Crotonoside exhibits selective post-inhibition effect in AML cells via inhibition of FLT3 and HDAC3/6
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Yu-Zhi Li1,*, Si Yu1,*, Pei-Ao Yan1, Dao-Yin Gong1, Fang-Li Wu2, Zhi He2, Yu-Yao Yuan2, An-Yan Zhao2, Xue Tang1, Ruo-Qi Zhang1, Cheng Peng1 and Zhi-Xing Cao1
1Pharmacy College, Chengdu University of Traditional Chinese Medicine, The Ministry of Education Key Laboratory of Standardization of Chinese Herbal Medicine, Key Laboratory of Systematic Research, Development and Utilization of Chinese Medicine Resources in Sichuan Province-Key Laboratory Breeding Base of Co-founded by Sichuan Province and MOST, Sichuan, China
2Second Clinical Medical College, Chengdu University of Traditional Chinese Medicine, Sichuan, China
*These authors have contributed equally to this work
Zhi-Xing Cao, email: [email protected]
Cheng Peng, email: [email protected]
Keywords: AML, crotonoside, FLT3, HDAC3, HDAC6
Received: February 10, 2017 Accepted: August 02, 2017 Published: September 08, 2017
Targeted therapies for the treatment of acute myeloid leukemia (AML), specifically the FLT3 inhibitors, have shown promising results. Nevertheless, it is very unlikely that inhibitors which target a single pathway will provide long-term disease control. Here, we report the characterization of crotonoside, a natural product extracted from Chinese medicinal herb, Croton, for the treatment of AML via inhibition of FLT3 and HDAC3/6. In vitro, crotonoside exhibited selective inhibition in AML cells. In vivo, crotonoside treatment at 70 and 35 mg/kg/d produced significant AML tumor inhibition rates of 93.5% and 73.6%, respectively. Studies on the anti-AML mechanism of crotonoside demonstrated a significant inhibition of FLT3 signaling, cell cycle arrest in G0/G1 phase, and apoptosis. In contrast to classic FLT3 inhibitor; sunitinib, crotonoside was able to selectively suppress the expression of HDAC3 and HDAC6 without altering the expression of other HDAC isoforms. Inhibitors of HDAC3 and HDAC6; RGFP966 and HPOB, respectively, also exhibited selective inhibition in AML cells. Furthermore, we established novel signaling pathways including HDAC3/NF-κB-p65 and HDAC6/c-Myc besides FLT3/c-Myc which are aberrantly regulated in the progression of AML. In addition, crotonoside alone or the combination of sunitinib/RFP966/HPOB exhibited a significant post-inhibition effect in AML cells by the inhibition of FLT3 and HDAC3/6. Inhibitors targeting the FLT3 and HDAC3/6 might provide a more effective treatment strategy for AML. Taken together, the present study suggests that crotonoside could be a promising candidate for the treatment of AML, and deserves further investigations.
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