Turning a painkiller into a cancer killer

Without knowing exactly why, scientists have long observed that people who regularly take non-steroidal anti-inflammatory drugs (NSAIDs) like aspirin have lower incidences of certain types of cancer.

Now, in a study appearing in Cancer Cell on June 15, investigators at Sanford-Burnham Medical Research Institute (Sanford-Burnham) and their colleagues have figured out how one NSAID, called Sulindac, inhibits tumor growth. The study reveals that Sulindac shuts down cancer cell growth and initiates cell death by binding to nuclear receptor RXRá, a protein that receives a signal and carries it into the nucleus to turn genes on or off.

“Nuclear receptors are excellent targets for drug development,” explained Xiao-kun Zhang, Ph.D., professor at Sanford-Burnham and senior author of the study. “Thirteen percent of existing drugs target nuclear receptors, even though the mechanism of action is not always clear.”

RXRá normally suppresses tumors, but many types of cancer cells produce a truncated form of this nuclear receptor that does just the opposite. This study showed that shortened RXRá enhances tumor growth by stimulating other proteins that help cancer cells survive. Luckily, the researchers also found that Sulindac can be used to combat this deviant RXRá by switching off its pro-survival function and turning on apoptosis, a process that tells cells to self-destruct.

Sulindac is currently prescribed for the treatment of pain and fever, and to help relieve symptoms of arthritis. The current study demonstrates a new application for Sulindac as a potential anti-cancer treatment that targets truncated RXRá protein in tumors. However, some NSAIDs have gotten a lot of bad press for their potentially dangerous cardiovascular side effects. To overcome this limitation, the researchers tweaked Sulindac, creating a new version of the drug – now called K-80003 – that both decreases negative consequences and increases binding to truncated RXRá.

“Depending on the conditions, the same protein, such as RXRá, can either kill cancer cells or promote their growth,” Dr. Zhang said. “The addition of K-80003 shifts that balance by blocking survival pathways and sensitizing cancer cells to triggers of apoptosis.”

For more information about Sanford-Burnham research, visit www.beaker.sanfordburnham.org.

Original paper:

Zhou H, Liu W, Su Y, Wei Z, Liu J, Kolluri SK, Wu H, Cao Y, Chen J, Wu Y, Yan T, Cao X, Gao W, Molotkov A, Li W-G, Lin B, Zhang H-P, Yu J, Luo S-P, Zeng J-z, Duester G, Huang P-Q, Zhang X-k. NSAID Sulindac and Its Analog Bind RXRá and Inhibit RXRá-dependent AKT Signaling. Cancer Cell. Published online June 15, 2010.

About Sanford-Burnham Medical Research Institute

Sanford-Burnham Medical Research Institute (formerly Burnham Institute for Medical Research) is dedicated to discovering the fundamental molecular causes of disease and devising the innovative therapies of tomorrow. Sanford-Burnham, with operations in California and Florida, is one of the fastest-growing research institutes in the country. The Institute ranks among the top independent research institutions nationally for NIH grant funding and among the top organizations worldwide for its research impact. From 1999 – 2009, Sanford-Burnham ranked #1 worldwide among all types of organizations in the fields of biology and biochemistry for the impact of its research publications, defined by citations per publication, according to the Institute for Scientific Information. According to government statistics, Sanford-Burnham ranks #2 nationally among all organizations in capital efficiency of generating patents, defined by the number of patents issued per grant dollars awarded.

Sanford-Burnham utilizes a unique, collaborative approach to medical research and has established major research programs in cancer, neurodegeneration, diabetes, and infectious, inflammatory, and childhood diseases. The Institute is especially known for its world-class capabilities in stem cell research and drug discovery technologies. Sanford-Burnham is a nonprofit public benefit corporation. For more information, please visit www.sanfordburnham.org.