A novel SAHA-bendamustine hybrid induces apoptosis of leukemia cells
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Jing Yu1, Shaowei Qiu1, Qiufu Ge2, Ying Wang1, Hui Wei1, Dianwu Guo2, Shuying Chen1, Shuang Liu1, Shouyun Li1, Haiyan Xing1, Qing Rao1, Jianxiang Wang1 and Min Wang1
1 State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
2 Hangzhou Minsheng Institute of Pharmaceutical Research, Hangzhou, China
Jianxiang Wang, email:
Min Wang, email:
Keywords: histone deacetylase inhibitor; alkylating agent; hybrid; leukemia; apoptosis
Received: December 30, 2014 Accepted: April 23, 2015 Published: May 08, 2015
Hybrid anticancer drugs are of great therapeutic interests as they can potentially overcome the deficiencies of conventional chemotherapy drugs and improve the efficacy. Many studies have revealed that the combination of histone deacetylase inhibitors (HDACi) and alkylating agents have synergistic effects. We reported a novel hybrid NL-101, in which the side chain of bendamustine was replaced with the hydroxamic acid of HDACi vorinostat (SAHA). NL-101 exhibited efficient anti-proliferative activity on myeloid leukemia cells especially Kasumi-1 and NB4 cells, accompanied by S phase arrest and caspase-3 dependent apoptosis. Importantly, it presented both the properties of HDAC inhibition and DNA damaging, as assessed by the acetylation of histone H3 and DNA double-strand breaks marker γ-H2AX. NL-101 also down-regulated the expression of anti-apoptotic protein Bcl-xL which was involved in the mitochondrial death pathway. Meanwhile, NL-101 induced apoptosis and DNA damage in primary cells from acute myeloid leukemia (AML) patients. NL-101 treatment could significantly prolong the survival time of t(8;21) leukemia mice with enhanced efficacy than bendamustine. These data demonstrate that NL-101 could be a potent and selective agent for leukemia treatment.
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