Yu C, Bruzek LM, Meng XW, Gores GJ, Carter CA, Kaufmann SH et al.. The role of Mcl-1 downregulation in the proapoptotic activity of the multikinase inhibitor BAY 43-9006. Oncogene 24: 6861-6869

Division of Medical Oncology, Mayo Clinic, 200 First Street. SW, Rochester, MN 55905, USA.
Oncogene (Impact Factor: 8.46). 11/2005; 24(46):6861-9. DOI: 10.1038/sj.onc.1208841
Source: PubMed


BAY 43-9006, a multikinase inhibitor that targets Raf, prevents tumor cell proliferation in vitro and inhibits diverse human tumor xenografts in vivo. The mechanism of action of BAY 43-9006 remains incompletely defined. In the present study, the effects of BAY 43-9006 on the antiapoptotic Bcl-2 family member Mcl-1 were examined. Treatment of A549 lung cancer cells with BAY 43-9006 diminished Mcl-1 levels in a time- and dose-dependent manner without affecting other Bcl-2 family members. Similar BAY 43-9006-induced Mcl-1 downregulation was observed in ACHN (renal cell), HT-29 (colon), MDA-MB-231 (breast), KMCH (cholangiocarcinoma), Jurkat (acute T-cell leukemia), K562 (chronic myelogenous leukemia) and MEC-2 (chronic lymphocytic leukemia) cells. Mcl-1 mRNA levels did not change in BAY 43-9006-treated cells. Instead, BAY 43-9006 enhanced proteasome-mediated Mcl-1 degradation. This Mcl-1 downregulation was followed by mitochondrial cytochrome c release and caspase activation as well as enhanced sensitivity to other proapoptotic agents. The caspase inhibitor Boc-D-fmk inhibited BAY 43-9006-induced caspase activation but not cytochrome c release. In contrast, Mcl-1 overexpression inhibited cytochrome c release and other features of BAY 43-9006-induced apoptosis. Conversely, Mcl-1 downregulation by short hairpin RNA enhanced BAY 43-9006-induced apoptosis. Collectively, these findings demonstrate that drug-induced Mcl-1 downregulation contributes to the proapoptotic effects of BAY 43-9006.

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Available from: Xuewei Meng, May 13, 2014
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    • "There are no FDA approved therapies to address MCL1 copy number amplification at this time, but investigations focused on small molecule inhibitors of MCL1 are underway. In addition, the multikinase inhibitor sorafenib has been shown to down-regulate MCL1 and thereby induce apoptosis in preclinical studies.[43] Also, preclinical studies of patient-derived tumor cells suggest that increased MCL1 levels may confer resistance to antitubulin therapies such as paclitaxel.[44] "
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