cycle arrest induction, drug-drug interactions, dose-dependent
tumor volume decrease, and angiogenesis\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
(54)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
\textbf{Combretastatin}\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Combretum caffrum\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
mice\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
IC50 = 80-190 \selectlanguage{greek}µ\selectlanguage{english}M\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Tubulin binding results in the microtubules being less stable\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
(55)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{Ginkgetin}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Ginkgo biloba\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
mouse\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
IC50 = 10 \selectlanguage{greek}µ\selectlanguage{english}M\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Autolysosome production and redox environment are mediated by
p62/SQSTM1, and the signaling transducer and activator of transcription
3 activity is inhibited\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
(56)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
\textbf{Noscapine}\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Papaver somniferum\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
mice\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
IC50 = 45 \selectlanguage{greek}µ\selectlanguage{english}M\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Triggering several signaling cascades, such as apoptosis\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
(57)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
\textbf{Cryptotanshinone}\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Salvia prionitis\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
mice\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
IC50 = 1.1 \selectlanguage{greek}µ\selectlanguage{english}M\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Multifaceted mechanisms of action include apoptosis, G2/M arrest, and
cellular movement inhibition. All these pathways are orchestrated by NFB
inhibition\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
(58)\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

\textbf{Table 4. Clinical studies of plant-derived anticancer substances
for breast cancer}\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
\begin{minipage}[b]{0.24\columnwidth}\raggedright\strut
\textbf{Natural} \textbf{Compounds}\strut
\end{minipage} & \begin{minipage}[b]{0.24\columnwidth}\raggedright\strut
\textbf{Identifiers}\strut
\end{minipage} & \begin{minipage}[b]{0.24\columnwidth}\raggedright\strut
\textbf{Titles}\strut
\end{minipage} & \begin{minipage}[b]{0.24\columnwidth}\raggedright\strut
\textbf{Observations}\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{Resveratrol}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
NCT04266353\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Effect of Resveratrol on Serum IGF2 in African American Women\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Participants will be given 150 mg of resveratrol per day for six
weeks\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{Ginseng}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
NCT00631852\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
A Phase II Biomarker Trial of Gelatin Encapsulated Extract of American
Ginseng Root (LEAG) in Breast Cancer\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
American ginseng extract from the roots was administered as follows:
four 250 mg tablets were taken daily for five to fourteen days prior to
surgery\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{Artemisimin} \textbf{(Artesunate)}\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
NCT00764036\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Patients with metastatic or locally advanced breast cancer are being
studied in a prospective open uncontrolled phase I study to determine
the compatibility, safety, and pharmacokinetics of the semi-synthetic
artemisinin derivative artesunate from the Chinese herb artemisia
annua\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
The medication was given orally once day for four weeks in dosages of
100, 150, or 200 mg of artesunate.\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{EGCG}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
NCT00917735\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Study of the Green Tea Extract's Efficacy on Breast Cancer Risk
Biomarkers in High-Risk Women With Different Catechol-O-Methyl
Transferase (COMT) Genotypes under Placebo Control\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Two green tea extract capsules containing 51.7\% EGCG should be taken
orally twice day, after breakfast and supper, for a period of one
year.\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{Curcumin}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
NCT03980509\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Curcumin, the active ingredient in turmeric, in a ''Window Trial'' for
primary invasive breast cancer tumors\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
From the time surgical resection is scheduled until the night before
surgical resection, 500 mg of curcumin will be given orally twice daily,
after each meal\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

\textbf{Figure legends:}

\textbf{Figure. 1) Main agents involved in the development of cancer.}

\textbf{Figure. 2) Anticancer mechanisms of some plant-derived
compounds} .

\textbf{Figure. 3) Extraction, characterization, testing, and
prospective use of a bioactive chemical as a cancer treatment agent.}

\textbf{Hosted file}

\verb`Figures.docx`  available at \url{https://authorea.com/users/676031/articles/673740-plant-based-anticancer-compounds-with-a-focus-on-breast-cancer}

\selectlanguage{english}
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