ABT‐263 enhances sorafenib‐induced apoptosis associated with Akt activity and the expression of Bax and p21^(CIP1/WAF1) in human cancer cells

Abstract

BACKGROUND AND PURPOSESorafenib, a potent inhibitor that targets several kinases associated with tumourigenesis and cell survival, has been approved for clinical treatment as a single agent. However, combining sorafenib with other agents improves its anti-tumour efficacy in various preclinical tumour models. ABT-263, a second-generation BH3 mimic, binds to the anti-apoptotic family members Bcl-2, Bcl-xL and Bcl-w, and has been demonstrated to enhance TNFSF10 (TRAIL)-induced apoptosis in human hepatocarcinoma cells. Hence, we investigated the effects of ABT-263 treatment combined with sorafenib. EXPERIMENTAL APPROACHThe effects of ABT-263 combined with sorafenib were investigated in vitro, on cell viability, clone formation and apoptosis, and the mechanism examined using western blot and flow cytometry. This combination was also evaluated in vivo, in a mouse xenograft model; tumour growth, volume and weights were measured and a TUNEL assay performed. KEY RESULTSABT-263 enhanced sorafenib-induced apoptosis while sparing non-tumourigenic cells. Although ABT-263 plus sorafenib significantly stimulated intracellular reactive oxygen species production and subsequent mitochondrial depolarization, this was not sufficient to trigger cell apoptosis. ABT-263 plus sorafenib significantly decreased Akt activity, which was, at least partly, involved in its effect on apoptosis. Bax and p21 (CIP1/WAF1) were shown to play a critical role in ABT-263 plus sorafenib-induced apoptosis. Combining sorafenib with ABT-263 dramatically increased its efficacy in vivo. CONCLUSION AND IMPLICATIONSThe anti-tumour activity of ABT-263 plus sorafenib may involve the induction of intrinsic cell apoptosis via inhibition of Akt, and reduced Bax and p21 expression. Our findings offer a novel effective therapeutic strategy for tumour treatment. AbbreviationsΔΨm, mitochondrial membrane potential; CsA, cyclosporine A; NAC, N-acetyl-L-cysteine; PI, propidium iodide; ROS, reactive oxygen species BJP British Journal of Pharmacology

MicroRNA-301a promotes cell proliferation via PTEN targeting in Ewing's sarcoma cells

“…Akt activates the mTOR signaling pathway (37) and represses p21, as well as Bax, to enhance cell proliferation preventing apoptosis (38,39). Therefore, Akt downregulation by PTEN in ES cells induced the upregulation of p21 and Bax, which might have resulted in cell cycle inhibition and apoptosis in ES cells.…”

Synergistic anti‐tumour effects of tetrandrine and chloroquine combination therapy in human cancer: a potential antagonistic role for p21

“…An empty vector pHAGE.puro plasmid was kindly provided by Dr Zan Huang (College of Life Sciences, Wuhan University, China), and pHAGE.puro-p21 plasmid was obtained from our laboratory (Li et al, 2014a). The empty vector p-USE and p-USE-CA-Akt plasmids were obtained from Upstate Biotechnology (Lake Placid, NY, USA).…”

“…p21 expression is involved in apoptosis induced by combination treatment p21 CIP1/WAF1 , a potent inhibitor of cyclin-dependent kinase (CDK), has been identified as a key element in chemotherapeutic agent-and DNA-damaging agent-induced apoptosis (Stivala et al, 2012;Lee et al, 2013a). We previously reported that p21 is a critical regulator of combination treatmentinduced apoptosis (Li et al, 2014a). Thus, we next examined whether p21 expression was related to the sensitivity of cancer cells to apoptosis induced by tetrandrine/chloroquine…”

Activation of Caspase‐9/3 and Inhibition of Epithelial Mesenchymal Transition are Critically Involved in Antitumor Effect of Phytol in Hepatocellular Carcinoma Cells

“…Although liver transplantation, surgery, and interventional radiology, Sorafenib (or Nexavar) as a receptor tyrosine kinase inhibitor has been applied to over half of the patients with HCC for years, recent 1 year relative survival rate is less than 50% (Fukuda et al, 2014;Graf et al, 2014). Because the side effects of Sorafenib are known severe with erythema multifomre, hand-foot syndrome (Yang et al, 2008), diarrhea, and vomiting and nausea (Berk et al, 2013), recently, herbal drugs (Hu et al, 2013) or natural compounds (Huynh et al, 2014) are attractive for the prevention or treatment for HCC alone or by combination therapy with Sorafenib (Cao et al, 2011;Hu et al, 2013;Huynh et al, 2014;Li et al, 2014a).…”