Lani
06-15-2010, 09:56 AM
IT IS CALLED SULINDAC OR CLINORIL
HAS BEEN ON THE MARKET MORE THAN 30 YEARS
Turning a Painkiller into a Cancer Killer
[Sanford Burnham Institute for Medical Research]
LA JOLLA, Calif., June 15, 2010 - 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 RXRα, 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."
RXRα 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 RXRα 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 RXRα 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 RXRα 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 RXRα.
"Depending on the conditions, the same protein, such as RXRα, 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."
ABSTRACT: NSAID Sulindac and Its Analog Bind RXRα and Inhibit RXRα-Dependent AKT Signaling
[Cancer Cell]
Nonsteroidal anti-inflammatory drugs (NSAIDs) exert their anticancer effects through cyclooxygenase-2 (COX-2)-dependent and independent mechanisms. Here, we report that Sulindac, an NSAID, induces apoptosis by binding to retinoid X receptor-α (RXRα). We identified an N-terminally truncated RXRα (tRXRα) in several cancer cell lines and primary tumors, which interacted with the p85α subunit of phosphatidylinositol-3-OH kinase (PI3K). Tumor necrosis factor-α (TNFα) promoted tRXRα interaction with the p85α, activating PI3K/AKT signaling. When combined with TNFα, Sulindac inhibited TNFα-induced tRXRα/p85α interaction, leading to activation of the death receptor-mediated apoptotic pathway. We designed and synthesized a Sulindac analog K-80003, which has increased affinity to RXRα but lacks COX inhibitory activity. K-80003 displayed enhanced efficacy in inhibiting tRXRα-dependent AKT activation and tRXRα tumor growth in animals.
HAS BEEN ON THE MARKET MORE THAN 30 YEARS
Turning a Painkiller into a Cancer Killer
[Sanford Burnham Institute for Medical Research]
LA JOLLA, Calif., June 15, 2010 - 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 RXRα, 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."
RXRα 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 RXRα 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 RXRα 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 RXRα 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 RXRα.
"Depending on the conditions, the same protein, such as RXRα, 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."
ABSTRACT: NSAID Sulindac and Its Analog Bind RXRα and Inhibit RXRα-Dependent AKT Signaling
[Cancer Cell]
Nonsteroidal anti-inflammatory drugs (NSAIDs) exert their anticancer effects through cyclooxygenase-2 (COX-2)-dependent and independent mechanisms. Here, we report that Sulindac, an NSAID, induces apoptosis by binding to retinoid X receptor-α (RXRα). We identified an N-terminally truncated RXRα (tRXRα) in several cancer cell lines and primary tumors, which interacted with the p85α subunit of phosphatidylinositol-3-OH kinase (PI3K). Tumor necrosis factor-α (TNFα) promoted tRXRα interaction with the p85α, activating PI3K/AKT signaling. When combined with TNFα, Sulindac inhibited TNFα-induced tRXRα/p85α interaction, leading to activation of the death receptor-mediated apoptotic pathway. We designed and synthesized a Sulindac analog K-80003, which has increased affinity to RXRα but lacks COX inhibitory activity. K-80003 displayed enhanced efficacy in inhibiting tRXRα-dependent AKT activation and tRXRα tumor growth in animals.