Statins as New Targets for Cancer Therapy

Statins are well-known as cholesterol-lowering medication. They arecompetitive inhibitors of 3-hydroxy-3- methylglutaryl-coenzyme Areductase (HMGCR) which is the key enzyme in the mevalonate pathway.Mevalonate is the precursor of isoprenoids and cholesterol in thispathway. After statins blockage of HMGCR, the production of isoprenoidpyrophosphates (farnesyl diphosphate (FPP) and geranylgeranyldiphosphate (GGPP)) will be abolished. Besides lowering cholesterol,this inhibits the prenylation of small Rho GTPases and blocks theirtranslocation to the plasma membrane which results in attenuated cellgrowth. Therefore, statins are not only involved in lowering cholesterolbiosynthesis but also are involved in the activation of small Rho GTPase.Recently, a large cohort study has been investigated about the possiblebenefits of statins in cancer patients in approximately 200 000 individualsand showed a beneficial effect of long-term statin use on the survivalrate of patients with different types of cancers. In another investigationit has been reported a similar increase in survival time in glioblastomamultiform patients who had been taking statins for longer than one year.In the past five years, my group has shown that statins induce apoptoticcell death in a broad range of human tumor cells with different originsincluding breast cancer, lung cancer and brain tumor cell lines. Ourinvestigations have shown that statins induced intrinsic apoptosis cellin all of these cells affecting GGPP. In addition, our investigationshave shown that statins sensitize GBM cells to temozolomide inducedapoptosis via inhibition of autophagy flux. My group continues theinvestigation on the possible mechanism of statins on cancer cells forpossible future application of these medications as combination therapywith other chemotherapy agents in different types of cancer.Funding Agency: Saeid Ghavami and Shahla Shojaei were supported byHealth Science Foundation general operating grant. Shahla Shojaei wasalso supported by Mitacs Accelerate PDF.

کلیدواژه ها:

Statin ، Glioblastoma ، Temozolomide ، Prenylation ، Cancer therapy