A natural plant compound may help overcome a built-in defense that allows many cancers to resist a class of drugs designed to restore normal gene activity, according to a study by researchers at the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center.

The researchers found that triptolide, a natural compound from Tripterygium wilfordii, commonly known as thunder god vine, blocks an enzyme called DCTPP1 that cancer cells can use to break down DNA methyltransferase inhibitors, or DNMT inhibitors, before the drugs can fully work. When researchers combined triptolide or related compounds with the DNMT inhibitor decitabine, it dramatically boosted the drug's ability to reactivate tumor suppressor genes and kill cancer cells in laboratory models.

The findings, published Aug. 26 in Nature Communications, suggest a potential strategy for overcoming resistance to DNMT inhibitors and expanding their use to more types of cancer.

"This gives us a potential way to remove one of the barriers that prevents these drugs from working effectively in many cancers," says senior study author Vasan Yegnasubramanian, M.D., Ph.D., professor of oncology, pathology, and radiation oncology and molecular radiation sciences at the Johns Hopkins Kimmel Cancer Center and director of inHealth Precision Medicine at Johns Hopkins Medicine.

An epigenetic process called DNA methylation is one of the ways cells control which genes are turned on or off. DNMTs are enzymes that add chemical tags called methyl groups to DNA, helping regulate whether genes are on or off. Cancer cells can hijack this biological process, using abnormal DNA methylation to shut down genes that normally help prevent uncontrolled cell growth.

Drugs such as decitabine and azacitidine, known as DNMT inhibitors, can help remove abnormal methylation and reactivate cancer-fighting genes. The drugs have been effective against certain blood cancers, including myelodysplastic syndromes and leukemia, but have had limited success against solid tumors, which can have built-in defenses that neutralize the therapies before they can begin to work, Yegnasubramanian explains.

Researchers screened chemical libraries for compounds that could disable these defenses and resensitize cancer cells to the drugs. Among the compounds they identified was triptolide, an active ingredient found in thunder god vine. In laboratory-grown cancer cells and animal models, triptolide significantly increased both the gene-regulating and cancer-killing effects of decitabine.

DNMT inhibitors such as decitabine must first be converted inside cells into an active form that can become incorporated into DNA. Once there, they interfere with enzymes that maintain DNA methylation, allowing previously silenced genes to become active again. However, DCTPP1 acts like a cellular shredder, destroying the active form of DNMT inhibitors before the drugs can be incorporated into DNA.

“Triptolide jams the shredder, inhibiting DCTPP1. By blocking this enzyme, the DNMT inhibitors survive, successfully integrating into the tumor DNA, allowing them to work as they are supposed to by inhibiting DNMTs, restoring the expression of crucial tumor suppressor genes and killing cancer cells,” says Yegnasubramanian.

The findings build on related research from the Johns Hopkins team published earlier this year. In that study, investigators examined the atomic structure of DCTPP1 and identified several classes of small molecules specifically designed to inhibit it. When the experimental inhibitors were combined with decitabine in prostate cancer cells, the cancer cells became more sensitive to the drug.

The new study reaches the same target from a different direction. Rather than starting with DCTPP1 and designing molecules to block it, researchers screened chemical libraries for compounds that enhanced decitabine's effects and discovered that triptolide did so by inhibiting DCTPP1.

Researchers also found that high levels of DCTPP1 were associated with resistance to DNMT inhibitors, providing further evidence that the enzyme may be an important source of cancer drug resistance and a potential target for making these drugs more effective.

“Combining these standard therapies with triptolide or its derivatives may give clinicians a rational strategy to overcome drug resistance, potentially expanding the reach of epigenetic therapy to a much broader range of cancers,” says Yegnasubramanian.

The researchers caution that the findings are preclinical. Their study tested triptolide and related compounds experimentally and does not establish that the herb itself is a cancer treatment. Additional research will be needed to develop DCTPP1 inhibitors with the potency, safety and drug properties needed for testing in people.

In addition to co-senior authors Yegnasubramanian and William Nelson, and lead author Jianyong Liu, other researchers were Qing-Li He, Jianya Zhou, Ajay M. Vaghasia, Roshan Chikarmane, Glenn Hauk, Archana Rachakonda, Nicole Castagna, Ruchama Steinberg, Minh-Tam Pham, Jordan Gregg, Alok Mishra, Yuhan Yang, Talha Anwar, Roy Elias, Pengshan Li, Jasmine Yun-Tong Kung, Anthony O'Donnell, Nicole Anders, Teresia Wanjiku, Philipp Nuhn, Joong Sup Shim, Hugh Giovinazzo, David M. Esopi, Kunhwa Kim, Jonathan Coulter, Rulin Wang, Michelle Rudek, Kathleen Gabrielson, Angelo De Marzo, James Berger and Jun Liu.

The research was supported by the National Institutes of Health/National Cancer Institute grants P50CA058236, R01CA183965, R01CA070196, P30CA006973, S10RR026824, UL1TR003098, Prostate Cancer Foundation Challenge Awards, the Patrick C. Walsh Koch Research Award, the Ellen B. Masenheimer Fellowship, the Flight Attendant Medical Research Institute and the Commonwealth Foundation.

Jianyong Liu, Jun Liu, William Nelson and Srinivasan Yegnasubramanian are inventors on a provisional patent related to this work.

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