Combination regimen with statins and NSAIDs: A promising strategy for cancer chemoprevention

Abstract

Statins and nonsteroidal antiinflammatory drugs (NSAIDs) are commonly prescribed for lowering cholesterol and antiinflammation, respectively. Recently, their potential roles as cancer chemopreventive agents have been subject to intensive studies. Human trials have not provided conclusive results on the protective effects of statins against different cancers, while more convincing results have been observed for cancer preventive effects of NSAIDs, especially on colorectal cancer. A promising strategy to enhance the cancer preventive efficacy of statins and NSAIDs is to use them in combination, which may produce synergy and lower the dose required for each agent. This strategy is of particular interest for potential use of low doses of statins and NSAIDs on a long-term basis for cancer chemoprevention; increased risks for gastrointestinal and cardiovascular side effects associated with the use of NSAIDs have been observed in colorectal cancer chemopreventive trials. This article reviews the evidence for the cancer preventive actions of statins and NSAIDs, as well as their possible synergistic action and the mechanisms involved. ' 2008 Wiley-Liss, Inc.Key words: statins; NSAIDs; cancer chemoprevention While the mortality from major chronic diseases, such as cardiovascular and cerebrovascular diseases, has decreased substantially during the past half century in the United States, the mortality from cancer has just begun to show a slight decrease. Cancer has become the number one killer of both men and women under age 85 years in the United States.1 A promising approach to controlling cancer is to prevent it before malignant events have occurred.2 Cancer chemoprevention refers to the use of natural or synthetic substances to inhibit, retard or reverse the carcinogenesis.3 A wealth of evidence from preclinical studies have convincingly demonstrated the cancer preventive efficacy of various agents in different animal models. However, the data from observational, case-control, cohort studies, and randomized trials in humans have overall demonstrated mixed results. Statins and nonsteroidal antiinflammatory drugs (NSAIDs) have been reported to be potential cancer chemopreventive agents. This review focuses on an attractive approach of chemoprevention using the combination of statins and NSAIDs. Statin and cancer chemopreventionStatins are small-molecule inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, which are widely used as cholesterol-lowering drugs. Besides their use in the treatment of lipid disorders, statins have showed anticarcinogenic activities in many in vitro and in vivo preclinical studies, and attracted much attention in exploring their roles in cancer chemoprevention. Several observational human studies reported potential protective effects of statin use against overall risk of cancer, 4-6 whereas other studies did not 7,8 (Table I). In a case-control study in Quebec, Canada, statin use was found to be associated with a 28% reduction in the risk of developing cancer (RR 5 0.72, 95% ...

Simvastatin sensitizes human gastric cancer xenograft in nude mice to capecitabine by suppressing nuclear factor-kappa B-regulated gene products

“…Simvastatin has been used in combination therapy with several chemotherapeutic agents/targeted therapies such as farnesyl transferase inhibitors, EGFR inhibitors geftinib and cetuximab, doxorubicin, non-steroidal anti-inflammatory drugs, and vitamin-E gamma tocotrienol in diverse tumor cell lines and in vivo cancer models [10,13,16,[32][33][34] but so far its effects either alone or in combination with anticancer therapies in gastric cancer mouse models has never been studied before. Recently conducted couple of populationbased case-control studies clearly indicate that statins uptake can reduce the risk of gastric cancer [35], and our findings provide further scientific evidence that simvastatin has significant potential for the treatment of gastric cancer and its effects can be further enhanced by capecitabine.…”

Anticancer Agents in Combination with Statins

“…In azoxymethane induced colon carcinogenesis rat model, the low dose combination of atorvastatin and celecoxib decreased the incidence of adenocarcinomas by 71% [61]. Atorvastatin combination with celecoxib decreased the membrane association of RhoA [58,62]. Here, atorvastatin is preventing the prenylation of RhoA and celecoxib is synergizing the effect and causing cell cycle arrest.…”

“…This combination reduced the risk of colorectal cancer by 62% if used for 5 or more years [58]. Moreover, NSAIDS with statins also lowers the risk of prostate cancer if used for 5 years [59].…”

“…Long term use may cause gastro intestinal and cardiovascular adverse effects. To avoid this problem, we can combine the NSIADS with other chemotherapeutic agents and can reduce their dose [58].…”

Constitutive Overexpression of the Oncogene Racl in the Airway of Recurrent Respiratory Papillomatosis Patients Is a Targetable Host-Susceptibility Factor

“…It is expressed at elevated levels in many cancers, including lung and head and neck (17,18). Celecoxib is a selective COX-2 inhibitor that inhibits synthesis of PGE 2 and has been used in multiple clinical chemoprevention studies (19). E6 and E7 are early genes that are not only essential to the viral lifecycle, but code for the proteins most implicated in HPV-induced carcinogenesis (20,21).…”