HMG-CoA reductase inhibitors and the malignant cell: the statin family of drugs as triggers of tumor-specific apoptosis

Abstract

The statin family of drugs target HMG-CoA reductase, the ratelimiting enzyme of the mevalonate pathway, and have been used successfully in the treatment of hypercholesterolemia for the past 15 years. Experimental evidence suggests this key biochemical pathway holds an important role in the carcinogenic process. Moreover, statin administration in vivo can provide an oncoprotective effect. Indeed, in vitro studies have shown the statins can trigger cells of certain tumor types, such as acute myelogenous leukemia, to undergo apoptosis in a sensitive and specific manner. Mechanistic studies show bcl-2 expression is down-regulated in transformed cells undergoing apoptosis in response to statin exposure. In addition, the apoptotic response is in part due to the depletion of the downstream product geranylgeranyl pyrophosphate, but not farnesyl pyrophosphate or other products of the mevalonate pathway including cholesterol. Clinically, preliminary phase I clinical trials have shown the achievable plasma concentration corresponds to the dose range that can trigger apoptosis of tumor types in vitro. Moreover, little toxicity was evident in vivo even at high concentrations. Clearly, additional clinical trials are warranted to further assess the safety and efficacy of statins as novel and immediately available anti-cancer agents. In this article, the experimental evidence supporting a role for the statin family of drugs to this new application will be reviewed.

Bax activation and stress-induced apoptosis delayed by the accumulation of cholesterol in mitochondrial membranes

“…This mechanism could contribute at least in part to the proapoptotic activity of statins, which are inhibitors of the ratelimiting enzyme of the mevalonate pathway involved in the synthesis of cholesterol, and which are under clinical trial as chemotherapeutic agents. 39 Previous studies suggested that lipids modulate the process of MOM permeabilization; our in vitro and in vivo experiments now reveal that Bax oligomerization is tightly controlled by the physical properties of bilayers. MOM permeabilization is crucial for the completion of many apoptotic programmes, and it is becoming clear that its comprehension will require a better understanding of the process, integrating both protein and lipid partners.…”

The association between 3‐hydroxy‐3‐methylglutaryl conenzyme A inhibitor use and breast carcinoma risk among postmenopausal women

“…A population-based cohort study conducted by Olsen et al 9 comprising women of a wide age span, found no 13 The current study results are supportive of the growing body of laboratory data that suggests regular statin use may protect against certain cancers, including invasive breast carcinoma. 27 At least one statin, lovastatin, has been found to reduce mouse mammary tumor formation and metastatic diffusion of established mammary carcinoma. 25 Small clinical trials have evaluated the dosing and scheduling of statins as adjuncts to chemotherapeutic agents.…”

“…[23][24][25][26] Although not completely understood, many of the products of the mevalonate pathway are necessary for diverse cellular functions including the G 1 -Sphase transition of cell proliferation and the formation of cell membranes. 27 Statins may inhibit cancer cell growth and lead to apoptotic cell death through their inhibition of the mevalonate pathway, although other mechanisms also have been suggested. 27 To assess the association between statin use and invasive breast carcinoma, we analyzed data from a population-based, case-control study conducted among older women in western Washington State.…”

“…27 Statins may inhibit cancer cell growth and lead to apoptotic cell death through their inhibition of the mevalonate pathway, although other mechanisms also have been suggested. 27 To assess the association between statin use and invasive breast carcinoma, we analyzed data from a population-based, case-control study conducted among older women in western Washington State.…”

Statin use and cancer risk in the General Practice Research Database

“…Rodent studies indicate that statins are carcinogenic (Newman and Hulley, 1996). Other evidence, however, suggests that statins may inhibit the growth of cancer cells by triggering apoptosis (Muller et al, 1998;Dimitroulakos et al, 2002;Wong et al, 2002), inhibiting angiogenesis (Weis et al, 2002;Park et al, 2002), or impairing the metastatic process (Alonso et al, 1998;Kusama et al, 2002). We undertook a matched case -control study of the relation between statin use and cancer risk.…”