Modulation of NOXA and MCL-1 as a strategy for sensitizing melanoma cells to the BH3-mimetic ABT-737
| Autor: | David C.S. Huang, Diana Lau, Wolfgang Weninger, K. M. Lucas, Xudong Zhang, John F. Allen, Peter Hersey, Nikolas K. Haass, Nethia Mohana-Kumaran |
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| Rok vydání: | 2011 |
| Předmět: |
Male
Cancer Research BH3 Mimetic ABT-737 Immunoblotting Antineoplastic Agents Mice SCID Piperazines Nitrophenols Mice In vivo Mice Inbred NOD Transduction Genetic hemic and lymphatic diseases Cell Line Tumor medicine Cytotoxic T cell Animals Humans RNA Small Interfering Melanoma Gene knockdown Sulfonamides business.industry Biphenyl Compounds medicine.disease Xenograft Model Antitumor Assays Biphenyl compound Leukemia Oncology Proto-Oncogene Proteins c-bcl-2 Cell culture Gene Knockdown Techniques Immunology Cancer research Myeloid Cell Leukemia Sequence 1 Protein business |
| Zdroj: | Clinical cancer research : an official journal of the American Association for Cancer Research. 18(3) |
| ISSN: | 1557-3265 |
| Popis: | 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. Clin Cancer Res; 18(3); 783–95. ©2011 AACR. |
| Databáze: | OpenAIRE |
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