Xanthohumol as a potential therapeutic strategy for acute myeloid leukemia: Targeting the FLT3/SRPK1 signaling axis
Duan-Na Zhanga, Wen-Ya Yanga, Xiao-Xue Hua, Xiao-Min-Ting Songa,b, Chuan-Jie Guoa,c, Fu Pengd, Yu-Zhi Lia,**, Zhi-Xing Caoa*
a The State Key Laboratory of Southwest Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
b State Key Laboratory Breeding Base of Systematic Research, Development and Utilization of Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
c School of Basic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, China
d West China School of Pharmacy, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
Xanthohumol (XN) is an isoprene chalcone found in hops (Humulus lupulus L.), a food ingredient with a wide range of pharmacological activities. The aim of this study was to reveal the therapeutic effect of XN on acute myeloid leukemia (AML) and the potential underlying molecular mechanism. Through network pharmacology analysis, molecular docking, and HTRF determination, XN was shown to inhibit the kinase activities of FLT3 and SRPK1 by targeting their ATP-binding domains, with IC50 values of 1.51 ± 0.44 μM and 0.37 ± 0.15 μM, respectively. By inhibiting AML cell proliferation, promoting apoptosis, regulating autophagy, and inhibiting invasion, XN, which targets the unique FLT3/SRPK1 signaling pathway, exerts anti-AML effects. XN also significantly inhibited FLT3 inhibitor-resistant AML cells and exhibited synergistic interactions with gilteritinib. Moreover, XN at 40 mg/kg effectively inhibited the growth of AML subcutaneous tumors with good tolerance. These results suggest that XN could be a promising therapeutic agent for AML treatment. XN effectively targets the FLT3/SRPK1 signaling axis, demonstrating strong anti-AML effects and offering a potent strategy to address AML.
Keywords: Acute myeloid leukemia, Apoptosis, FLT3/SRPK1, Xanthohumol