The role of Mcl-1 downregulation in the proapoptotic activity of the multikinase inhibitor BAY 43-9006

Yu, Chunrong; Bruzek, Laura M.; Meng, Xue; Gores, Gregory J.; Carter, Christopher A.; Kaufmann, Scott H.; Adjei, Alex A.

doi:10.1038/sj.onc.1208841

Cited by 254 publications

(272 citation statements)

References 38 publications

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“…This critical step is controlled and mediated by the BCL-2 family of proteins [22]. MCL-1, one of the BCL-2 family members that inhibits cytochrome c release and caspase activation, has been shown to be downregulated following sorafenib treatment in a variety of human tumour cell lines [23][24][25][26].…”

Section: Discussionmentioning

confidence: 99%

The multikinase inhibitor sorafenib induces caspase-dependent apoptosis in PC-3 prostate cancer cells

Huang¹,

Chen²,

Zhang³

et al. 2010

Asian J Androl

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The present study investigated the effects of the multikinase inhibitor sorafenib on androgen-independent cancer cells viability and intracellular signaling. Human androgen-independent PC-3 prostate cancer cells were treated with sorafenib. At concentration that suppresses extracellular signal-regulated kinase phosphorylation, sorafenib treatment reduced the mitochondrial transmembrane potential. Sorafenib also down-modulated the levels of myeloid cell leukemia 1, survivin and cellular inhibitor of apoptosis protein 2. Sorafenib induced caspase-3 cleavage and the mitochondrial release of cytochrome c. However, no nuclear translocation of apoptosis inducing factor was detected after treatment and the pan-caspase inhibitor Z-VAD-FMK had an obvious protective effect against the drug. In conclusion, sorafenib induces apoptosis through a caspase-dependent mechanism with down-regulated antiapoptotic proteins in androgen-independent prostate cancer cells in vitro.

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Section: Discussionmentioning

confidence: 99%

The multikinase inhibitor sorafenib induces caspase-dependent apoptosis in PC-3 prostate cancer cells

Huang¹,

Chen²,

Zhang³

et al. 2010

Asian J Androl

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“…The initiation factor eIF4E regulates the translation of a large number of mRNAs, including the Bcl-2 family member Mcl-1. Constitutive overexpression of Mcl-1 in cells significantly inhibits sorafenib-induced apoptosis, whereas Mcl-1 down-regulation by RNA interference enhances sorafenibinduced apoptosis (38). Down-regulation of Mcl-1 by sorafenib is associated with the release of cytochrome c from mitochondria into the cytosol, caspase activation, and apoptotic cell death.…”

Section: Targets For Sorafenibmentioning

confidence: 99%

“…In the A549 xenograft model, sorafenib induced complete tumor stasis (27). Sorafenib induces apoptosis in A549 or NCI-H460 NSCLC cells by down-regulating Mcl-1, but no such effect has been observed with the MEK inhibitor U0126, suggesting that sorafenib acts independently of signaling through MEK and ERK in these NSCLC lines (38). There is evidence to suggest that Raf-1 is involved in mediating the posttranslational up-regulation of Mcl-1 to prevent apoptosis in tumor cells and that inhibition of Raf-1 down-regulates Mcl-1 protein levels in tumor cells (71).…”

Section: Non-small Cell Lung Cancermentioning

confidence: 99%

“…Although the precise mechanism of sorafenib-medicated apoptosis is not fully understood, the compound clearly sensitizes tumor cells to apoptosis induced by other agents in vitro. The proapoptotic activity of sorafenib is significantly enhanced when combined with chemotherapy and signal transduction inhibitors, such as the mammalian target of rapamycin inhibitor (38,40,41). The full clinical activity of sorafenib may therefore be manifest in combination with chemotherapy and/or signal transduction inhibitors targeting other pathways important in tumor cell growth and survival (13, 42 -45).…”

Section: Targets For Sorafenibmentioning

confidence: 99%

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Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling

Wilhelm

Adnane

Newell

et al. 2008

Molecular Cancer Therapeutics

1,271

861

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Although patients with advanced refractory solid tumors have poor prognosis, the clinical development of targeted protein kinase inhibitors offers hope for the future treatment of many cancers. In vivo and in vitro studies have shown that the oral multikinase inhibitor, sorafenib, inhibits tumor growth and disrupts tumor microvasculature through antiproliferative, antiangiogenic, and/or proapoptotic effects. Sorafenib has shown antitumor activity in phase II/III trials involving patients with advanced renal cell carcinoma and hepatocellular carcinoma. The multiple molecular targets of sorafenib (the serine/threonine kinase Raf and receptor tyrosine kinases) may explain its broad preclinical and clinical activity. This review highlights the antitumor activity of sorafenib across a variety of tumor types, including renal cell, hepatocellular, breast, and colorectal carcinomas in the preclinical setting. In particular, preclinical evidence that supports the different mechanisms of action of sorafenib is discussed. [Mol Cancer Ther 2008;7(10):3129 -40]

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“…cells of the tumour vasculature to inhibit angiogenesis (Wilhelm et al, 2004). Sorafenib also induces apoptosis in several human cancer cell lines (Rahmani et al, 2005;Yu et al, 2005), including melanoma cells (Panka et al, 2006b). Sorafenib downregulates Mcl-1 protein levels in a time-and dose-dependent manner to induce apoptosis in renal, colon and breast tumour lines (Rahmani et al, 2005;Yu et al, 2005).…”

Section: Sd Pdmentioning

confidence: 99%

Sorafenib in advanced melanoma: a Phase II randomised discontinuation trial analysis

et al. 2006

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The effects of sorafenib -an oral multikinase inhibitor targeting the tumour and tumour vasculature -were evaluated in patients with advanced melanoma enrolled in a large multidisease Phase II randomised discontinuation trial (RDT). Enrolled patients received a 12-week run-in of sorafenib 400 mg twice daily (b.i.d.). Patients with changes in bi-dimensional tumour measurements o25% from baseline were then randomised to sorafenib or placebo for a further 12 weeks (ie to week 24). Patients with X25% tumour shrinkage after the run-in continued on open-label sorafenib, whereas those with X25% tumour growth discontinued treatment. This analysis focussed on secondary RDT end points: changes in bi-dimensional tumour measurements from baseline after 12 weeks and overall tumour responses (WHO criteria) at week 24, progression-free survival (PFS), safety and biomarkers (BRAF, KRAS and NRAS mutational status). Of 37 melanoma patients treated during the run-in phase, 34 were evaluable for response: one had X25% tumour shrinkage and remained on open-label sorafenib; six (16%) had o25% tumour growth and were randomised (placebo, n ¼ 3; sorafenib, n ¼ 3); and 27 had X25% tumour growth and discontinued. All three randomised sorafenib patients progressed by week 24; one remained on sorafenib for symptomatic relief. All three placebo patients progressed by week-24 and were re-started on sorafenib; one experienced disease re-stabilisation. Overall, the confirmed best responses for each of the 37 melanoma patients who received sorafenib were 19% stable disease (SD) (ie n ¼ 1 open-label; n ¼ 6 randomised), 62% (n ¼ 23) progressive disease (PD) and 19% (n ¼ 7) unevaluable. The overall median PFS was 11 weeks. The six randomised patients with SD had overall PFS values ranging from 16 to 34 weeks. The most common drug-related adverse events were dermatological (eg rash/desquamation, 51%; hand-foot skin reaction, 35%). There was no relationship between V600E BRAF status and disease stability. DNA was extracted from the biopsies of 17/22 patients. Six had V600E-positive tumours (n ¼ 4 had PD; n ¼ 1 had SD; n ¼ 1 unevaluable for response), and 11 had tumours containing wild-type BRAF (n ¼ 9 PD; n ¼ 1 SD; n ¼ 1 unevaluable for response). In conclusion, sorafenib is well tolerated but has little or no antitumour activity in advanced melanoma patients as a single agent at the dose evaluated (400 mg b.i.d.). Ongoing trials in advanced melanoma are evaluating sorafenib combination therapies.

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The role of Mcl-1 downregulation in the proapoptotic activity of the multikinase inhibitor BAY 43-9006

Cited by 254 publications

References 38 publications

The multikinase inhibitor sorafenib induces caspase-dependent apoptosis in PC-3 prostate cancer cells

The multikinase inhibitor sorafenib induces caspase-dependent apoptosis in PC-3 prostate cancer cells

Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling

Sorafenib in advanced melanoma: a Phase II randomised discontinuation trial analysis

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