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.