br Glioblastoma Enhanced radiation sensitization
Glioblastoma Enhanced radiation sensitization Hydroxychloroquine Lysosomal pH Melanoma Enhanced antitumor eﬀect Bafilomycin A1 Vacuolar-ATPase Nasopharyngeal carcinoma Enhanced antitumor eﬀect
Gastric cancer cells
Colon cancer cells
Spautin-1 Inhibits ubiquitin-specific Breast cancer cells Induced cell death
peptidases Ovarian cancer cells Induced cell death
Chronic myeloid leukemia Enhanced antitumor eﬀect
Pepstatin-A Lysosomal protease Cervical cancer cells Enhanced antitumor eﬀect
siRNAs Autophagic Cycloheximide mRNA Several cancer cells Enhanced antitumor eﬀect/
enhanced radiation sensitization
Activation of autophagy
Temsirolimus (CCI-779) mTORC1 inhibitors Mantle cell lymphoma Enhanced antitumor eﬀect (Yazbeck et al., 2008) Everolimus (RAD-001) mTORC1 inhibitors Acute lymphoblastic Enhanced antitumor eﬀect (Crazzolara et al., 2009)
Rapamycin mTORC1 inhibitors Malignant glioma Enhanced antitumor eﬀect (Carayol et al., 2010)
Chronic myeloid leukemia
Imatinib (Gleevec) Tyrosine kinase inhibitors Chronic myeloid leukemia Enhanced antitumor eﬀect (Ertmer et al., 2007)
Glioma Enhanced antitumor eﬀect (Milano et al., 2009) Erlotinib (Tarceva)
Non-small cell lung cancer Enhanced antitumor eﬀect (Gorzalczany et al., 2011) Butyrate, suberoylanilide hydroxamic HDAC inhibitors Cervical cancer cells Enhanced antitumor eﬀect (Shao et al., 2004) acid (SAHA)
Chronic myeloid leukemia
Arsenic Trioxide Toxin Leukemia cells Induced cell death (Qian et al., 2007)
(Kanzawa et al., 2005) Resveratrol Antioxidant Ovarian cancer cells Induced cell death (Opipari et al., 2004) Polygonatum cyrtonema lectin Lectin Murine fibrosarcoma Induced cell death (B. Liu et al., 2010, F. Liu et al.,
(Liu et al., 2009) Epigallocatechin-3-gallate Polyphenol Oral squamous cell carcinoma Induced cell death (Irimie et al., 2015) Curcumin Polyphenol Malignant glioma Induced cell death (Aoki et al., 2007)
Breast cancer cells
(Xiao et al., 2013) Allicin Thiosulfinate Liver cancer cells Induced cell death (Chu et al., 2012) Ginsenosides Saponins Breast cancer stem cells Induced cell death (Mai et al., 2012)
i. Repressors of autophagosome formation: Class III PI3K inhibitors 3-methyladenine (3-MA), Wortmannin, LY294002, SAR405 and recently developed Viridiol were shown to block the formation of autophago-some (Del Bel et al., 2017; Pasquier, 2015; Rubinsztein et al., 2012).
ii. Repressors of lysosomal acidification: Lysosomotropic agents in-cluding CQ, HCQ, Lys0569 and monensin prevent acidification of ly-sosomes and thus inhibit degradation of the cargo in the autophago-somes. r> iii. Inhibitors of autophagosome-lysosome fusion: Vacuolar-ATPase in-hibitors, including variants of Bafilomycin (Baf A1, Baf B1 and Baf C1) and Concanamycin variants (Con A, Con B and Con C) interferes with the fusion of autophagosomes with lysosomes whereas, Spautin-1 tar-gets Beclin-1 subunit of Vps34 complexes (Bowman et al., 2004; Shao et al., 2014).
iv. Silencing expression of autophagy-related proteins at transcription level: By utilizing siRNA- or miRNA-mediated silencing strategies, knockdown of autophagy-related genes subsequently inhibited autop-hagic activity.
The Class III PI3K VPS34 (also called PIK3C3) is a positive regulator of autophagy, which was originally identified in Saccharomyces cerevi-siae (Kihara et al., 2001). VPS34 mediates initiation and maturation of autophagosomes by forming protein complexes with various autophagy regulator proteins. PI3K inhibitors, including 3-methyladenine (3-MA) (Seglen and Gordon, 1982), Wortmannin, LY294002, (Blommaart et al., 1997), recent selective PIK3C3 inhibitors SAR405 (Pasquier, 2015) and Viridiol (Del Bel et al., 2017) have been proposed to suppress autop-hagy by inhibiting the production of PI3P (Petiot et al., 2000), which is essential for the recruitment of other ATG proteins at the isolation membrane or phagophore (Zeng, 2006).
A number of reports supported the idea that autophagy inhibition through PI3K inhibitors enhanced the eﬃcacy of chemo- and/or radio-therapies (Cheong et al., 2012). For example, deregulation of autop-hagy with 3-MA contributed to radiation sensitization of esophageal squamous carcinoma cells (Chen et al., 2011). Similarly, 3-MA-medi-ated inhibition of autophagy enhanced 5-FU- and cisplatin-induced apoptosis in colon and lung cancer cells respectively (Li et al., 2009; Liu et al., 2013). Furthermore, wortmannin treatment was able to enhance the antitumor eﬀect of silver nanoparticles in the in vivo (Lin et al., 2014). SAR405 inhibited autophagosome biogenesis and combination of SAR405 with everolimus, the FDA-approved mTOR inhibitor, pro-posed to reduce proliferation of renal tumor cells (Pasquier, 2015).