Modulation of NOXA and MCL-1 as a strategy for sensitizing melanoma cells to the BH3-mimetic ABT-737

Lucas, Keryn M., Mohana-Kumaran, Nethia, Lau, Diana, Zhang, Xu Dong, Hersey, Peter, Huang, David C., Weninger, Wolfgang, Haass, Nikolas K. and Allen, John D. (2012) Modulation of NOXA and MCL-1 as a strategy for sensitizing melanoma cells to the BH3-mimetic ABT-737. Clinical Cancer Research, 18 3: 783-795. doi:10.1158/1078-0432.CCR-11-1166


Author Lucas, Keryn M.
Mohana-Kumaran, Nethia
Lau, Diana
Zhang, Xu Dong
Hersey, Peter
Huang, David C.
Weninger, Wolfgang
Haass, Nikolas K.
Allen, John D.
Title Modulation of NOXA and MCL-1 as a strategy for sensitizing melanoma cells to the BH3-mimetic ABT-737
Journal name Clinical Cancer Research   Check publisher's open access policy
ISSN 1078-0432
1557-3265
Publication date 2012-02-01
Year available 2012
Sub-type Article (original research)
DOI 10.1158/1078-0432.CCR-11-1166
Volume 18
Issue 3
Start page 783
End page 795
Total pages 13
Place of publication Philadelphia, PA United States
Publisher American Association for Cancer Research
Collection year 2013
Language eng
Subject 1306 Cancer Research
2730 Oncology
Abstract Purpose: 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. Experimental Design: 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. Conclusion: 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.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: UQ Diamantina Institute Publications
 
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Created: Sat, 31 May 2014, 03:39:15 EST by Nikolas Haass on behalf of UQ Diamantina Institute