title: Modulation of NOXA and MCL-1 as a strategy for sensitizing melanoma cells to the BH3-mimetic ABT-737.
abstract: OBJECTIVE
  Drug resistance in melanoma is commonly attributed to ineffective apoptotic pathways. Inhibiting antiapoptotic BCL-2 and its relatives is an attractive strategy for sensitizing lymphoid malignancies to drugs but it has been largely unsuccessful for melanoma and other solid tumors. ABT-737, a small-molecule BH3-mimetic, selectively inhibits BCL-2, BCL-XL, and BCL-w and shows promise for treating leukemia, lymphoma, and small-cell lung cancer. Melanoma cells are insensitive to ABT-737, but MCL-1 inhibition reportedly increases the sensitivity of other tumors to the compound.
  
  
  METHODS
  The efficacy of MCL-1 and BFL-1 inhibition for sensitizing melanoma cells to ABT-737 was investigated by short hairpin RNA-mediated knockdown or overexpression of their antagonist NOXA in two-dimensional cell culture, a three-dimensional organotypic spheroid model, and an in vivo model.
  
  
  RESULTS
  MCL-1 downregulation or NOXA overexpression strongly sensitized melanoma cells to ABT-737 in vitro. NOXA-inducing cytotoxic drugs also strongly sensitized melanomas to ABT-737 but, surprisingly, not vice versa. The drugs most suitable are not necessarily those normally used to treat melanoma. Resistance to ABT-737 occurred quickly in three-dimensional melanoma spheroids through reduced NOXA expression, although experiments with both xenografts and three-dimensional spheroids suggest that penetration of ABT-737 into tumor masses may be the principal limitation, which may be obviated through use of more diffusible BH3-mimetics.
  
  
  CONCLUSIONS
  Sensitization of tumors to BH3-mimetics by cytotoxic drugs that induce NOXA is a therapeutic strategy worth exploring for the treatment of melanoma and other solid cancers.
authors.affiliation: The Centenary Institute, Newtown, New South Wales, Australia.
authors.forename: Keryn M
authors.initials: KM
authors.lastname: Lucas
authors.forename: Nethia
authors.initials: N
authors.lastname: Mohana-Kumaran
authors.forename: Diana
authors.initials: D
authors.lastname: Lau
authors.forename: Xu Dong
authors.initials: XD
authors.lastname: Zhang
authors.forename: Peter
authors.initials: P
authors.lastname: Hersey
authors.forename: David C
authors.initials: DC
authors.lastname: Huang
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Weninger
authors.forename: Nikolas K
authors.initials: NK
authors.lastname: Haass
authors.forename: John D
authors.initials: JD
authors.lastname: Allen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D045744:Cell Line, Tumor; D055785:Gene Knockdown Techniques; D006801:Humans; D015151:Immunoblotting; D008297:Male; D008545:Melanoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009596:Nitrophenols / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering; D013449:Sulfonamides / Q000494:pharmacology*; D014161:Transduction, Genetic; D023041:Xenograft Model Antitumor Assays
chemical_list: C501332:ABT-737; D000970:Antineoplastic Agents; D001713:Biphenyl Compounds; C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009596:Nitrophenols; C498702:PMAIP1 protein, human; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D013449:Sulfonamides