Cerivastatin triggers tumor-specific apoptosis with higher efficacy than lovastatin

The statin family of drugs inhibits 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA ) reductase, the rate-limiting enzyme of the mevalonate pathway, and is use d clinically as a safe and effective approach in the control of hypercholes terolemia, We have shown previously (Dimitroulakos, J., Nohynek, D., Backwa y, K, L., Hedley, D, W., Yeger, H., Freedman, M.H., Minden, MD,, and Penn, L.Z. Increased sensitivity of acute myelogenous leukemias to lovastatin-ind uced apoptosis: a potential therapeutic approach. Blood, 93: 1308-1318, 199 9) that lovastatin, a prototypic member of the statin family, can induce ap optosis of human acute myeloid leukemia (AML) cells in a sensitive and spec ific manner. In the present study, we evaluated the relative potency and me chanism of action of the newer synthetic statins, fluvastatin, atorvastatin , and cerivastatin, to trigger tumor-specific apoptosis, Cerivastatin is at least 10 times more potent than the other statins at inducing apoptosis in AML cell lines. Cerivastatin-induced apoptosis is reversible with the addi tion of the immediate product of the HMG-CoA reductase reaction, mevalonate , or with a distal product of the pathway, geranylgeranyl pyrophosphate, Th is suggests protein geranylgeranylation is an essential downstream componen t of the mevalonate pathway for cerivastatin similar to lovastatin-induced apoptosis, The enhanced potency of cerivastatin expands the number of AML p atient samples as well as the types of malignancies, which respond to stati n-induced apoptosis with acute sensitivity. Cells derived from acute lympho cytic leukemia are only weakly sensitive to lovastatin cytotoxicity but sho w robust response to cerivastatin, Importantly, cerivastatin is not cytotox ic to nontransformed human bone marrow progenitors. These results strongly support the further testing of cerivastatin as a novel anticancer therapeut ic alone and in combination with other agents in vivo.