Triptolide sensitizes cancer cells to nucleoside DNA methyltransferase inhibitors through inhibition of DCTPP1-mediated cell-intrinsic resistance

Abnormal DNA hypermethylation mediated by DNA methyltransferases (DNMT) is a nearly universal hallmark of human cancers. However, while DNA methyltransferase inhibitors (DNMTi) such as decitabine and azacitidine are effective in treating myelodysplatic syndrome/leukemia, they have had limited utility for the majority of other cancers. Through a chemical library screen, we identify that triptolide, a diterpenoid epoxide from Tripterygium wilfordii, and multiple of its analogs, significantly augment the epigenetic and anti-cancer effects of decitabine in vitro and in vivo. These effects are attributable to inhibition of DCTPP1-mediated cleavage of 5-aza-deoxycytidine triphosphate, the convergent activated metabolite of nucleoside DNMTi, leading to enhanced drug incorporation into genomic DNA, increased DNMT degradation, enhanced DNA demethylation and associated transcriptional reprogramming. We show that high DCTPP1 expression mediates cell-intrinsic resistance to nucleoside DNMTi, and that triptolide and its analogs could overcome this resistance. These findings nominate combining DNMTi with triptolide or its analogs as a rational cancer therapeutic strategy. Abnormal DNA hypermethylation is common in cancer, but DNA methyltransferase inhibitors show limited activity in many tumors. Here, the authors employ a chemical library screen to identify triptolide as an active agent that enhances these drugs by blocking DCTPP1, increasing drug incorporation into DNA, promoting demethylation and epigenetic reprogramming, and improving anti-cancer effects.

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Journal
Nature Communications
Published
2026-08-26
DOI
https://doi.org/10.1038/s41467-026-76852-2
Citations
5
Primary Topic
Natural Compounds in Disease Treatment
Type
article
Field-Weighted Citation Impact
25.20

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article

Triptolide sensitizes cancer cells to nucleoside DNA methyltransferase inhibitors through inhibition of DCTPP1-mediated cell-intrinsic resistance

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5 citations
Nature Communications
Natural Compounds in Disease Treatment
25.20
article

Triptolide sensitizes cancer cells to nucleoside DNA methyltransferase inhibitors through inhibition of DCTPP1-mediated cell-intrinsic resistance

Nicole M. Anders, Jianya Zhou, Joong Sup Shim, Pengshan Li, Michelle A. Rudek, Jun O. Liu, Glenn Hauk, Jordan Gregg, William G. Nelson, David Esopi, Jianying Zhou, Ruchama C. Steinberg, Ajay Vaghasia, Hugh Giovinazzo, James M. Berger, Anthony C. O'Donnell, Teresia Wanjiku, Nicole Castagna, Minh‐Tam Pham, Qingli He, Kathleen Gabrielson, Angelo M. De Marzo, Kunhwa Kim, Srinivasan Yegnasubramanian, Roshan Chikarmane, Archana Rachakonda, Rulin Wang, Jianyong Liu, Jasmine Yun-Tong Kung, Yuhan Yang, Philipp Nuhn, Alok Mishra, Roy Elias, Talha Anwar, Jonathan Coulter
article en
5 citations

Abstract

Abnormal DNA hypermethylation mediated by DNA methyltransferases (DNMT) is a nearly universal hallmark of human cancers. However, while DNA methyltransferase inhibitors (DNMTi) such as decitabine and azacitidine are effective in treating myelodysplatic syndrome/leukemia, they have had limited utility for the majority of other cancers. Through a chemical library screen, we identify that triptolide, a diterpenoid epoxide from Tripterygium wilfordii, and multiple of its analogs, significantly augment the epigenetic and anti-cancer effects of decitabine in vitro and in vivo. These effects are attributable to inhibition of DCTPP1-mediated cleavage of 5-aza-deoxycytidine triphosphate, the convergent activated metabolite of nucleoside DNMTi, leading to enhanced drug incorporation into genomic DNA, increased DNMT degradation, enhanced DNA demethylation and associated transcriptional reprogramming. We show that high DCTPP1 expression mediates cell-intrinsic resistance to nucleoside DNMTi, and that triptolide and its analogs could overcome this resistance. These findings nominate combining DNMTi with triptolide or its analogs as a rational cancer therapeutic strategy. Abnormal DNA hypermethylation is common in cancer, but DNA methyltransferase inhibitors show limited activity in many tumors. Here, the authors employ a chemical library screen to identify triptolide as an active agent that enhances these drugs by blocking DCTPP1, increasing drug incorporation into DNA, promoting demethylation and epigenetic reprogramming, and improving anti-cancer effects.

Nature Communications
Johns Hopkins University (US), University of Macau (MO), Johns Hopkins Medicine (US), Sidney Kimmel Comprehensive Cancer Center (US), First Affiliated Hospital Zhejiang University (CN), Zhejiang University (CN)
Foundation for the National Institutes of Health, U.S. Department of Energy, Prostate Cancer Foundation, Flight Attendant Medical Research Institute, Johns Hopkins University, National Institutes of Health, Office of Science, National Cancer Institute, National Institute of General Medical Sciences, Biological and Environmental Research, Brookhaven National Laboratory
Good health and well-being
Openalex Percentile: Top 1%
Natural Compounds in Disease Treatment
25.20
DOIOpen Access PDFOpenAlex
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