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  • br Pharmacological inhibition of autophagy by the administra

    2020-08-18


    Pharmacological inhibition of autophagy by the administration of lysosomotropic agents CQ, HCQ, Lys0569 or monensin, block the fusion of autophagosomes with lysosomes, have been shown to exert antic-ancer effects or enhance the efficacy of antineoplastic treatments (Cheong et al., 2012; Wu et al., 2014). Therefore, CQ-derivatives seem to be promising drug candidates for developing novel treatment stra-tegies against cancer. For example, the addition of chloroquine to bevacizumab-based treatment was able to yield a more effective tumor control in non-small-cell lung cancer (Selvakumaran et al., 2013). The impact of CQ increase the efficiency and activity of CQ-derivatives in order to reach the requirements in clinical applications. For example, structurally-generated dimeric version of CQ, Lys01 and its soluble form, Lys05 exhibited much greater effect than CQ in terms of autop-hagy inhibition and cytotoxicity (McAfee et al., 2012). As a combina-tory approach, mTOR and autophagy inhibition in phase I trial of hy-droxychloroquine and temsirolimus in cancer patients was found to be well tolerable and displayed significant antitumor activity (Rangwala et al., 2014). Similarly, adding chloroquine to conventional cancer treatment was shown to potentiate the effect of chemo-therapy in glioblastoma multiformation (Sotelo et al., 2006) and colon cancer Ko 143 (Sasaki et al., 2010). Furthermore, 3-methyladenine and chloroquine  European Journal of Pharmaceutical Sciences 134 (2019) 116–137
    combination was able to sensitize cancer cells to radiotherapy (Cerniglia et al., 2012). On one hand, autophagy-inhibition-mediated NOTCH1 signal regulation by utilizing CQ was also controlled che-moresistance in gastric cancer stem cells when combined with 5-FU (Li et al., 2018). On the other hand, CQ provided an alternative approach for vasculature normalization by upregulating NOTCH1 signaling as an autophagy-independent manner (Maes et al., 2014).
    Bafilomycin A1 (Baf A1) is a macrolide antibiotic and inhibits va-cuolar H+ ATPase (V-ATPase). Binding of Bafilomycin A1 to V-ATPase complex inhibits H+ translocation that in turn resulted in altered H+ balance in cytoplasm (Bowman et al., 2004; Ohta et al., 1998). Bafi-lomycin A1 was shown to exert its effect on autophagy inhibition and promoting apoptosis favoring for cancer treatment, but only at high concentrations. Therefore, toxicity potential limited its medical appli-cations. However, growing number of reports could show the successful use of Bafilomycin A1 in combined anti-cancer therapies (Cheong et al., 2012). As an example, combined Baf A1 and 3-Methyladenine (3-MA) treatment enhanced the antitumoral effect of nedaplatin in cisplatin-resistant nasopharyngeal carcinoma cells (Liu et al., 2015). Similarly, Baf A1 was reported to confer chemosensitivity in gastric cancer cells (Li et al., 2016), osteosarcoma cells (Xie et al., 2014) and colon cancer cells (Greene et al., 2013).
    Spautin-1, 6-Fluoro-N-(4-fluorobenzyl) quinozaline-4-amine was shown to block the autophagy pathway in cancer cells thereby pro-viding the potential to be exploited as an anti-cancer agent. Spautin-1 exerts its inhibitory effect on autophagy through degradation of VPS34 and PI3K complexes by inhibiting the activities of USP10 and USP13 ubiquitin-specific peptidases that further target Beclin-1 of VPS34 complexes. (Liu et al., 2011). Furthermore, the effect of Spautin-1 on Beclin-1 was further affected cellular p53 level. For instance, spautin-1 enhanced the cellular Imatinib-induced apoptosis in chronic myeloid leukemia through inactivation of PI3K/AKT signaling while activating the downstream GSK3β pathway (Shao et al., 2014). Therefore, spautin-1 as an autophagy-inhibiting anti-cancer agent carries a great potential for clinical usage.
    Sequence-specific DNA or RNA analogs blocking the expression of genetic sequences with high specify offer the possibility for designing custom made molecules with potential anti-cancer effects at relatively inexpensive costs. In this sense, in addition to oncogenes, several es-sential modulators of the autophagic machinery such as ATG3, ATG4B, ATG4C, ATG5, Beclin-1, ATG10, and ATG12 have also been targeted. siRNA-based deregulation of major autophagy modulators was able to sensitize several cancer cells to chemo- and radio-therapies as critically discussed Ko 143 in (Wu et al., 2012). For example, siRNA-mediated decrease in ATG5 correlated with reduced level of autophagy and enhanced norcantharidin-induced cell death in hepatocellular carcinoma cells (Xiong et al., 2015). In line with this, ATG7 knockdown favored for cell G2/M cell cycle arrest by promoting p27 expression in bladder cancer in vitro and in vivo (J. Zhu et al., 2017, X. Zhu et al., 2017).