Exposure to a drug that disrupts cancer cells’ DNA appears to make prostate tumor cells more vulnerable to radiation therapy, according to City of Hope researchers. The findings, published in the April issue of Molecular Cancer Research, show the drug acts in an unexpected way.

Eric Radany, left, and Xufeng Chen explore methods to make tumors more sensitive to radiation therapy. (Photo by p.cunningham)

A team of researchers led by Xufeng Chen, M.D., staff scientist in the Department of Radiation Oncology, and Eric Radany, M.D., Ph.D., clinical associate professor of radiation oncology, studied the effects of low doses of a drug called valproic acid in the lab. They were surprised to find that the drug boosted the effects of an important protein in the body that suppresses cancer growth.

The protein, called p53, normally stifles cancer by driving tumor cells to kill themselves through a process called apoptosis. Cells overproduce p53 when exposed to genetic damage, such as that caused by therapeutic radiation. But some cancer cells harbor mutations in p53 that keep the protein from fighting cancer. That allows the cancers to grow unhampered.

The team found that valproic acid helps p53 do its job.

Valproic acid belongs to a group of drugs called histone deacetylase, or HDAC, inhibitors. In recent years, cancer researchers have explored the anticancer effects of these drugs, which disrupt the structure of cancer cells’ DNA.

Research has shown that HDAC inhibitors loosen coils of DNA in cancer cells, making

the DNA more open and vulnerable to radiation therapy. Questions remained, however, about exactly how the drugs improve radiation’s effectiveness.

The team found that valproic acid stabilizes a modified form of p53 that works through mitochondria, the tiny compartments in cells that generate cells’ energy. The newly stabilized p53 then drives cancer cells to die.

“This was certainly unexpected, since p53 normally works in the cell nucleus,” said Jeffrey Y.C. Wong, M.D., chair of the Department of Radiation Oncology and co-author on the study. “It opens up new possibilities for anticancer drug targets. The radiosensitization effects occur with low doses of HDAC inhibitors, which are more likely achieved at the tumor site in patients than higher doses.

“We are also interested in similar strategies in other tumor model systems.”

The team hopes to identify other drugs that boost radiation therapy as well as other ways p53 and similar proteins may increase cancer cells’ sensitivity to therapeutic radiation.

Patty Wong, senior research associate in the Department of Radiation Oncology, also contributed to the study.