br Combinatory approach in cancer treatment br Tumors
4.3. Combinatory approach in cancer treatment
Tumors exhibit heterogeneous, irregular and branched blood vessel network (Nagy et al., 2010). These heterogeneity in vascularization resulted in permeability imbalances and inadequate blood supply to diﬀerential compartments of the tumor tissue further associated with metabolic stresses, including hypoxia and starvation, which in turn provided invasion and decreased immune response (Cárdenas-Navia et al., 2008; Dalerba et al., 2011). Therefore, targeting cancer with combinatory therapy even at a single cell level provide an alternative strategy to combat with tumor progression. The use of miRNAs and nano-sized carriers become an alternative therapeutic approach for targeted therapies. Beside from their increased usage and benefits, nano-sized carriers tend to accumulate in spleen or liver by macro-phages-mediated endocytosis.
4.3.1. Autophagy regulating miRNAs in cancer
MicroRNAs (miRNAs) are involved in a class of short RNAs (∼ 21 nucleotides) that target partially complementary transcripts to con-trol key biological processes post-transcriptionally. miRNAs are tran-scribed from several diﬀerent loci in the genome which encode for long RNAs (pri-miRNAs) with a hairpin structure. Then RNase III enzyme Drosha processes the pri-miRNAs to give the precursor miRNAs (pre-miRNAs) (Lee et al., 2003). Pre-miRNAs are subsequently transported into the nucleus and then processed further by RNase III enzyme, DICER (also known as DICER1), to yield a mature miRNA (Gurtan and Sharp, 2013). Mature miRNA is then loaded into an argonaute protein within the RNA-induced silencing complex (RISC) acting as a guide strand through the target-specific seed sequence (Gurtan and Sharp, 2013).The miRNA-processing enzyme DICER and the main miRNA eﬀector, AGO2 can be targeted for degradation by the selective autophagy receptor NDP52 (also known as calcium binding and coiled-coil domain 2 (CALCOCO2)) (Gibbings et al., 2012).
The complicated autophagy-mediated diﬀerential regulatory
4.3.2. Autophagy modulation through nano-sized material systems in cancer
Multi-drug resistance defined as the phenomenon in which cancer Pepstatin-A develop resistance mechanisms to chemotherapeutics and limit the eﬀective use of approved clinical treatments (Panzarini and Dini, 2014). As recently critically reviewed, several mechanisms, including altered drug-uptake, keeping the drug out of the cell by eﬄux pumps, increased capacity metabolize drugs, alterations in cell death mechan-isms etc., played diﬀering roles in multidrug resistance (Panzarini and Dini, 2014). Being a central player in regulation of metabolic and stress-response pathways, autophagy plays a dual role in drug resistance likewise in the case of carcinogenesis. Recent advances in designing nanosized drug delivery systems opened a new perspective for targeted delivery of chemotherapeutics at specific sites and controlled drug re-lease into tumor cells (Upadhyay, 2014). Even some of the tested nano-materials found to modulate autophagic activity in some cancer cells.
Giving the importance of nanoparticle usage in the clinicals, it has been emerging issue to combine CQ-derivatives with nanoparticles to target cancer cells, due to the decreased eﬀect of CQ on accumulation of nano-sized carriers in liver or spleen (Pelt et al., 2018). For instance, CQ was suggested as a promising candidate in order to decrease accumu-lation of nano-sized carriers in organs by inhibiting macrophage up-take, therefore promoted their distribution and localization on their targets for cancer therapy (Wolfram et al., 2017). As a multidrug complex example, CQ was included in the nanocapsulated erlotinib and shRNA survivin co-delivery treatment system and CQ-mediated vessel normalization increased the targeting ratio of erlotinib and shRNA survivin (Lv et al., 2018).
In line with this, C60 (Nd) nanoparticles were shown to promote autophagy-mediated chemo-sensitization of cancer cells (Wei et al., 2010; Zhang et al., 2009). The therapeutic use of iron core‑gold shell nanoparticles was able to inhibit growth of oral cancer through in-duction of reactive oxygen species and autophagy (Wu et al., 2013). Similarly, reports by others also showed that both the iron oxide (Khan et al., 2012) and alpha-alumina-nanoparticles (Li et al., 2011) exhibited autophagy-induced anti-tumor eﬀects. Furthermore, combining nano-sized delivery systems with autophagy modulating agents may provide even a wider range of strategies to circumvent drug resistance me-chanisms adopted by cancer cells. For example, in breast cancer cells, anti-cancer therapeutic treatment was achieved by the utilization of chloroquine-loaded gold nanoparticle conjugates (GNP-Chl) (Joshi et al., 2012). In a similar context, a single intravenous injection of the nano-liposomal C6-ceramide together with vinblastine combination was shown to tremendous decrease in tumor growth in both hepato-cellular carcinoma and colorectal cancer (Adiseshaiah et al., 2013). Additionally, chitosan nanoparticle-mediated delivery of miRNA-34a