As far as malignancy is concerned, autophagy may function as both a tumor suppressor and tumor promoter (5). regulation of autophagy has been identified over the last decades illustrating that autophagy represents a genetically controlled process (4). As far as malignancy is concerned, autophagy may function as both a tumor suppressor and tumor promoter (5). One explanation is the dual function of autophagy being either cytoprotective or cytotoxic in a context-dependent fashion. By definition, autophagic cell death (ACD) refers to a mode of cell death that is inhibited specific blockage of the autophagic pathway (6). Anticancer treatments can participate A 943931 2HCl autophagy in malignancy cells on the one side as part of a cytoprotective solution in response to a harmful insult with the aim to mitigate cellular stress (7). On the other side, anticancer therapy can stimulate autophagy pathways that mediate ACD (8). In the following, prototypic examples of ACD upon anticancer treatments will be discussed. Anticancer Drug-Induced ACD Chemotherapeutic Drugs Several chemotherapeutic drugs have been reported to engage autophagy (9C12). While chemotherapy-mediated autophagy has mostly been linked to A 943931 2HCl a cytoprotective response that allows malignancy cells to cope with the cellular stress imposed upon anticancer drug treatment, there are also A 943931 2HCl cases of ACD. For example, the DNA-alkylating agent temozolomide (TMZ) has been implicated to elicit ACD. TMZ belongs to the class of DNA-alkylating drugs that triggers the formation of (28). These studies confirmed the contribution of autophagy to THC-mediated antitumor activity both and accumulation of ceramide and phosphorylation of eukaryotic translation initiation factor 2 alpha, resulting in upregulation of CHOP and tribbles homolog 3 (TRB3), two ER stress-related proteins (28). TRB3 then engages autophagy by blocking AKT/mTOR signaling (28). In sharp contrast to THC-triggered ACD in various types of malignancy cells, THC did not possess a comparable cytotoxicity against normal non-malignant cells (28). This indicates that THC preferentially targets cancer rather than normal cells and thus may offer a therapeutic window that could be exploited for malignancy therapy. JWH-015 is a cannabinoid receptor 2-selective agonist that has been shown to participate ACD in HCC that involved AMPK activation and inhibition of AKT/mTOR signaling (29). Of notice, ATG5 silencing or 3-MA guarded from JWH-015-induced reduction of HCC growth (29). Histone Deacetylase Inhibitors (HDACIs) Histone deacetylase inhibitors represent another class of anticancer brokers that have been reported to engage autophagy associated with the induction of cell death in chondrosarcoma cell lines. Suberoylanilide hydroxamic acid (SAHA) has been shown to stimulate autophagy-associated cell death accompanied by ultrastructural changes in autophagosome formation and increased lipidation of LC3 (30). Pharmacological inhibition Goat polyclonal to IgG (H+L)(Biotin) of autophagy using 3-MA significantly guarded from SAHA-mediated loss of cell viability (30). However, no genetic evidence has been provided in this study to confirm that autophagy is indeed required for the induction of cell death. Thus, it remains to be confirmed that SAHA in fact triggers ACD in chondrosarcoma cells. In HeLa A 943931 2HCl cervical carcinoma cells, SAHA has been reported to induce characteristic autophagic features including morphological changes and LC3-II conversion (31). Genetic silencing of BECN1 and ATG7 inhibited SAHA-stimulated autophagy (31). However, the question as to whether or not autophagy genes are also required for SAHA-induced cell death has not yet been clarified (31). In HCC, HDACIs including SAHA and OSU-HDAC-42 have been described to trigger ACD based on both genetic- and pharmacological blocking experiments underscoring that SAHA- or OSU-HDAC-42-stimulated autophagy is required for the induction of cell death, as either silencing of ATG5 or 3-MA guarded cells from your cytotoxicity of SAHA (32). Also, autophagosome formation, LC3 lipidation, and downregulation of p62 have been observed upon treatment with SAHA (32). SAHA and OSU-HDAC-42 might stimulate autophagy by blocking the mTOR pathway, as they suppress AKT/mTOR activity (32). New Combinations The tricyclic antidepressant (TCA) imipramine (IM) and the A 943931 2HCl anticoagulant ticlopidine (TIC), two drugs approved by the US Food and Drug Administration, have been shown to synergistically trigger autophagy and cell death in glioblastoma cells (33). In addition, this combination proved to be effective to suppress glioblastoma growth in a murine model. ACD was emphasized by genetic knockdown of ATG7 that significantly rescued combination treatment-induced cell death. The authors went on to show that IM and TIC increase the autophagic flux by upregulating 3-5-cyclic adenosine monophosphate (cAMP) levels distinct mechanisms. While IM treatment activates adenylate cyclase.
As far as malignancy is concerned, autophagy may function as both a tumor suppressor and tumor promoter (5)
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