Homoharringtonine suppresses imatinib resistance via the Bcl-6/p53 pathway in chronic myeloid leukemia cell lines

Abstract

// Qian Wang 1 , Wei Ding 1 , Yihan Ding 1 , Jingjing Ma 1 , Zhaoye Qian 2 , Jingxian Shao 2 and Yufeng Li 1 1 Department of Hematology, Huai’an First People’s Hospital, Nanjing Medical University, Huai’an, 223300, China 2 Department of Oncology, Huai’an First People’s Hospital, Nanjing Medical University, Huai’an, 223300, China Correspondence to: Yufeng Li, email: liyufeng99@netease.com Keywords: Bcl-6/p53 pathway, homoharringtonine, imatinib, drug-resistance, chronic myeloid leukemia Received: March 04, 2016      Accepted: March 08, 2017      Published: March 30, 2017 ABSTRACT Background: The anti-leukemic mechanism of homoharringtonine (HHT) differs from that of IM, and HHT is one of the most useful agents for use in patients with IM resistance or intolerance. The Bcl-6/p53 pathway has been shown to regulate the sensitivity of tumor cells to antitumor drugs. We tested whether HHT blocked the Bcl-6/p53 pathway in order to promote the apoptosis of IM-resistant cells in vitro and in vivo . Results: Ph+ acute lymphoblastic leukemia (ALL) cells and IM-resistant chronic myeloid leukemia (CML) cells showed high expression of Bcl-6 protein. Bcl-6 mediated the upregulation of p53, and and Bcl-6 induced growth inhibition of IM-resistant cells as well as its apoptosis by targeting p53. In addition, Bcl-6 was downregulated moderately after HHT treatment in different cells. The Bcl-6 expression was significantly increased in patients with CML when compared with healthy subjects. Furthermore, the expression of Bcl-6 was higher in patients with CML-blastic phase (CML-BP) than in those with CML-chronic phase (CML-CP). Methods: The inhibitory effect of drugs on cell growth was detected by Cell Counting Kit-8 (CCK-8), The apoptosis rate and the cell cycle were investigated by flow cytometry. The expression of Bcl-6, p53, Bcl-2, caspase9, and caspase3 proteins was assayed by western blot, Real- Time PCR (qPCR) detect Bcl-6 and p53 mRNA. Conclusions: HHT can suppress the growth and induce apoptosis of IM-resistant cells, the mechanism of which is associated with blocking of the Bcl-6/p53 pathway. Our results could offer a theoretical explanation for HHT use in patients with IM resistance or intolerance.