Sorafenib induces apoptosis of AML cells via Bim-mediated activation of the intrinsic apoptotic pathway

Abstract

Raf/MEK/Erk signaling is activated in the majority of acute myeloid leukemias (AMLs), providing rationale for targeting this pathway with therapeutic intent. We investigated growthinhibitory and proapoptotic effects of sorafenib in AML. Our studies demonstrated that sorafenib significantly inhibited the phosphorylation levels of Raf downstream target proteins MEK1/2 and Erk, induced apoptosis and inhibited colony formation in AML cell lines and in primary AML samples. Mechanistically, treatment with sorafenib resulted in upregulation of proapoptotic Bim, accompanied by an increase in Bad, Bax and Bak protein levels and decreased Mcl-1, X-linked inhibitor of apoptosis and surviving levels, which mainly led to the activation of the intrinsic apoptotic pathway. Silencing of Bim protein expression significantly abrogated sorafenibinduced apoptosis, suggesting a critical function of Bim in the activation of the intrinsic mitochondrial pathway induced by sorafenib. Importantly, sorafenib also modulated phospho-Erk, Bim, Bax and Mcl-1 levels in samples procured from patients in an ongoing Phase I clinical trial of sorafenib in AML. Combination of sorafenib with cytarabine or the novel small molecule Bcl-2 inhibitor ABT-737 synergistically induced cell death in AML cell lines. Our results strongly suggest potential activity of sorafenib as a novel mechanism-based therapeutic agent in AML.

A novel Bim-BH3-derived Bcl-XL inhibitor: Biochemical characterization, in vitro, in vivo and ex-vivo anti-leukemic activity

“…25,26 Homozigous deletion of Bim is associated with mantle cell lymphoma 27 and survival of autoreactive T and B cells, 28,29 and repression of Bim expression by EBV has a significant role in Burkitt lymphoma. 30 Several antitumor chemotherapies were demonstrated to kill neoplastic cells through Bim-activated pathways, including a Raf kinase inhibitor in acute myeloid cells, 31 glucocorticoids in leukaemia cell lines and primary leukemia cells, 32,33 ABT-737 for chronic lymphocytic leukaemia cells and myeloma cell lines 18 and paclitaxel in xenografts of epithelial cancer cells. 34 Altogether, Bim can be classified as a powerful tumour suppressor, and its strong pro-apoptotic activity is regulated both at transcriptional and post-translational levels.…”

Involvement of p53 and Raf/MEK/ERK pathways in hematopoietic drug resistance

“…2,3 These mutations may render these hematopoietic cells exquisitely sensitive to inhibitors that target this pathway. 3,15 Germline mutations in C-Raf (Raf-1), which may contribute to malignant transformation, have been identified in patients with therapy-related AML, p53, signaling pathways and hematopoietic drug resistance JA McCubrey et al which may predispose these individuals to cancer. 62 These results point toward important roles of the Raf/MEK/ERK pathway in the drug resistance of hematopoietic cells.…”

“…p53/MDM-2, Raf/MEK/ERK, PI3K/Akt and apoptotic pathways are frequently implicated in drug resistance of various types of cancers. [13][14][15][16][17][18][19][20] The p53 transcription factor is a highly complex tumor suppressor gene, which is mutated in approximately 50% human cancers. 2,18,[21][22][23][24] It is often activated by genotoxic stresses, such as those generated upon doxorubicin treatment.…”

Differential effects of anti-apoptotic Bcl-2 family members Mcl-1, Bcl-2, and Bcl-xL on Celecoxib-induced apoptosis

“…Synergistic activation of the Noxa/Mcl-1 and Bad/Bcl-xL pathways is mimicked by using the relatively unspecific BH3-mimetic obatoclax (GX15-070) targeting both pathways at the same time [42]. However, enhanced apoptosis was also observed, when the Bad-mimetic ABT-737 was combined with bortezomib, homoharringtonine, N-(4-hydroxy-phenyl)retinamid, Sorafenib, Carboplatin, or TRAIL [43][44][45][46][47][48]. Since ABT-737 targets only Bcl-2, Bcl-xL, and Bcl-w, the former mentioned drugs probably activate the Noxa/Mcl-1 pathway.…”