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  • br Glioblastoma Enhanced radiation sensitization

    2020-08-07


    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 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)
    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. 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 Cycloheximide 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).