Differential sensitivity of various pediatric cancers and squamous cell carcinomas to lovastatin-induced apoptosis: Therapeutic implications

3-Hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase is the rate-limiting enz yme of the mevalonate pathway, the diverse array of end products of which a re vital for a variety of cellular functions, including cholesterol synthes is and cell cycle progression. We showed previously that this enzyme holds a critical role in regulating tumor cell fate, including cell death, as its expression is down-regulated in response to retinoic acid, a potent antica ncer therapeutic, Indeed, direct inhibition of HMG-CoA reductase with lovas tatin, a competitive inhibitor of this enzyme, induced a pronounced apoptot ic response in neuroblastoma and acute myeloid leukemic cells, We have now extended this work and evaluated a wide variety and large number of tumor-d erived cell lines for their sensitivity to lovastatin-induced apoptosis, Th ese cell lines were exposed to a wide range (0-100 muM) of lovastatin for 2 days and assayed for cell viability using the 3,4,5-dimethyl thiazlyl-2,2, 5-diphenyltetrazolium bromide assay and the induction of apoptosis by flow cytometric and ultrastructural analyses. Lovastatin induced a pronounced ap optotic response in cells derived from juvenile monomyelocytic leukemia, pe diatric solid malignancies (rhabdomyosarcoma and medulloblastoma), and squa mous cell carcinoma of the cervix and of the head and neck. Interestingly, the subset of malignancies that are particularly sensitive to lovastatin-in duced apoptosis correspond to those tumor subtypes that are sensitive to th e biological and antiproliferative effects of retinoids in vitro, The natur e of the biologically active form of lovastatin has been challenged recentl y as the growth-inhibitory effects of this drug were attributed to its prod rug lactone form that does not inhibit HMG-CoA reductase function. In this report, we demonstrate that the apoptotic properties of lovastatin are trig gered by the open ring acid form that is a potent inhibitor of HMG-CoA redu ctase activity. Thus, we have identified a subset of tumors that are sensit ive to lovastatin-induced apoptosis and show HMG-CoA reductase as a potenti al therapeutic target of these cancers.