Low doses of the active form of vitamin D and non-steroidal anti-inflammatory drugs form one-two punch against prostate cancer cells

Sep 1 2005

Low doses of the active form of vitamin D and non-steroidal anti-inflammatory drugs, taken in combination, have been shown to act as a powerful one-two punch that knocks down the growth of prostate cancer cells.

In a study published in the journal "Cancer Research", scientists from Stanford University discovered that the amount of both -- activated vitamin D, or calcitriol, and the NSAIDs -- could be reduced by half to one-tenth the dosage to thwart prostate cancer cell growth in cell lines and primary tissue cultures.

If work in animal models and human trials confirm the findings, the drug combination may help to keep the NSAID family of drugs among the pharmaceutical choices for the prevention and treatment of cancer. This list includes ibuprofen, indomethacin and naproxen, in addition to other so-called COX-2 inhibitors linked to increased risk for cardiovascular disease, including Vioxx® and Celebrex®.

"NSAIDs have their own risks," said David Feldman, M.D., professor of Medicine in the Division of Endocrinology, Gerontology and Metabolism at the Stanford University School of Medicine. "So, we have to be careful even with lower doses and we still need to watch the patients very closely if we intend to keep them on these drugs for extended periods of time. But we are aiming to find doses that are less toxic and far more tolerable for the patient."

As outlined in their study, the Stanford scientists discovered that vitamin D, known as the "sunshine vitamin," works to limit the growth of prostate cancer cells by interfering with the same molecules attacked by NSAIDs -- the prostaglandin/COX-2 pathway.

Prostaglandins are responsible for activating the inflammatory response that results in pain and fever. NSAIDs work by blocking an enzyme called cyclooxygenase-2 or COX-2 which is essential for prostaglandin synthesis, thereby relieving some of the effects of pain and fever.

In this study, activated vitamin D or calcitriol was shown to act as a triple threat against this pathway, in prostate cancer cells:

• First, it limits the expression of a key enzyme needed to synthesize prostaglandins into COX-2.
• Second, it increases the expression of an enzyme that rapidly disassembles active prostaglandin molecules, thus promoting the breakdown of the hormone.
• Third, the scientists discovered that calcitriol inhibits the production of two cell receptors used by prostaglandins to regulate gene expression and control tumor proliferation.

While the scientists showed that activated vitamin D, calcitriol, works by itself to limit prostate cancer growth, it is equally effective in much smaller doses when used in combination with NSAIDs. Furthermore, calcitriol dramatically reduces the amount of NSAIDs necessary to curb prostate cancer cell growth.

This is particularly important now, in light of recent studies showing that some NSAIDs that are selective for COX-2 targeting, such as rofecoxib (Vioxx®) and celecoxib (Celebrex®), are linked to cardiovascular disease at their prescribed doses.

While their studies provide insight into cellular activities controlled by both calcitriol and the NSAIDs, Feldman and his colleagues remain cautious about advancing their new-found understanding of prostaglandin chemistry into patients.

"We need to verify that vitamin D and NSAIDs work in synergy not just in these cell lines, but also work in the same manner, in humans which have a vastly more complex physiology than simple cells in a culture plate," Feldman said.

Vitamin D is converted in the liver and kidney to the active form called calcitriol, a hormone that has widespread actions in the body. The Feldman laboratory used calcitriol in the experiments reported in the Cancer Research article. Vitamin D in the form available over the counter is useful for protection of bones, but would not achieve the therapeutic levels of calcitriol needed to inhibit cancer cell growth, since the body has mechanisms to limit its activation to calcitriol, Feldman explained.