Sorafenib Induces Apoptosis Specifically in Cells Expressing BCR/ABL by Inhibiting Its Kinase Activity to Activate the Intrinsic Mitochondrial Pathway

Abstract

Although the BCR/ABL tyrosine kinase inhibitor imatinib is highly effective for treatment of chronic myelogenous leukemia and Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia, relapse with emerging imatinib resistance mutations in the BCR/ABL kinase domain poses a significant problem. Here, we show that the multikinase inhibitor sorafenib inhibits proliferation and induces apoptosis at much lower concentrations in Ton.B210 cells when driven by inducibly expressed BCR/ABL than when driven by interleukin-3. The increased sensitivity to sorafenib was also observed in cells inducibly expressing BCR/ABL with the imatinib-resistant E255K or T315I mutation. Sorafenibinduced apoptosis in these cells and Ph+ leukemic cells was synergistically enhanced by rottlerin, bortezomib, or ABT-737 and inhibited by the pan-caspase inhibitor BOC-d-fmk or the overexpression of Bcl-XL. It was further revealed that sorafenib activates Bax and caspase-3 and reduces mitochondrial membrane potential specifically in BCR/ABL-driven cells. Sorafenib also inhibited BCR/ABL-induced tyrosine phosphorylation of its cellular substrates and its autophosphorylation in Ton.B210. It was finally shown that sorafenib inhibits the kinase activity of BCR/ABL as well as its E255K and T315I mutants in in vitro kinase assays. These results indicate that sorafenib induces apoptosis of BCR/ABLexpressing cells, at least partly, by inhibiting BCR/ABL to activate the mitochondria-mediated apoptotic pathway. Thus, sorafenib may provide an effective therapeutic measure to treat Ph+ leukemias, particularly those expressing the T315I mutant, which is totally resistant to imatinib and the second generation BCR/ABL inhibitors. [Cancer Res 2009;69(9):3927-36]

Gallic Acid as a Cancer-Selective Agent Induces Apoptosis in Pancreatic Cancer Cells

“…Bax expression could be quantified through a fixation and permeabilization method [29]. The kinetics of in situ Bax production in MiaPaCa-2 cells was shown in figure 7.…”

Inhibition of Bcl-2 antiapoptotic members by obatoclax potently enhances sorafenib-induced apoptosis in human myeloid leukemia cells through a Bim-dependent process

“…16,17 Interestingly, Mcl-1 downregulation by sorafenib was found to be related to translation inhibition through a mechanism(s) independent of MEK1/2/ERK1/2 signaling. 16,22 Recent evidence suggests that Bcl-2 and Bcl-xL may also confer resistance to sorafenib-mediated apoptosis in transformed cells 23,39 raising the possibility that inhibition of the antiapoptotic proteins Bcl-2 and Bcl-xL may enhance sorafenib lethality. The present results indicate that combined sorafenib/obatoclax exposure triggers pronounced lethality in and markedly reduces the clonogenic survival of various primary AML blast specimens and cell lines, while exerting only modest effects on normal CD34 ϩ cells.…”

Enhancement of imatinib-induced apoptosis of BCR/ABL-expressing cells by nutlin-3 through synergistic activation of the mitochondrial apoptotic pathway

“…pRevTRE-p53-DD was constructed by subcloning the BamHI/SalI fragment coding for p53-DD from pBABE-hygro-p53-DD into pRevTRE. pMXs-puro-Bcl-XL and pMXs-puro, kindly provided by Dr. Kitamura, have been described previously [28]. A luciferase reporter plasmid with p53 binding sites, PG13-luc (Addgene plasmid 16442) [29] was from Addgene.…”