br Erlotinib another commonly used tyrosine kinase inhibitor
Erlotinib another commonly used tyrosine kinase inhibitor en-hanced autophagy in various diﬀerent cancer cells, including non-small cell lung cancer (Li et al., 2013). Similar to other tyrosine kinase in-hibitors, erlotinib-mediated autophagy induction confer resistance to death. Overcoming TKI-derived resistance to death become emerging for cancer treatment. Autophagy inhibition keeps a great potential in order to reach this demand. CQ (Zou et al., 2013), 3-MA (Wang et al., 2016) and clozapine (Yin et al., 2015). On the other hand, combined treatment of sertraline and erlotinib induced autophagy by regulating AMPK/mTOR pathway and this combination significantly reduced tumor formation and induced survival rate (Jiang et al., 2018). Accu-mulating data suggest that TKIs are key drugs with a great anti-tumoral eﬀects and their influence on survival are tightly regulated by autop-hagy mechanism. r> 4.2.3. Histone deacetylase inhibitors
Dysregulation of enzymes function as epigenetic regulators are in-volved in human tumors has led to development inhibitors such as the histone deacetylases (HDACs) which target the cancer epigenome (Lakshmaiah et al., 2014). Based on their chemical structure, inhibitors of HDACs are classified into several groups including hydroxamic acids (e.g., trichostatin A, vorinostat, suberoylanilide hydroxamic acid), carboxylic acids (e.g., valproate, butyrate), aminobenzamides (e.g., entinostat, mocetinostat), cyclic peptides (e.g., apicidin, romidepsin), epoxyketones (e.g., trapoxins), and hybrid molecules (West and Johnstone, 2014). The eﬀects of histone deacetylase inhibitors on cell death are well-diﬀerentiated from their eﬀects on chromatin and ex-hibit wide eﬀect on diﬀerent types of cancers (Luchenko et al., 2014). HDAC inhibitors are induced apoptosis through regulating PepstatinA arrest and aﬀected to diﬀerent molecular mechanisms such as angio-genesis, metastasis and autophagy. Among the inhibitors of HDAC, Vorinostat and romidepsin are the FDA approved drugs for the treat-ment of T-cell lymphoma. Varinostat treatment induced cell death through activating p38/MAPK pathway in breast cancer cells (Uehara et al., 2012). In addition to their roles in apoptosis, HDAC inhibitors can also induce autophagy. Interestingly, there have been identified link between the HDAC inhibitor resistancy and cellular autophagy level. Short- and long-term varinostat induced autophagy and furthermore, autophagy provided acquired resistancy to varinostat in mammalian cells (Dupéré-Richer et al., 2013). On the other hand, the anti-tumoral eﬀect of varinostat further accelatered when combined with HCQ. In-deed, varinostat and HCQ improved immunity in pre-clinical models as well as early phase clinical trials of metastatic colorectal cancer (Patel et al., 2016). As a similar approach, genistein and varinostat cotreat-ment enhanced cell death in prostate cancer cells regulating cell cycle check points, WNT and TNF signaling (Phillip et al., 2012).
Another HDAC inhibitor, suberoylanilide hydroxamic acid (SAHA) also activated autophagy by inhibiting mTOR and upregulating LC3 expression where autophagy favored for survival of cells (Gammoh et al., 2012). In a diﬀerent experimental setup, SAHA also promoted caspase-independent autophagic cell death through p53-linked me-chanisms suggesting that indirect and non-specific eﬀects on autophagy regulation might be involved (Shao et al., 2004). SAHA-linked tumor suppressive eﬀects were also correlated with enhanced autophagic ac-tivity in collaboration with apoptosis in the late stage of glioblastoma stem cells as well as glioblastoma biophsy-originated cultured cells (Chiao et al., 2013).
Arsenic trioxide (As2O3) is a well-known toxin originated from the traditional Chinese medicine and proposed to have therapeutic on dif-ferent types of malignancies, particularly multiple myeloma and mye-lodysplastic syndromes (Emadi and Gore, 2010). In addition to acti-vation of apoptotic pathways, AS2O3 also promoted cytotoxicity in cancer cells through induction of autophagy (Zhou et al., 2015).
As2O3–mediated autophagy activation was shown to occur through MEK/ERK pathway rather than the AKT/mTOR or JNK pathways (Goussetis et al., 2010). Additionally, As2O3 can induce autophagic cell death in leukemia cell lines through upregulation of Beclin-1 (Qian et al., 2007) and rapid degradation of pro-myelocytic protein con-tributed to distruption of glioma stem cells and increased survival of the tumor-bearing animals (Zhou et al., 2015). Interestingly, autophagy-inducing potential of As2O3 therefore promoting autophagic cell death oﬀers a great therapeutic approach for apoptosis-resistant cancer types.