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  • br Autophagy activators as anti cancer agents br Since

    2020-08-07


    4.2. Autophagy activators as anti-cancer agents
    Since excessive autophagic activity acts as a pro-death mechanism, the autophagy induction is a direct strategy that may promote tumor cell death. As mentioned in the previous sections, certain tumor Dihexa (PNB-0408) are resistant to apoptosis and this enables them to escape from death. Therefore, autophagy comes into play as an alternative cell death me-chanism in cancer cells with defects in apoptosis (Tsujimoto and Shimizu, 2005). Inhibition of mTOR or disruption of Beclin-1/BCL-2 interaction is among the most common strategies implemented to
    induce autophagy directly complex. Additionally, a number of agents introduced that directly or indirectly promote autophagy have been described (Cheong et al., 2012). Below we will briefly discuss some of the chemical agents, which are known to directly act on autophagic pathways.
    The major kinase complex of autophagy mTOR considered as a promising drug target for the cancer treatment strategies. The mTOR inhibitor rapamycin have been reported to sensitize various tumor cells to radiation therapy (Cheong et al., 2012) and inhibited cell prolifera-tion of malignant glioma cells (Takeuchi et al., 2005). Rapamycin formed a complex with the small protein FKBP12 which binds to the FKBP12-rapamycin domain of mTORC1 and inhibits its kinase activity (Sabers et al., 1995). Beside from its anti-tumoral activity, the clinical use of rapamycin was limited due to its low solubility and poor stability. First generation of rapamycin analogs include temsirolimus (CCI-779, Wyeth) (Wu et al., 2005), everolimus (RADD001, Novartis) (Gorshtein et al., 2009), and ridaforolimus (AP23573, Ariad Pharmaceuticals) (Mita et al., 2008). Among these rapamycin analogs temsirolimus and everolimus exerted their effects on autophagy through downregulation of AKT signaling. mTOR inhibitors are shown to induce cell death in various cancer cells including, breast cancer (Hurvitz and Peddi, 2013), renal cell carcinoma (Motzer et al., 2010), thyroid cancer (Wagle et al., 2014), non-small cell lung cancer (Choueiri et al., 2015), hepatocellular carcinoma (Zhu et al., 2011) and mesothelioma Dihexa (PNB-0408) (Pignochino et al., 2015). However, due to the reports on possible off-target effects of rapamycin and its analogs more selective and potent ATP-competitive inhibitors of both mTORC1 and mTORC2 and the dual PI3K-mTOR inhibitor NVP-BEZ235 have been developed. Clinical use of dual in-hibitors carries great potential for highly aggressive tumors with a high mortality and low treatment possibility such as uterine sarcoma. Treatment with dual inhibitors significantly reduced tumor growth in patient-derived mouse models (Cuppens et al., 2017).
    4.2.2. Tyrosine kinase inhibitors
    Tyrosine kinases are a class of protein involved in the phosphor-ylation of tyrosine residues on polipeptides and their cellular expres-sions are limited in non-proliferating cells. Enhanced enzymatic activity and expression were linked to tumorigenesis and proliferative ab-normalities (Baselga, 2006). Imatinib, a tyrosine kinase inhibitor (TKI) commonly used drug for the treat of chronic myeloid leukemia and also gastrointestinal stromal tumor (Ertmer et al., 2007). The mechanistic details of imatinib on tumors was correlated with downregulation of BCR/ABL, disassociation of the complex as well as autophagy induction (Elzinga et al., 2013). But alternatively, tyrosine kinase mediated au-tophagy activation in leukemia could promote cancer cell survival due to the reverse effects on these pathways on leukemic cells (Drullion et al., 2012). To support this theme, combined treatment of imatinib and its derivatives like nilotinib with CQ or BafA induced cell death both in vivo and in vitro (Bellodi et al., 2009; Shingu et al., 2009; Tiwari et al., 2009; Wu et al., 2010).
    Another tyrosine kinase inhibitor, gefitinib treatment significantly resulted in tumor regression in patients bearing non-small cell lung cancer (Paez et al., 2004). Similar results also obtained in the case of lung adenocarcinoma that exhibit hypersensitivity to gefitinib. Some of the commercially available tyrosine kinase inhibitors include sorafenib (Abou-Alfa et al., 2010), lapatinib (Awada et al., 2011) and vandetanib (Karras et al., 2014). Sorafenib is the key chemotherapeutics which enhanced survival rates of hepatocellular carcinoma (HCC) patients (Estfan et al., 2013). Not only the HCC, but also a number of different types of cancer were included in the sorafenib treatment targets, in-cluding renal cell carcinoma (Escudier et al., 2007), prostate cancer, thyroid cancer (Shen et al., 2014) and also amyloid leukemia (Antar et al., 2015). Sorafenib-mediated autophagy induction is related to both death and survival of the cancer cells in a context-dependent manner.  European Journal of Pharmaceutical Sciences 134 (2019) 116–137
    AKT inhibition provided a key regulatory node for determination of hepatocellular carcinoma cell faith from protective autophagy to au-tophagic cell death (Zhai et al., 2014). AKT-mediated regulation of sorafenib-induced autophagic cell death occurred through in an ERK1/ 2-independently in renal cell carcinoma (Serrano-Oviedo et al., 2018). Sorafenib treatment favored for cell death also through necroptosis in autophagy-deficient cancer cells (Kharaziha et al., 2015).