Vitamin C promotes anti-leukemia of DZNep in acute myeloid leukemia

• Published in: Biochimica et biophysica acta. Molecular basis of disease Vol. 1868; no. 5; p. 166357
• Main Authors: Long, Bing, Shan, Yongli, Sun, Yanling, Wang, Tianyu, Li, Xudong, Huang, Ke, Zhang, Wenwen, He, Yi, Wen, Ruijuan, Li, Yuhang, Mai, Yuchan, Feng, Yashu, Zhang, Tian, Kang, Baoqiang, Zhang, Cong, Zhu, Yanling, Gu, Jiaming, Liu, Jiajun, Zhang, Xiangzhong, Pan, Guangjin
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.05.2022
• Subjects: 3-Deazaneplanocin-A; Acute myeloid leukemia; Adenosine - analogs & derivatives; Anti-leukemia; Ascorbic Acid - pharmacology; D-3-phosphoglycerate dehydrogenase; Enhancer of Zeste Homolog 2 Protein - genetics; Histone Methyltransferases; Humans; Leukemia, Myeloid, Acute - drug therapy; Leukemia, Myeloid, Acute - metabolism; Vitamin C; 3-Deazaneplanocin-A; D-3-phosphoglycerate dehydrogenase; Anti-leukemia; Acute myeloid leukemia; Vitamin C
• ISSN: 0925-4439; 1879-260X
• DOI: 10.1016/j.bbadis.2022.166357

The epigenetic treatment by 3-Deazaneplanocin A (DZNep), a histone methyltransferase inhibitor, shows great potential against acute myeloid leukemia (AML). However, the variant sensitivity and incomplete response to DZNep are commonly observed. Here, we reveal that vitamin C (Vc) dramatically promotes DZNep response against leukemic cells in different cell lines and primary AML samples. Vc enhances apoptosis and differentiation induced by DZNep in different AML cell lines in vitro and reduces leukemia progression in vivo. At the molecular level, Vc downregulates an enzyme of serine synthesis named D-3-phosphoglycerate dehydrogenase (PHGDH), as well as BCL2, an anti-apoptotic gene. Over-expression of PHGDH reverses the Vc-enhanced anti-leukemic effect of DZNep in AML cells. Therefore, our findings provide an effective approach to reduce the resistance against epigenetic treatment by Vc, which shows a potential improvement of their combination in AML patients. •Vc enhances anti-leukemia effect of DZNep in vitro and in vivo.•Vc promotes differentiation and maturation gene program in AML cells triggered by DZNep.•PHGDH is essential in Vc enhanced anti-leukemia effect of DZNep.