Non-pump resistance

Non-pump resistance is not dependent on the drug efflux pump, and it is based on non-pump proteins such as superfamily Bcl-2, VEGF, and PLK1 which contributes to escape of cancer cells from apoptosis (W. Zhu, Shan, Wang, Shu, & Liu, 2010) (Figure 4). Non-pump proteins provide resistance of cancer cells through modifying the target cell of the drug, activating the DNA repair system, detoxifying system (the cytochrome p450 mixed-function oxidase), activating antioxidant pathways such as reactive oxygen species (ROS), changing in cell-cycle checkpoints signals, prohibiting the onset of apoptosis and blocking it. Bcl-2, as the first anti-cell death protein, contains anti-apoptotic (Bcl-XL, MCL-1, Bcl-w, Bcl-2, etc.) and pro-apoptotic (Bak, Bid, Bax, Bad, etc.) members. PLK1 has been investigated as a pancreatic cancer drug target, which caused by K-ras mutations (S. Kumar & Kim, 2015). Many studies established that silencing PLK1 gene expression can lead to K-ras mutated pancreatic cancer cell death (S. Kumar, Sharma, Sharma, Chakraborty, & Kim, 2016). As a consequence, co-delivery of PLK1 siRNA and chemotherapeutic agents has been extensively studied as a novel promising approach for the treatment of various types of cancer (Yu et al., 2019) (Figure 5).
In recent years, the development of innovative multifunctional delivery systems offers a new potential therapeutic avenue for pancreatic cancer including both pump and non-pump resistance genes targeting, through co-delivery of siRNAs and chemotherapeutic agents together with imaging (Figure 5).
Figure 5. A new potential therapeutic avenue for pancreatic cancer including both pump and non-pump resistance genes targeting, via co-delivery of siRNAs and chemotherapy agents, and imaging.
Co-delivery of chemotherapy agents and siRNA for anti-MDR pancreatic cancer therapy
Despite increasing understanding of the mechanisms underlying chemoresistance in pancreatic cancer, the therapeutic potential of their pharmacological inhibition has not been successfully exploited yet.
Recently, the combination of nanoparticle-based delivery systems, siRNAs, and chemotherapy drugs has emerged as a robust strategy for cancer therapy (Godsey, Suryaprakash, & Leong, 2013) (Figure 5). Examples of co-delivery of chemotherapeutic agents and siRNAs for the pancreatic cancer therapy are listed in Table 3.
To deliver anti-HER-2 siRNA, Pirollo et al . (Pirollo et al., 2007) designed an anti-transferrin receptor (TfR) single-chain antibody fragment-directed nanoimmunoliposome (scL) and then intravenously injected in the mouse model bearing subcutaneous human PANC-1 xenografts. Smaller tumor size was reported in mice treated with scL-HoKC/HER-2 siRNA plus GEM than mice treated with GEM alone.
Fuente et al . (de la Fuente et al., 2015) used third-generation poly(propylenimine) dendrimers (DAB-Am16) to transfer anti-ITCH siRNA and shRNA in MIA PaCa-2 and PANC-1 cells and mice bearing MIA PaCa-2 xenografts. The dendriplexes/anti-ITCH siRNA and shRNA complexes showed high cellular uptake and gene silencing in vitro ; and when co-delivered with GEM demonstrated great efficiency in gene knockdown against mice bearing PaCa-2 xenografts via i.v. administration. This co-delivery strategy also increases the chemosensitivity of pancreatic cancer cells.
Notch1 has a central role in the regulation of cell differentiation, proliferation, survival, and maintenance of various types of cancer cells (Paryan et al., 2016; Takebe, Harris, Warren, & Ivy, 2011). Yanget al . (C. Yang et al., 2017) co-delivered K-ras and Notch1 siRNA and GEM into MiaPaCa-2 cells using biodegradable charged polyester-based vectors (BCPVs). Cotreatment of BCPV-siRNAK-ras-siRNANotch1 nanocomplexes and GEM significantly reinforced antitumor efficacy, apoptosis, and also reversed the epithelia-mesenchymal transition (EMT) with high efficacy. Therefore, the combination of siRNA therapy and chemotherapy enhances cellular apoptosis and chemosensitivity.