Abstract 2092: Effects of Yi Sui Granules, an herbal medicine, on MDS/AML: Similar to decitabine or other mechanisms

Abstract

Abstract Objective Yi Sui Granules (YSG) has been clinically used and proved efficacious in patients with myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) for 25 years, however, its mechanism remains unclear. This study is to evaluate the effects of YSG on DNA methylation of AML/MDS. Methods and Results From cytotoxicity assays using CCK-8 method, we found out YSG inhibited SKM-1, HL-60, K-562 and CEM cells in a dose-dependent manner with an IC50 of 1.173±0.165 mg/ml, 1.70±0.2 mg/ml, 2.85±0.05 mg/ml, 1.70±0.2 mg/ml respectively. In vivo, decitabine inhibited tumor growth in terms of tumor volume and tumor weight but led to significant weight loss of SKM-1 xenographed BALB/c-nu mice. While YSG (50.69%) showed similar tumor weight inhibition rate to decitabine (56.64%) without side effects including body weight loss. To explore its mechanism, we discovered that DNA methyltransferase 1 (DNMT1) expression was significantly down-regulated(P<0.05) and SFRP5 gene was demethylated(P<0.01) after treated with either YSG or decitabine using RT-PCR, western blot and bisulfite amplicon sequencing methods. Furthermore, we found significant up-regulation of SFRP5 expression(P<0.05), down-regulation of Wnt3a protein(P<0.05) and β-catenin expression(P<0.05), as well as down-regulation of C-myc(P<0.05) and CyclinD1 expression(P<0.05) in decitabine group and YSG group. Equally interestingly, survival benefits were observed in YSG high-dose group but not in Decitabine group(P<0.05). Conclusion Similar to decitabine, YSG's suppression of SKM1 tumor may be related to the inhibition of DNMT1 expression, de-methylation of SFRP5 and up-regulation of SFRP5 expression, preventing Wnt3a from binding to Frizzled receptors, therefore inhibiting the abnormal activation of Wnt signaling, and down-regulating its target gene expression including C-myc and CyclinD1. Unlike decitabine, YSG prolong overall survival though other mechanisms, which will be further investigated in our future research. Corresponding Author: Jing Wang and Xinyi Chen, Address: No.5 Haiyuncang, Dongcheng District, Beijing, 100700, China; Email: Jing.Wang@bucm.edu.cn and chenxinyi0729@126.comAcknowledgement: This work was supported by the Young Scientist Fund (81503575) and Key Program (81630080) of National Natural Science Foundation of China, the Golden Bridge Project of Beijing Association for Science and Technology(ZZ20059) and the Elite Program of Dongcheng district of Beijing (2020-dchrcpyzz-38). Citation Format: Jing Wang, Chong Gao, Elizabeth Gullen, Jieya Wu, Xiaoyuan Zhang, Xinyi Chen. Effects of Yi Sui Granules, an herbal medicine, on MDS/AML: Similar to decitabine or other mechanisms [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2092.