title: Targeting the intrinsic apoptosis pathway as a strategy for melanoma therapy.
abstract: Melanoma drug resistance is often attributed to abrogation of the intrinsic apoptosis pathway. Targeting regulators of apoptosis is thus considered a promising approach to sensitizing melanomas to treatment. The development of small-molecule inhibitors that mimic natural antagonists of either antiapoptotic members of the BCL-2 family or the inhibitor of apoptosis proteins (IAPs), known as BH3- or SMAC-mimetics, respectively, are helping us to understand the mechanisms behind apoptotic resistance. Studies using BH3-mimetics indicate that the antiapoptotic BCL-2 protein MCL-1 and its antagonist NOXA are particularly important regulators of BCL-2 family signaling, while SMAC-mimetic studies show that both XIAP and the cIAPs must be targeted to effectively induce apoptosis of cancer cells. Although most solid tumors, including melanoma, are insensitive to these mimetic drugs as single agents, combinations with other therapeutics have yielded promising results, and tests combining them with BRAF-inhibitors, which have already revolutionized melanoma treatment, are a clear priority.
authors.affiliation: The Centenary Institute, Newtown, NSW, Australia; School of Biological Sciences, Universiti Sains Malaysia, Penang, Malaysia.
authors.forename: Nethia
authors.initials: N
authors.lastname: Mohana-Kumaran
authors.forename: David S
authors.initials: DS
authors.lastname: Hill
authors.forename: John D
authors.initials: JD
authors.lastname: Allen
authors.forename: Nikolas K
authors.initials: NK
authors.lastname: Haass
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000627:therapeutic use*; D006801:Humans; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism; D010446:Peptide Fragments / Q000737:chemistry / Q000627:therapeutic use*; D057786:Peptidomimetics / Q000737:chemistry / Q000627:therapeutic use*; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000627:therapeutic use*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000737:chemistry* / Q000378:metabolism; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism
chemical_list: C474007:Bax protein (53-86); D004791:Enzyme Inhibitors; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; C498702:PMAIP1 protein, human; D010446:Peptide Fragments; D057786:Peptidomimetics; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf
keywords: BH3-mimetic; IAP antagonist; MCL-1 antagonist; SMAC-mimetic; drug resistance; intrinsic apoptosis pathway; melanoma therapy