Journal
CANCER SCIENCE
Volume 113, Issue 9, Pages 3032-3043Publisher
WILEY
DOI: 10.1111/cas.15470
Keywords
cancer plasticity; energy metabolism reprogramming; ovarian cancer; redox homeostasis; tumor microenvironment
Categories
Funding
- National Natural Scientific Foundation of China [81770148]
- Guangdong Medical Research Foundation [A2022159]
- Scientific Research Start Plan of Shunde Hospital, Southern Medical University [YNZX0002, YNZX0003, SRSP2019002, SRSP2019003]
- Shunde Hospital of Southern Medical University [2019014]
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Metabolic reprogramming is a hallmark of malignant tumors. This study demonstrates that Silybin, a nontoxic flavonoid, exhibits notable anti-tumor effects on human ovarian cancer cells. Silybin targets and inhibits IDH1 in ovarian cancer cells, leading to reduced reactive oxygen species generation.
Metabolic reprogramming is a sign of malignant tumors, and targeting the metabolism of tumor cells has become a promising therapeutic approach. Here, we report that Silybin (a nontoxic flavonoid commonly used for liver protection) exhibits prominent anti-tumor effects on human ovarian cancer cells. Treatment of an ovarian cancer cell line with Silybin interfered with glutamine metabolism and the tricarboxylic acid cycle. We applied the drug affinity responsive target stability approach to show that Silybin binds to isocitrate dehydrogenase 1 (IDH1). This combination leads to reduced phosphorylation of IDH1 and inhibits enzyme activity. IDH1 dysfunction significantly increases the ratio of NADP/NADPH in the cell, causing an increase in reactive oxygen species generation. Immunohistochemistry demonstrated that IDH1 was increased in ovarian cancer samples compared with normal para-tumoral tissues. Xenograft murine experiments indicated that Silybin administered orally suppressed the growth of the tumor formed by ovarian cancer cells. In combination, our data strongly suggest that Silybin targets IDH1 in ovarian cancer cells and may be a novel treatment candidate.
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