- Title
- Modulation of NOXA and MCL-1 as a strategy for sensitizing melanoma cells to the BH3-mimetic ABT-737
- Creator
- Lucas, Keryn M.; Mohana-Kumaran, Nethia; Lau, Diana; Zhang, Xu Dong; Hersey, Peter; Huang, David C.; Weninger, Wolfgang; Haass, Nikolas K.; Allen, John D.
- Relation
- NHMRC.1003637
- Relation
- Clinical Cancer Research Vol. 18, Issue 3, p. 783-795
- Publisher Link
- http://dx.doi.org/10.1158/1078-0432.CCR-11-1166
- Publisher
- American Association for Cancer Research
- Resource Type
- journal article
- Date
- 2012
- Description
- 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.
- Subject
- drug resistance; melanoma; NOXA; MCL-1
- Identifier
- http://hdl.handle.net/1959.13/1304592
- Identifier
- uon:20878
- Identifier
- ISSN:1078-0432
- Language
- eng
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