All-trans retinoic acid enhances the cytotoxic effect of decitabine on myelodysplastic syndromes and acute myeloid leukaemia by activating the RARα-Nrf2 complex

Autor: Lu Wang, Qi Zhang, Li Ye, Xingnong Ye, Wenli Yang, Hua Zhang, Xinping Zhou, Yanling Ren, Liya Ma, Xiang Zhang, Chen Mei, Gaixiang Xu, Kongfei Li, Yingwan Luo, Lingxu Jiang, Peipei Lin, Shuanghong Zhu, Wei Lang, Yuxia Wang, Chuying Shen, Yueyuan Han, Xiaozhen Liu, Haiyang Yang, Chenxi Lu, Jie Sun, Jie Jin, Hongyan Tong
Rok vydání: 2022
Předmět:
Zdroj: British Journal of Cancer. 128:691-701
ISSN: 1532-1827
0007-0920
DOI: 10.1038/s41416-022-02074-0
Popis: Background Decitabine (DAC) is used as the first-line therapy in patients with higher-risk myelodysplastic syndromes (HR-MDS) and elderly acute myeloid leukaemia (AML) patients unsuitable for intensive chemotherapy. However, the clinical outcomes of patients treated with DAC as a monotherapy are far from satisfactory. Adding all-trans retinoic acid (ATRA) to DAC reportedly benefitted MDS and elderly AML patients. However, the underlying mechanisms remain unclear and need further explorations from laboratory experiments. Methods We used MDS and AML cell lines and primary cells to evaluate the combined effects of DAC and ATRA as well as the underlying mechanisms. We used the MOLM-13-luciferase murine xenograft model to verify the enhanced cytotoxic effect of the drug combination. Results The combination treatment reduced the viability of MDS/AML cells in vitro, delayed leukaemia progress, and extended survival in murine xenograft models compared to non- and mono-drug treated models. DAC application as a single agent induced Nrf2 activation and downstream antioxidative response, and restrained reactive oxygen species (ROS) generation, thus leading to DAC resistance. The addition of ATRA blocked Nrf2 activation by activating the RARα-Nrf2 complex, leading to ROS accumulation and ROS-dependent cytotoxicity. Conclusions These results demonstrate that combining DAC and ATRA has potential for the clinical treatment of HR-MDS/AML and merits further exploration.
Databáze: OpenAIRE
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