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
cells
Gastric cancer cells
Osteosarcoma 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
cells
Pepstatin-A
Lysosomal protease
Cervical cancer cells
Enhanced antitumor effect
inhibitor
siRNAs
Autophagic Ko143 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)
leukemia
Rapamycin
mTORC1 inhibitors
Malignant glioma
Enhanced antitumor effect
(Carayol et al., 2010)
Chronic myeloid leukemia
cells
Imatinib (Gleevec)
Tyrosine kinase inhibitors
Chronic myeloid leukemia
Enhanced antitumor effect
(Ertmer et al., 2007)
cells
Dasatinib (Sprycel)
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
cells
Arsenic Trioxide
Toxin
Leukemia cells
Induced cell death
(Qian et al., 2007)
Malignant glioma
(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.,
Melanoma cells
(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)
Malignant glioma
Breast cancer cells
Lung cancer
(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.
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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).