Phenoxodiol, an isoflavone analogue, can induce cell death in 100 percent of human ovarian cancer cells, including cell lines that are resistant to standard agents such as paclitaxel and carboplatin, according to an article in the May issue of the journal Oncogene.
The drug works by altering a signal pathway in cancerous cells that does not allow unhealthy cells to die. These general findings on phenoxodiol’s effectiveness at reopening the pathway for apoptosis indicate that the drug could be successful at treating other cancer types as well.
A total of 5 phase I human trials with phenoxodiol have been completed; they showed few if any side effects of treatment. Preliminary data from 1 trial found that over half the patients treated showed some degree of response: The patients had different types of advanced cancer refractory to chemotherapy. A phase II trial is underway for women with chemoresistant ovarian cancer.

In the current study, the research team determined that phenoxodiol induces cell death in primary ovarian cancer cells by inducing apoptosis and that it restores the sensitivity of ovarian cancer cells to Fas-mediated apoptosis, one of the main cell-death pathways for cancer cells that is otherwise turned off in ovarian cancer cells.

"For years Yale researchers have studied cells of woman patients with chemoresistant ovarian cancer," said Graham Kelly, PhD., chairman of the company that produces phenoxodiol. "They used these samples to predict which chemotherapy agents are most likely to work on which particular women. So when phenoxodiol was tested, they were surprised to see that our compound kills all ovarian cancer cells, regardless of their immunity to chemo agents."

Gil Mor, M.D., the senior author of the study, believes apoptosis occurs because phenoxodiol blocks the abnormal activity of two key signaling pathways, known as FLIP and XIAP, that inhibits cell death in the ovarian cancer cells.

The researchers also tested phenoxodiol in mice and found that when dosed at 20mg/kg every day for 6 days there was a 3-fold reduction in tumor mass compared with tumor size in a control group. No side effects were noted.

The potential clinical significance of the research findings is clear: Although the initial response to chemotherapy in ovarian cancer is greater than 80 percent, the majority of tumors ultimately recur due to resistance to chemotherapy.

"Phenoxodiol may unlock a mystery that has been plaguing cancer researchers -- how to get a cancer cell to die when it for some reason has been programmed to live," said Mor. "A key objective in cancer therapy is to restore sensitivity to apoptosis. It's our hope that phenoxodiol does that."