Triptolide plant compound could improve response to epigenetic cancer drugs

A natural plant compound could help overcome a mechanism that allows cancer cells to resist drugs designed to restore normal gene activity, according to researchers at the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center.

Their research found that triptolide, a compound derived from Tripterygium wilfordii (thunder god vine), can block an enzyme that breaks down DNA methyltransferase inhibitors (DNMT inhibitors) before they can take effect. 

Combining triptolide with the DNMT inhibitor decitabine significantly increased the drug’s ability to reactivate tumour suppressor genes and kill cancer cells in laboratory and animal models. The findings could lead to new approaches for overcoming resistance to these therapies and potentially extending their use to more cancer types.

“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, Professor of Oncology, Pathology and Radiation Oncology and Molecular Radiation Sciences at the Johns Hopkins Kimmel Cancer Center. 

Overcoming a defence against cancer drugs

DNA methylation is an epigenetic process that helps control which genes are switched on or off. Enzymes called DNA methyltransferases (DNMTs) add chemical tags known as methyl groups to DNA, regulating gene activity. 

Cancer cells can exploit this process by using abnormal DNA methylation to silence genes that would normally prevent uncontrolled cell growth.

DNMT inhibitors such as decitabine and azacitidine can reverse abnormal methylation, allowing previously silenced tumour suppressor genes to become active again. Although these drugs have been effective against certain blood cancers, including leukaemia and myelodysplastic syndromes, their success against solid tumours has been more limited.

To investigate why, the researchers screened chemical libraries for compounds that could overcome cellular defences against DNMT inhibitors. They identified triptolide as a potential candidate. 

Blocking an enzyme that destroys drugs

The team discovered that an enzyme called DCTPP1 can break down the active form of DNMT inhibitors before they become incorporated into DNA. This prevents the drugs from disrupting DNA methylation and restoring the activity of tumour suppressor genes. 

Triptolide inhibits DCTPP1, allowing more of the active drug to survive and reach its intended target.

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

The researchers found that combining triptolide with decitabine greatly enhanced gene reactivation and cancer cell death in laboratory experiments and animal models. They also found that higher DCTPP1 levels were associated with greater resistance to DNMT inhibitors.

Potential to expand epigenetic therapies

The findings add to earlier research by the Johns Hopkins team, which examined the structure of DCTPP1 and identified small molecules designed to inhibit the enzyme. Combining these experimental inhibitors with decitabine also increased the sensitivity of prostate cancer cells to the drug.

The latest study identified triptolide through a different approach, screening for compounds that enhanced decitabine’s effects before establishing DCTPP1 as the target.

“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.

Further research will now be needed to develop DCTPP1 inhibitors with the potency, safety and drug properties required for testing in humans.