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  • Relebactam Initiation Mutated Goi et al Colorectal

    2020-08-07

    Initiation Mutated (Goi et al., 2003) Colorectal carcinomas UVRAG Initiation Mutated (Ionov et al., 2004) Gastric carcinomas UVRAG Initiation Mutated (Kim et al., 2008) Colorectal carcinomas AMBRA1 Initiation Mutated (Cianfanelli et al., 2015) Gastric and prostate carcinomas Bif-1 Initiation Decreased (Lee et al., 2006) Breast carcinomas FIP200 Initiation Mutated (Chano et al., 2002) Meningiomas BECN1 Initiation Decreased (Miracco et al., 2007) Colorectal and gastric carcinomas BECN1 Initiation Increased (Ahn et al., 2007) Breast carcinomas BECN1 Initiation Decreased (Liang et al., 1999) Epithelial ovarian cancer BECN1 Initiation Decreased (Shen et al., 2008) Melanoma ATG5 Elongation Decreased (Marino et al., 2007) Benign liver tumor ATG5 Elongation Decreased (Takamura et al., 2011) Colorectal and gastric carcinomas ATG5 Elongation Mutated (Kang et al., 2009) Colorectal and gastric carcinomas ATG12 Elongation Mutated (Kang et al., 2009) Leukemia ATG3 Elongation Increased (Ma et al., 2013) Fibrosarcomas ATG4C Elongation Decreased (Marino et al., 2007) Leukemia RAB7A Fusion Mutated (Kashuba et al., 1997) Colorectal and gastric carcinomas ATG2B Fusion Mutated (Kang et al., 2009) Colorectal and gastric carcinomas ATG9B Fusion Mutated (Kang et al., 2009) Oncogenic role
    Cervical carcinomas PIK3CA Upstream Increased (Ma et al., 2000) Multiple myeloma PDPK1 Upstream Increased (Chinen et al., 2014) Prostate carcinomas RHEB Upstream Increased (Nardella et al., 2008) Chronic myeloid leukemia ATG4B Elongation Increased (Rothe et al., 2014) Hepatocellular carcinomas ULK1 Initiation Increased (Xu et al., 2013) Breast carcinomas ULK1 Initiation Increased (Pike et al., 2013) Esophageal squamous cell carcinomas ULK1 Initiation Increased (Jiang et al., 2011) Oral squamous cell carcinoma ATG16L1 Elongation Increased (Tang et al., 2015) Thyroid carcinomas ATG16L1 Elongation Mutated (Huijbers et al., 2012) Colorectal carcinomas ATG16L1 Elongation Mutated (Nicoli et al., 2014)
    2013). In this context, inhibition of autophagy can be exploited as a novel strategy to re-sensitize the cancer Relebactam to chemo−/radio-therapy. For example, combined therapy of siRNA-mediated LC3 depletion with imatinib treatment sensitized the breast cancer cells to trastuzumab treatment in MCL (Bellodi et al., 2009). Similarly, autophagy inhibitors chloroquine (CQ) and hydroxychloroquine (HCQ) were also promoted accumulation of autophagic vacuoles that often leads to apoptotic and necrotic cell death (Solomon et al., 2009). We have provided a more detailed discussion on the role of autophagy inhibitors and activators in cancer treatment.
    4. Targeting autophagy for cancer treatment
    The involvement of the shared regulatory pathways makes autop-hagy as a promising target in cancer treatment, even though the re-lationship between autophagy and cancer is still controversial.
    Table 2
    Regulating autophagy for cancer treatment.
    Concerning the dual roles of autophagy in tumor development mainly two different therapeutic strategies can be adopted. The first approach includes sensitizing the cancer cells for chemo−/radio-therapy through inhibition of the cytoprotective role of autophagy. The other strategy aims to target induction of autophagic cell death in apoptosis-resistant cells (Zhou et al., 2012). Targeted autophagic proteins and autophagy inhibitors for cancer treatment are listed in Tables 1 and 2, respectively.
    4.1. Autophagy inhibitors as anti-cancer agents
    The role of autophagy as a mechanism that promotes resistance to chemo- or radio-therapies compromises the efficacy of anti-cancer treatment strategies. Hence, inhibition of autophagy may serve as a tool for sensitizing the tumor cells for treatment. The most common au-tophagy-inhibiting molecules could be categorized into four groups according to their mode of action:
    Compound Target Tumor/Cancer cell type Effect Reference
    Inhibition of autophagy
    3-MA(3-methyladenin) PIK3C3 Esophageal squamous cell Enhanced radiation sensitization
    cancer
    Colorectal cancer Enhanced antitumor effect
    Lung cancer Enhanced antitumor effect Wortmannin PIK3C3 Mouse melanoma cell Enhanced antitumor effect SAR405 PIK3C3 Renal tumor cells Reduced proliferation Chloroquine Lysosomal pH Non-small cell lung cancer Enhanced antitumor effect
    Glioblastoma multiform Enhanced antitumor effect
    Colon cancer cells Enhanced antitumor effect
    Head and neck cancer cells Enhanced radiation sensitization