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Spotlight on Molecular Targeted Therapy

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 rate-limiting 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.

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References

  1. Schmitt CA, Lowe SW . Apoptosis and therapy J Pathol 1999 187: 127–137

    Article  CAS  PubMed  Google Scholar 

  2. Kaufmann SH, Gores GJ . Apoptosis in cancer: cause and cure Bioessays 2000 22: 1007–1017

    Article  CAS  PubMed  Google Scholar 

  3. Penn LZ . Apoptosis modulators as cancer therapeutics Curr Opin Invest Drugs 2001 2: 684–692

    CAS  Google Scholar 

  4. Schimmer AD, Hedley DW, Penn LZ, Minden MD . Receptor and mitochondrial-mediated apoptosis in acute leukemia – a translational review Blood 2001 98: 3541–3553

    Article  CAS  PubMed  Google Scholar 

  5. Budihardjo I, Oliver H, Lutter M, Luo X, Wang X . Biochemical pathways of caspase activation during apoptosis Annu Rev Cell Dev Biol 1999 15: 269–290

    Article  CAS  PubMed  Google Scholar 

  6. Ashkenazi A, Dixit VM . Apoptosis control by death and decoy receptors Curr Opin Cell Biol 1999 11: 255–260

    Article  CAS  PubMed  Google Scholar 

  7. Reed JC . Bcl-2 family proteins Oncogene 1998 17: 3225–3236

    Article  PubMed  Google Scholar 

  8. Evan G, Littlewood T . A matter of life and cell death Science 1998 281: 1317–1322

    Article  CAS  PubMed  Google Scholar 

  9. Gross A, McDonnell JM, Korsmeyer SJ . BCL-2 family members and the mitochondria in apoptosis Genes Dev 1999 13: 1899–1911

    Article  CAS  PubMed  Google Scholar 

  10. Raff M . Cell suicide for beginners Nature 1998 396: 119–122

    Article  CAS  PubMed  Google Scholar 

  11. Earnshaw WC, Martins LM, Kaufmann SH . Mammalian caspases: structure, activation, substrates, and functions during apoptosis Annu Rev Biochem 1999 68: 383–424

    Article  CAS  PubMed  Google Scholar 

  12. Hanahan D, Weinberg RA . The hallmarks of cancer Cell 2000 100: 57–70

    Article  CAS  PubMed  Google Scholar 

  13. Kaufmann SH, Earnshaw WC . Induction of apoptosis by cancer chemotherapy Exp Cell Res 2000 256: 42–49

    Article  CAS  PubMed  Google Scholar 

  14. Goldstein JL, Brown MS . Regulation of the mevalonate pathway Nature 1990 343: 425–430

    Article  CAS  PubMed  Google Scholar 

  15. Russell DW . Cholesterol biosynthesis and metabolism Cardiovasc Drugs Ther 1992 6: 103–110

    Article  CAS  PubMed  Google Scholar 

  16. Olson RE, Rudney H . Biosynthesis of ubiquinone Vitam Horm 1983 40: 1–43

    Article  CAS  PubMed  Google Scholar 

  17. Sinensky M . Recent advances in the study of prenylated proteins Biochim Biophys Acta 2000 1484: 93–106

    Article  CAS  PubMed  Google Scholar 

  18. Kabakoff BD, Doyle JW, Kandutsch AA . Relationships among dolichyl phosphate, glycoprotein synthesis, and cell culture growth Arch Biochem Biophys 1990 276: 382–389

    Article  CAS  PubMed  Google Scholar 

  19. Farnier M, Davignon J . Current and future treatment of hyperlipidemia: the role of statins Am J Cardiol 1998 82: 3J–10J

    Article  CAS  PubMed  Google Scholar 

  20. Pedersen TR . Pro and con: low-density lipoprotein cholesterol lowering is and will be the key to the future of lipid management Am J Cardiol 2001 87: 8–12

    Article  Google Scholar 

  21. Davidson MH . Safety profiles for the HMG-CoA reductase inhibitors: treatment and trust Drugs 2001 61: 197–206

    Article  CAS  PubMed  Google Scholar 

  22. Illingworth DR, Tobert JA . HMG-CoA reductase inhibitors Adv Protein Chem 2001 56: 77–114

    Article  CAS  PubMed  Google Scholar 

  23. Buchwald H . Cholesterol inhibition, cancer, and chemotherapy Lancet 1992 339: 1154–1156

    Article  CAS  PubMed  Google Scholar 

  24. Larsson O . HMG-CoA reductase inhibitors: role in normal and malignant cells Crit Rev Oncol Hematol 1996 22: 197–212

    Article  CAS  PubMed  Google Scholar 

  25. Elson CE, Peffley DM, Hentosh P, Mo H . Isoprenoid-mediated inhibition of mevalonate synthesis: potential application to cancer Proc Soc Exp Biol Med 1999 221: 294–311

    Article  CAS  PubMed  Google Scholar 

  26. Kawata S, Takaishi K, Nagase T, Ito N, Matsuda Y, Tamura S, Matsuzawa Y, Tarui S . Increase in the active form of 3-hydroxy-3-methylglutaryl coenzyme A reductase in human hepatocellular carcinoma: possible mechanism for alteration of cholesterol biosynthesis Cancer Res 1990 50: 3270–3273

    CAS  PubMed  Google Scholar 

  27. Harwood HJ Jr, Alvarez IM, Noyes WD, Stacpoole PW . In vivo regulation of human leukocyte 3-hydroxy-3-methylglutaryl coenzyme A reductase: increased enzyme protein concentration and catalytic efficiency in human leukemia and lymphoma J Lipid Res 1991 32: 1237–1252

    CAS  PubMed  Google Scholar 

  28. Vitols S, Norgren S, Juliusson G, Tatidis L, Luthman H . Multilevel regulation of low-density lipoprotein receptor and 3-hydroxy-3-methylglutaryl coenzyme A reductase gene expression in normal and leukemic cells Blood 1994 84: 2689–2698

    CAS  PubMed  Google Scholar 

  29. Caruso MG, Notarnicola M, Santillo M, Cavallini A, Di Leo A . Enhanced 3-hydroxy-3-methyl-glutaryl coenzyme A reductase activity in human colorectal cancer not expressing low density lipoprotein receptor Anticancer Res 1999 19: 451–454

    CAS  PubMed  Google Scholar 

  30. Hentosh P, Yuh SH, Elson CE, Peffley DM . Sterol-independent regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase in tumor cells Mol Carcinog 2001 32: 154–166

    Article  CAS  PubMed  Google Scholar 

  31. Bennis F, Favre G, Le Gaillard F, Soula G . Importance of mevalonate-derived products in the control of HMG-CoA reductase activity and growth of human lung adenocarcinoma cell line A549 Int J Cancer 1993 55: 640–645

    Article  CAS  PubMed  Google Scholar 

  32. Blais L, Desgagne A, LeLorier J . 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors and the risk of cancer: a nested case-control study Arch Intern Med 2000 160: 2363–2368

    Article  CAS  PubMed  Google Scholar 

  33. Lovastatin Study Groups I through IV. Lovastatin 5-year safety and efficacy study Arch Intern Med 1993 153: 1079–1087

  34. Narisawa T, Fukaura Y, Terada K, Umezawa A, Tanida N, Yazawa K, Ishikawa C . Prevention of 1,2-dimethylhydrazine-induced colon tumorigenesis by HMG-CoA reductase inhibitors, pravastatin and simvastatin, in ICR mice Carcinogenesis 1994 15: 2045–2048

    Article  CAS  PubMed  Google Scholar 

  35. Narisawa T, Fukaura Y, Tanida N, Hasebe M, Ito M, Aizawa R . Chemopreventive efficacy of low dose of pravastatin, an HMG-CoA reductase inhibitor, on 1,2-dimethylhydrazine-induced colon carcinogenesis in ICR mice Tohoku J Exp Med 1996 180: 131–138

    Article  CAS  PubMed  Google Scholar 

  36. Corsini A, Maggi FM, Catapano AL . Pharmacology of competitive inhibitors of HMG-CoA reductase Pharmacol Res 1995 31: 9–27

    Article  CAS  PubMed  Google Scholar 

  37. Hanefeld M, Deslypere JP, Ose L, Durrington PN, Farnier M, Schmage N . Efficacy and safety of 300 micrograms and 400 micrograms cerivastatin once daily in patients with primary hypercholesterolaemia: a multicentre, randomized, double-blind, placebo-controlled study J Int Med Res 1999 27: 115–129

    Article  CAS  PubMed  Google Scholar 

  38. Thompson GR, Naoumova RP . Novel lipid-regulating drugs Expert Opin Invest Drugs 2000 9: 2619–2628

    Article  CAS  Google Scholar 

  39. Farmer JA, Torre-Amione G . Comparative tolerability of the HMG-CoA reductase inhibitors Drug Safety 2000 23: 197–213

    Article  CAS  PubMed  Google Scholar 

  40. Alberts AW, MacDonald JS, Till AE, Tobert JA . Lovastatin Cardiovasc Drug Rev 1989 7: 89–109

    Article  Google Scholar 

  41. Plosker GL, McTavish D . Simvastatin. A reappraisal of its pharmacology and therapeutic efficacy in hypercholesterolaemia Drugs 1995 50: 334–363

    Article  CAS  PubMed  Google Scholar 

  42. Haria M, McTavish D . Pravastatin. A reappraisal of its pharmacological properties and clinical effectiveness in the management of coronary heart disease Drugs 1997 53: 299–336

    Article  CAS  PubMed  Google Scholar 

  43. Plosker GL, Wagstaff AJ . Fluvastatin: a review of its pharmacology and use in the management of hypercholesterolaemia Drugs 1996 51: 433–459

    Article  CAS  PubMed  Google Scholar 

  44. Malinowski JM . Atorvastatin: a hydroxymethylglutaryl-coenzyme A reductase inhibitor Am J Health Syst Pharm 1998 55: 2253–2267 quiz 2302–2253

    CAS  PubMed  Google Scholar 

  45. Bischoff H, Angerbauer R, Bender J, Bischoff E, Faggiotto A, Petzinna D, Pfitzner J, Porter MC, Schmidt D, Thomas G . Cerivastatin: pharmacology of a novel synthetic and highly active HMG- CoA reductase inhibitor Atherosclerosis 1997 135: 119–130

    Article  CAS  PubMed  Google Scholar 

  46. McTaggart F, Buckett L, Davidson R, Holdgate G, McCormick A, Schneck D, Smith G, Warwick M . Preclinical and clinical pharmacology of rosuvastatin, a new 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor Am J Cardiol 2001 87: 28–32

    Article  Google Scholar 

  47. Kajinami K, Mabuchi H, Saito Y . NK-104: a novel synthetic HMG-CoA reductase inhibitor Expert Opin Invest Drugs 2000 9: 2653–2661

    Article  CAS  Google Scholar 

  48. Istvan ES, Palnitkar M, Buchanan SK, Deisenhofer J . Crystal structure of the catalytic portion of human HMG-CoA reductase: insights into regulation of activity and catalysis EMBO J 2000 19: 819–830

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Istvan ES, Deisenhofer J . Structural mechanism for statin inhibition of HMG-CoA reductase Science 2001 292: 1160–1164

    Article  CAS  PubMed  Google Scholar 

  50. Tang BK, Kalow W . Variable activation of lovastatin by hydrolytic enzymes in human plasma and liver. 4 Eur J Clin Pharmacol 1995 47: 449–451

    Article  CAS  PubMed  Google Scholar 

  51. Mauro VF . Clinical pharmacokinetics and practical applications of simvastatin Clin Pharmacokinet 1993 24: 195–202

    Article  CAS  PubMed  Google Scholar 

  52. Lennernas H, Fager G . Pharmacodynamics and pharmacokinetics of the HMG-CoA reductase inhibitors. Similarities and differences Clin Pharmacokinet 1997 32: 403–425

    Article  CAS  PubMed  Google Scholar 

  53. Muck W . Clinical pharmacokinetics of cerivastatin Clin Pharmacokinet 2000 39: 99–116

    Article  CAS  PubMed  Google Scholar 

  54. Hanefeld M . Clinical rationale for rosuvastatin, a potent new HMG-CoA reductase inhibitor Int J Clin Pract 2001 55: 399–405

    CAS  PubMed  Google Scholar 

  55. Bottorff M, Hansten P . Long-term safety of hepatic hydroxymethyl glutaryl coenzyme A reductase inhibitors: the role of metabolism-monograph for physicians Arch Intern Med 2000 160: 2273–2280

    Article  CAS  PubMed  Google Scholar 

  56. Bischoff KM, Rodwell VW . Biosynthesis and characterization of (S)- and (R)-3-hydroxy-3-methylglutaryl coenzyme A Biochem Med Metab Biol 1992 48: 149–158

    Article  CAS  PubMed  Google Scholar 

  57. Moghadasian MH . Clinical pharmacology of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors Life Sci 1999 65: 1329–1337

    Article  CAS  PubMed  Google Scholar 

  58. Brown MS, Goldstein JL . A receptor-mediated pathway for cholesterol homeostasis Science 1986 232: 34–47

    Article  CAS  PubMed  Google Scholar 

  59. Ucar M, Mjorndal T, Dahlqvist R . HMG-CoA reductase inhibitors and myotoxicity Drug Safety 2000 22: 441–457

    Article  CAS  PubMed  Google Scholar 

  60. Bogman K, Peyer AK, Torok M, Kusters E, Drewe J . HMG-CoA reductase inhibitors and P-glycoprotein modulation Br J Pharmacol 2001 132: 1183–1192

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Pogson GW, Kindred LH, Carper BG . Rhabdomyolysis and renal failure associated with cerivastatin- gemfibrozil combination therapy (see comments) Am J Cardiol 1999 83: 1146

    Article  CAS  PubMed  Google Scholar 

  62. Wang E . Casciano CN, Clement RP, Johnson WW. HMG-CoA reductase inhibitors (statins) characterized as direct inhibitors of P-glycoprotein Pharm Res 2001 18: 800–806

    Article  CAS  PubMed  Google Scholar 

  63. Wu X, Whitfield LR, Stewart BH . Atorvastatin transport in the Caco-2 cell model: contributions of P- glycoprotein and the proton-monocarboxylic acid co-transporter Pharm Res 2000 17: 209–215

    Article  CAS  PubMed  Google Scholar 

  64. Insull W Jr, Isaacsohn J, Kwiterovich P, Ra P, Brazg R, Dujovne C, Shan M, Shugrue-Crowley E, Ripa S, Tota R . Efficacy and safety of cerivastatin 0.8 mg in patients with hypercholesterolaemia: the pivotal placebo-controlled clinical trial. Cerivastatin Study Group J Int Med Res 2000 28: 47–68

    Article  CAS  PubMed  Google Scholar 

  65. Cozza KL, Armstrong SC . 3A4. In: Hales RE (ed.). Cytochrome p450 System:Drug Interaction Principles for Medical Practice American Psychiatric Publishing: Washington, DC 2001: pp 47–68

    Google Scholar 

  66. Weber W . Drug firm withdraws statin from the market Lancet 2001 358: 568

    Article  Google Scholar 

  67. Keyomarsi K, Sandoval L, Band V, Pardee AB . Synchronization of tumor and normal cells from G1 to multiple cell cycles by lovastatin Cancer Res 1991 51: 3602–3609

    CAS  PubMed  Google Scholar 

  68. Jakobisiak M, Bruno S, Skierski JS, Darzynkiewicz Z . Cell cycle-specific effects of lovastatin Proc Natl Acad Sci USA 1991 88: 3628–3632

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Gray-Bablin J, Rao S, Keyomarsi K . Lovastatin induction of cyclin-dependent kinase inhibitors in human breast cells occurs in a cell cycle-independent fashion Cancer Res 1997 57: 604–609

    CAS  PubMed  Google Scholar 

  70. Hengst L, Dulic V, Slingerland JM, Lees E, Reed SI . A cell cycle-regulated inhibitor of cyclin-dependent kinases Proc Natl Acad Sci USA 1994 91: 5291–5295

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Wachtershauser A, Akoglu B, Stein J . HMG-CoA reductase inhibitor mevastatin enhances the growth inhibitory effect of butyrate in the colorectal carcinoma cell line Caco-2 Carcinogenesis 2001 22: 1061–1067

    Article  CAS  PubMed  Google Scholar 

  72. Lee SJ, Ha MJ, Lee J, Nguyen P, Choi YH, Pirnia F, Kang WK, Wang XF, Kim SJ, Trepel JB . Inhibition of the 3-hydroxy-3-methylglutaryl-coenzyme A reductase pathway induces p53-independent transcriptional regulation of p21(WAF1/CIP1) in human prostate carcinoma cells J Biol Chem 1998 273: 10618–10623

    Article  CAS  PubMed  Google Scholar 

  73. Rao S, Lowe M, Herliczek TW, Keyomarsi K . Lovastatin mediated G1 arrest in normal and tumor breast cells is through inhibition of CDK2 activity and redistribution of p21 and p27, independent of p53 Oncogene 1998 17: 2393–2402

    Article  CAS  PubMed  Google Scholar 

  74. Rao S, Porter DC, Chen X, Herliczek T, Lowe M, Keyomarsi K . Lovastatin-mediated G1 arrest is through inhibition of the proteasome, independent of hydroxymethyl glutaryl-CoA reductase Proc Natl Acad Sci USA 1999 96: 7797–7802

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Wojcik C, Bury M, Stoklosa T, Giermasz A, Feleszko W, Mlynarczuk I, Pleban E, Basak G, Omura S, Jakobisiak M . Lovastatin and simvastatin are modulators of the proteasome Int J Biochem Cell Biol 2000 32: 957–965

    Article  CAS  PubMed  Google Scholar 

  76. Gardner RG, Hampton RY . A highly conserved signal controls degradation of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase in eukaryotes J Biol Chem 1999 274: 31671–31678

    Article  CAS  PubMed  Google Scholar 

  77. Denoyelle C, Vasse M, Korner M, Mishal Z, Ganne F, Vannier JP, Soria J, Soria C . Cerivastatin, an inhibitor of HMG-CoA reductase, inhibits the signaling pathways involved in the invasiveness and metastatic properties of highly invasive breast cancer cell lines: an in vitro study Carcinogenesis 2001 22: 1139–1148

    Article  CAS  PubMed  Google Scholar 

  78. Masters BA, Palmoski MJ, Flint OP, Gregg RE, Wang-Iverson D, Durham SK . In vitro myotoxicity of the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, pravastatin, lovastatin, and simvastatin, using neonatal rat skeletal myocytes Toxicol Appl Pharmacol 1995 131: 163–174

    Article  CAS  PubMed  Google Scholar 

  79. Dimitroulakos J, Ye LY, Benzaquen M, Moore MJ, Kamel-Reid S, Freedman MH, Yeger H, Penn LZ . Differential sensitivity of various pediatric cancers and squamous cell carcinomas to lovastatin-induced apoptosis: therapeutic implications Clin Cancer Res 2001 7: 158–167

    CAS  PubMed  Google Scholar 

  80. Perez-Sala D, Mollinedo F . Inhibition of isoprenoid biosynthesis induces apoptosis in human promyelocytic HL-60 cells Biochem Biophys Res Commun 1994 199: 1209–1215

    Article  CAS  PubMed  Google Scholar 

  81. Newman A, Clutterbuck RD, Powles RL, Millar JL . Selective inhibition of primary acute myeloid leukaemia cell growth by simvastatin Leukemia 1994 8: 2023–2029

    CAS  PubMed  Google Scholar 

  82. Dimitroulakos J, Nohynek D, Backway KL, Hedley DW, Yeger H, Freedman MH, Minden MD, Penn LZ . Increased sensitivity of acute myeloid leukemias to lovastatin-induced apoptosis: A potential therapeutic approach Blood 1999 93: 1308–1318

    CAS  PubMed  Google Scholar 

  83. Macaulay RJ, Wang W, Dimitroulakos J, Becker LE, Yeger H . Lovastatin-induced apoptosis of human medulloblastoma cell lines in vitro J Neurooncol 1999 42: 1–11

    Article  CAS  PubMed  Google Scholar 

  84. Rubins JB, Greatens T, Kratzke RA, Tan AT, Polunovsky VA, Bitterman P . Lovastatin induces apoptosis in malignant mesothelioma cells Am J Respir Crit Care Med 1998 157: 1616–1622

    Article  CAS  PubMed  Google Scholar 

  85. Muller C, Bockhorn AG, Klusmeier S, Kiehl M, Roeder C, Kalthoff H, Koch OM . Lovastatin inhibits proliferation of pancreatic cancer cell lines with mutant as well as with wild-type K-ras oncogene but has different effects on protein phosphorylation and induction of apoptosis Int J Oncol 1998 12: 717–723

    CAS  PubMed  Google Scholar 

  86. Dimitroulakos J, Yeger H . HMG-CoA reductase mediates the biological effects of retinoic acid on human neuroblastoma cells: lovastatin specifically targets P-glycoprotein-expressing cells Nat Med 1996 2: 326–333

    Article  CAS  PubMed  Google Scholar 

  87. Jones KD, Couldwell WT, Hinton DR, Su Y, He S, Anker L, Law RE . Lovastatin induces growth inhibition and apoptosis in human malignant glioma cells Biochem Biophys Res Commun 1994 205: 1681–1687

    Article  CAS  PubMed  Google Scholar 

  88. Marcelli M, Cunningham GR, Haidacher SJ, Padayatty SJ, Sturgis L, Kagan C, Denner L . Caspase-7 is activated during lovastatin-induced apoptosis of the prostate cancer cell line LNCaP Cancer Res 1998 58: 76–83

    CAS  PubMed  Google Scholar 

  89. Ghosh PM, Ghosh-Choudhury N, Moyer ML, Mott GE, Thomas CA, Foster BA, Greenberg NM, Kreisberg JI . Role of RhoA activation in the growth and morphology of a murine prostate tumor cell line Oncogene 1999 18: 4120–4130

    Article  CAS  PubMed  Google Scholar 

  90. Park C, Lee I, Kang WK . Lovastatin-induced E2F-1 modulation and its effect on prostate cancer cell death Carcinogenesis 2001 22: 1727–1731

    Article  CAS  PubMed  Google Scholar 

  91. Han Z, Wyche JH . Lovastatin induces apoptosis in metastatic ovarian cell line Cell Death Differ 1996 3: 223–228

    CAS  PubMed  Google Scholar 

  92. Park WH, Lee YY, Kim ES, Seol JG, Jung CW, Lee CC, Kim BK . Lovastatin-induced inhibition of HL-60 cell proliferation via cell cycle arrest and apoptosis Anticancer Res 1999 19: 3133–3140

    CAS  PubMed  Google Scholar 

  93. Kim JS, Pirnia F, Choi YH, Nguyen PM, Knepper B, Tsokos M, Schulte TW, Birrer MJ, Blagosklonny MV, Schaefer O, Mushinski JF, Trepel JB . Lovastatin induces apoptosis in a primitive neuroectodermal tumor cell line in association with RB down-regulation and loss of the G1 checkpoint Oncogene 2000 19: 6082–6090

    Article  CAS  PubMed  Google Scholar 

  94. Marom M, Ben-Baruch G, Roitelman J, Kloog Y . Lack of correlation between 3-hydroxy-3-methylglutaryl coenzyme A reductase activity and lovastatin resistance in nerve growth factor treated PC-12 cells Cell Mol Neurobiol 1994 14: 119–132

    Article  CAS  PubMed  Google Scholar 

  95. Wong WW, Tan MM, Xia Z, Dimitroulakos J, Minden MD, Penn LZ . Cerivastatin triggers tumor-specific apoptosis with higher efficacy than lovastatin Clin Cancer Res 2001 7: 2067–2075

    CAS  PubMed  Google Scholar 

  96. Feleszko W, Mlynarczuk I, Nowis D . In vitro antitumor activity of cerivastatin, a novel and potent HMG-CoA reductase inhibitor FEBS Lett 2001 503: 219–220

    Article  CAS  PubMed  Google Scholar 

  97. Luskey KL, Faust JR, Chin DJ, Brown MS, Goldstein JL . Amplification of the gene for 3-hydroxy-3-methylglutaryl coenzyme A reductase, but not for the 53-kDa protein, in UT-1 cells J Biol Chem 1983 258: 8462–8469

    CAS  PubMed  Google Scholar 

  98. Ravid T, Avner R, Polak-Charcon S, Faust JR, Roitelman J . Impaired regulation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase degradation in lovastatin-resistant cells J Biol Chem 1999 274: 29341–29351

    Article  CAS  PubMed  Google Scholar 

  99. Kikuchi T, Nagata Y, Abe T . In vitro and in vivo antiproliferative effects of simvastatin, an HMG-CoA reductase inhibitor, on human glioma cells J Neurooncol 1997 34: 233–239

    Article  CAS  PubMed  Google Scholar 

  100. Choi JW, Jung SE . Lovastatin-induced proliferation inhibition and apoptosis in C6 glial cells J Pharmacol Exp Ther 1999 289: 572–579

    CAS  PubMed  Google Scholar 

  101. Bouterfa HL, Sattelmeyer V, Czub S, Vordermark D, Roosen K, Tonn JC . Inhibition of Ras farnesylation by lovastatin leads to downregulation of proliferation and migration in primary cultured human glioblastoma cells Anticancer Res 2000 20: 2761–2771

    CAS  PubMed  Google Scholar 

  102. Agarwal B, Rao CV, Bhendwal S, Ramey WR, Shirin H, Reddy BS, Holt PR . Lovastatin augments sulindac-induced apoptosis in colon cancer cells and potentiates chemopreventive effects of sulindac Gastroenterology 1999 117: 838–847

    Article  CAS  PubMed  Google Scholar 

  103. Wang W, Macaulay RJ . Mevalonate prevents lovastatin-induced apoptosis in medulloblastoma cell lines Can J Neurol Sci 1999 26: 305–310

    Article  CAS  PubMed  Google Scholar 

  104. Xia Z, Tan MM, Wong WW, Dimitroulakos J, Minden MD, Penn LZ . Blocking protein geranylgeranylation is essential for lovastatin- induced apoptosis of human acute myeloid leukemia cells Leukemia 2001 15: 1398–1407

    Article  CAS  PubMed  Google Scholar 

  105. Newman A, Clutterbuck RD, DeLord C, Powles RL, Catovsky D, Millar JL . The sensitivity of leukemic bone marrow to simvastatin is lost at remission: a potential purging agent for autologous bone marrow transplantation J Invest Med 1995 43: 269–274

    CAS  Google Scholar 

  106. Newman A, Clutterbuck RD, Powles RL, Catovsky D, Millar JL . A comparison of the effect of the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors simvastatin, lovastatin and pravastatin on leukaemic and normal bone marrow progenitors Leuk Lymphoma 1997 24: 533–537

    Article  CAS  PubMed  Google Scholar 

  107. Clutterbuck RD, Millar BC, Powles RL, Newman A, Catovsky D, Jarman M, Millar JL . Inhibitory effect of simvastatin on the proliferation of human myeloid leukaemia cells in severe combined immunodeficient (SCID) mice Br J Haematol 1998 102: 522–527

    Article  CAS  PubMed  Google Scholar 

  108. Kawata S, Yamasaki E, Nagase T, Inui Y, Ito N, Matsuda Y, Inada M, Tamura S, Noda S, Imai Y, Matsuzawa Y . Effect of pravastatin on survival in patients with advanced hepatocellular carcinoma. A randomized controlled trial Br J Cancer 2001 84: 886–891

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Thibault A, Samid D, Tompkins AC, Figg WD, Cooper MR, Hohl RJ, Trepel J, Liang B, Patronas N, Venzon DJ, Reed E, Myers CE . Phase I study of lovastatin, an inhibitor of the mevalonate pathway, in patients with cancer Clin Cancer Res 1996 2: 483–491

    CAS  PubMed  Google Scholar 

  110. Larner J, Jane J, Laws E, Packer R, Myers C, Shaffrey M . A phase I–II trial of lovastatin for anaplastic astrocytoma and glioblastoma multiforme Am J Clin Oncol 1998 21: 579–583

    Article  CAS  PubMed  Google Scholar 

  111. Kim WS, Kim MM, Choi HJ, Yoon SS, Lee MH, Park K, Park CH, Kang WK . Phase II study of high-dose lovastatin in patients with advanced gastric adenocarcinoma Invest New Drugs 2001 19: 81–83

    Article  CAS  PubMed  Google Scholar 

  112. Dimitroulakos J, Thai S, Wasfy GH, Hedley DW, Minden MD, Penn LZ . Lovastatin induces a pronounced differentiation response in acute myeloid leukemias Leuk Lymphoma 2000 40: 167–178

    Article  CAS  PubMed  Google Scholar 

  113. Agarwal B, Bhendwal S, Halmos B, Moss SF, Ramey WG, Holt PR . Lovastatin augments apoptosis induced by chemotherapeutic agents in colon cancer cells Clin Cancer Res 1999 5: 2223–2229

    CAS  PubMed  Google Scholar 

  114. Schmidt F, Groscurth P, Kermer M, Dichgans J, Weller M . Lovastatin and phenylacetate induce apoptosis, but not differentiation, in human malignant glioma cells Acta Neuropathol (Berl) 2001 101: 217–224

    CAS  Google Scholar 

  115. Wang IK, Lin-Shiau SY, Lin JK . Induction of apoptosis by lovastatin through activation of caspase-3 and DNase II in leukaemia HL-60 cells Pharmacol Toxicol 2000 86: 83–91

    Article  CAS  PubMed  Google Scholar 

  116. Prendergast GC . Farnesyltransferase inhibitors: antineoplastic mechanism and clinical prospects Curr Opin Cell Biol 2000 12: 166–173

    Article  CAS  PubMed  Google Scholar 

  117. Jani JP, Specht S, Stemmler N, Blanock K, Singh SV, Gupta V, Katoh A . Metastasis of B16F10 mouse melanoma inhibited by lovastatin, an inhibitor of cholesterol biosynthesis Invasion Metastasis 1993 13: 314–324

    CAS  PubMed  Google Scholar 

  118. Alonso DF, Farina HG, Skilton G, Gabri MR, De Lorenzo MS, Gomez DE . Reduction of mouse mammary tumor formation and metastasis by lovastatin, an inhibitor of the mevalonate pathway of cholesterol synthesis Breast Cancer Res Treat 1998 50: 83–93

    Article  CAS  PubMed  Google Scholar 

  119. Matar P, Rozados VR, Binda MM, Roggero EA, Bonfil RD, Scharovsky OG . Inhibitory effect of Lovastatin on spontaneous metastases derived from a rat lymphoma Clin Exp Metastasis 1999 17: 19–25

    Article  CAS  PubMed  Google Scholar 

  120. Matar P, Rozados VR, Roggero EA, Scharovsky OG . Lovastatin inhibits tumor growth and metastasis development of a rat fibrosarcoma Cancer Biother Radiopharm 1998 13: 387–393

    Article  CAS  PubMed  Google Scholar 

  121. Wong B, Lumma WC, Smith AM, Sisko JT, Wright SD, Cai TQ . Statins suppress THP-1 cell migration and secretion of matrix metalloproteinase 9 by inhibiting geranylgeranylation J Leukoc Biol 2001 69: 959–962

    CAS  PubMed  Google Scholar 

  122. Kusama T, Mukai M, Iwasaki T, Tatsuta M, Matsumoto Y, Akedo H, Nakamura H . Inhibition of epidermal growth factor-induced RhoA translocation and invasion of human pancreatic cancer cells by 3-hydroxy-3-methylglutaryl-coenzyme a reductase inhibitor Cancer Res 2001 61: 4885–4891

    CAS  PubMed  Google Scholar 

  123. DeClue JE, Vass WC, Papageorge AG, Lowy DR, Willumsen BM . Inhibition of cell growth by lovastatin is independent of ras function Cancer Res 1991 51: 712–717

    CAS  PubMed  Google Scholar 

  124. Sebti SM, Tkalcevic GT, Jani JP . Lovastatin, a cholesterol biosynthesis inhibitor, inhibits the growth of human H-ras oncogene transformed cells in nude mice Cancer Commun 1991 3: 141–147

    Article  CAS  PubMed  Google Scholar 

  125. Jani JP, Tkalcevic GT, Sebti SM . Lovastatin inhibits in vivo tumour growth of H-ras and c-myc but not v-src oncogene-transformed cells Cell Pharmacol 1994 1: 67–72

    CAS  Google Scholar 

  126. Evan GI, Wyllie AH, Gilbert CS, Littlewood TD, Land H, Brooks M, Waters CM, Penn LZ, Hancock DC . Induction of apoptosis in fibroblasts by c-myc protein Cell 1992 69: 119–128

    Article  CAS  PubMed  Google Scholar 

  127. Holmberg M, Sandberg C, Nygren P, Larsson R . Effects of lovastatin on a human myeloma cell line: increased sensitivity of a multidrug-resistant subline that expresses the 170 kDa P-glycoprotein Anticancer Drugs 1994 5: 598–600

    Article  CAS  PubMed  Google Scholar 

  128. Hunakova L, Sedlak J, Sulikova M, Chovancova J, Duraj J, Chorvath B . Human multidrug-resistant (MRP,p190) myeloid leukemia HL-60/ADR cells in vitro: resistance to the mevalonate pathway inhibitor lovastatin Neoplasma 1997 44: 366–369

    CAS  PubMed  Google Scholar 

  129. Maksumova L, Ohnishi K, Muratkhodjaev F, Zhang W, Pan L, Takeshita A, Ohno R . Increased sensitivity of multidrug-resistant myeloid leukemia cell lines to lovastatin Leukemia 2000 14: 1444–1450

    Article  CAS  PubMed  Google Scholar 

  130. Lowe SW, Schmitt EM, Smith SW, Osborne BA, Jacks T . p53 is required for radiation-induced apoptosis in mouse thymocytes Nature 1993 362: 847–849

    Article  CAS  PubMed  Google Scholar 

  131. Kiener PA, Davis PM, Murray JL, Youssef S, Rankin BM, Kowala M . Stimulation of inflammatory responses in vitro and in vivo by lipophilic HMG-CoA reductase inhibitors Int Immunopharmacol 2001 1: 105–118

    Article  CAS  PubMed  Google Scholar 

  132. Montero MT, Hernandez O, Suarez Y, Matilla J, Ferruelo AJ, Martinez-Botas J, Gomez-Coronado D, Lasuncion MA . Hydroxymethylglutaryl-coenzyme A reductase inhibition stimulates caspase-1 activity and Th1-cytokine release in peripheral blood mononuclear cells Atherosclerosis 2000 153: 303–313

    Article  CAS  PubMed  Google Scholar 

  133. Kwak B, Mulhaupt F, Myit S, Mach F . Statins as a newly recognized type of immunomodulator Nat Med 2000 6: 1399–1402

    Article  CAS  PubMed  Google Scholar 

  134. Kwak BR, Mach F . Statins inhibit leukocyte recruitment: new evidence for their anti- inflammatory properties Arterioscler Thromb Vasc Biol 2001 21: 1256–1258

    Article  CAS  PubMed  Google Scholar 

  135. Diomede L, Albani D, Sottocorno M, Donati MB, Bianchi M, Fruscella P, Salmona M . In vivo anti-inflammatory effect of statins is mediated by nonsterol mevalonate products Arterioscler Thromb Vasc Biol 2001 21: 1327–1332

    Article  CAS  PubMed  Google Scholar 

  136. Kureishi Y, Luo Z, Shiojima I, Bialik A, Fulton D, Lefer DJ, Sessa WC, Walsh K . The HMG-CoA reductase inhibitor simvastatin activates the protein kinase Akt and promotes angiogenesis in normocholesterolemic animals Nat Med 2000 6: 1004–1010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Satoh K, Ichihara K, Landon EJ, Inagami T, Tang H . 3-Hydroxy-3-methylglutaryl-CoA reductase inhibitors block calcium-dependent tyrosine kinase Pyk2 activation by angiotensin II in vascular endothelial cells. Involvement of geranylgeranylation of small G protein Rap1 J Biol Chem 2001 276: 15761–15767

    Article  CAS  PubMed  Google Scholar 

  138. Dechend R, Fiebeler A, Park JK, Muller DN, Theuer J, Mervaala E, Bieringer M, Gulba D, Dietz R, Luft FC, Haller H . Amelioration of angiotensin II-induced cardiac injury by a 3-hydroxy-3- methylglutaryl coenzyme a reductase inhibitor Circulation 2001 104: 576–581

    Article  CAS  PubMed  Google Scholar 

  139. Gotto AM Jr, Farmer JA . Pleiotropic effects of statins: do they matter? Curr Opin Lipidol 2001 12: 391–394

    Article  CAS  PubMed  Google Scholar 

  140. Stark WW Jr, Blaskovich MA, Johnson BA, Qian Y, Vasudevan A, Pitt B, Hamilton AD, Sebti SM, Davies P . Inhibiting geranylgeranylation blocks growth and promotes apoptosis in pulmonary vascular smooth muscle cells Am J Physiol 1998 275: L55–63

    CAS  PubMed  Google Scholar 

  141. Negre-Aminou P, van Vliet AK, van Erck M, van Thiel GC, van Leeuwen RE, Cohen LH . Inhibition of proliferation of human smooth muscle cells by various HMG-CoA reductase inhibitors; comparison with other human cell types Biochim Biophys Acta 1997 1345: 259–268

    Article  CAS  PubMed  Google Scholar 

  142. Guijarro C, Blanco-Colio LM, Ortego M, Alonso C, Ortiz A, Plaza JJ, Diaz C, Hernandez G, Egido J . 3-Hydroxy-3-methylglutaryl coenzyme a reductase and isoprenylation inhibitors induce apoptosis of vascular smooth muscle cells in culture Circ Res 1998 83: 490–500

    Article  CAS  PubMed  Google Scholar 

  143. Dimmeler S, Aicher A, Vasa M, Mildner-Rihm C, Adler K, Tiemann M, Rutten H, Fichtlscherer S, Martin H, Zeiher AM . HMG-CoA reductase inhibitors (statins) increase endothelial progenitor cells via the PI 3-kinase/Akt pathway J Clin Invest 2001 108: 391–397

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Llevadot J, Murasawa S, Kureishi Y, Uchida S, Masuda H, Kawamoto A, Walsh K, Isner JM, Asahara T . HMG-CoA reductase inhibitor mobilizes bone marrow--derived endothelial progenitor cells J Clin Invest 2001 108: 399–405

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Guo YS, Jin GF, Houston CW, Thompson JC, Townsend CM Jr . Insulin-like growth factor-I promotes multidrug resistance in MCLM colon cancer cells J Cell Physiol 1998 175: 141–148

    Article  CAS  PubMed  Google Scholar 

  146. Bonapace IM, Addeo R, Altucci L, Cicatiello L, Bifulco M, Laezza C, Salzano S, Sica V, Bresciani F, Weisz A . 17 beta-Estradiol overcomes a G1 block induced by HMG-CoA reductase inhibitors and fosters cell cycle progression without inducing ERK-1 and -2 MAP kinases activation Oncogene 1996 12: 753–763

    CAS  PubMed  Google Scholar 

  147. Addeo R, Altucci L, Battista T, Bonapace IM, Cancemi M, Cicatiello L, Germano D, Pacilio C, Salzano S, Bresciani F, Weisz A . Stimulation of human breast cancer MCF-7 cells with estrogen prevents cell cycle arrest by HMG-CoA reductase inhibitors Biochem Biophys Res Commun 1996 220: 864–870

    Article  CAS  PubMed  Google Scholar 

  148. Carlberg M, Larsson O . Stimulatory effect of PDGF on HMG-CoA reductase activity and N-linked glycosylation contributes to increased expression of IGF-1 receptors in human fibroblasts Exp Cell Res 1996 223: 142–148

    Article  CAS  PubMed  Google Scholar 

  149. Kawata S, Kakimoto H, Ishiguro H, Yamasaki E, Inui Y, Matsuzawa Y . Effect of pravastatin, a potent 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor, on survival of AH130 hepatoma-bearing rats Jpn J Cancer Res 1992 83: 1120–1123

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Sumi S, Beauchamp RD, Townsend CM Jr, Uchida T, Murakami M, Rajaraman S, Ishizuka J, Thompson JC . Inhibition of pancreatic adenocarcinoma cell growth by lovastatin Gastroenterology 1992 103: 982–989

    Article  CAS  PubMed  Google Scholar 

  151. Hawk MA, Cesen KT, Siglin JC, Stoner GD, Ruch RJ . Inhibition of lung tumor cell growth in vitro and mouse lung tumor formation by lovastatin Cancer Lett 1996 109: 217–222

    Article  CAS  PubMed  Google Scholar 

  152. Maltese WA, Defendini R, Green RA, Sheridan KM, Donley DK . Suppression of murine neuroblastoma growth in vivo by mevinolin, a competitive inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase J Clin Invest 1985 76: 1748–1754

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Feleszko W, Mlynarczuk I, Balkowiec-Iskra EZ, Czajka A, Switaj T, Stoklosa T, Giermasz A, Jakobisiak M . Lovastatin potentiates antitumor activity and attenuates cardiotoxicity of doxorubicin in three tumor models in mice Clin Cancer Res 2000 6: 2044–2052

    CAS  PubMed  Google Scholar 

  154. Feleszko W, Balkowiec EZ, Sieberth E, Marczak M, Dabrowska A, Giermasz A, Czajka A, Jakobisiak M . Lovastatin and tumor necrosis factor-alpha exhibit potentiated antitumor effects against Ha-ras-transformed murine tumor via inhibition of tumor-induced angiogenesis Int J Cancer 1999 81: 560–567

    Article  CAS  PubMed  Google Scholar 

  155. Feleszko W, Lasek W, Golab J, Jakobisiak M . Synergistic antitumor activity of tumor necrosis factor-alpha and lovastatin against MmB16 melanoma in mice Neoplasma 1995 42: 69–74

    CAS  PubMed  Google Scholar 

  156. Feleszko W, Jakobisiak M . Lovastatin augments apoptosis induced by chemotherapeutic agents in colon cancer cells (letter; comment) Clin Cancer Res 2000 6: 1198–1199

    CAS  PubMed  Google Scholar 

  157. Soma MR, Pagliarini P, Butti G, Paoletti R, Paoletti P, Fumagalli R . Simvastatin, an inhibitor of cholesterol biosynthesis, shows a synergistic effect with N,N′-bis(2-chloroethyl)-N-nitrosourea and beta- interferon on human glioma cells Cancer Res 1992 52: 4348–4355

    CAS  PubMed  Google Scholar 

  158. Lishner M, Bar-Sef A, Elis A, Fabian I . Effect of simvastatin alone and in combination with cytosine arabinoside on the proliferation of myeloid leukemia cell lines J Invest Med 2001 49: 319–324

    Article  CAS  Google Scholar 

  159. Holstein SA, Hohl RJ . Interaction of cytosine arabinoside and lovastatin in human leukemia cells Leuk Res 2001 25: 651–660

    Article  CAS  PubMed  Google Scholar 

  160. Prasanna P, Thibault A, Liu L, Samid D . Lipid metabolism as a target for brain cancer therapy: synergistic activity of lovastatin and sodium phenylacetate against human glioma cells J Neurochem 1996 66: 710–716

    Article  CAS  PubMed  Google Scholar 

  161. Minden MD, Dimitroulakos J, Nohynek D, Penn LZ . Lovastatin induced control of blast cell growth in an elderly patient with acute myeloblastic leukemia Leuk Lymphoma 2000 40: 659–662

    Article  Google Scholar 

  162. Miller AC, Kariko K, Myers CE, Clark EP, Samid D . Increased radioresistance of EJras-transformed human osteosarcoma cells and its modulation by lovastatin, an inhibitor of p21ras isoprenylation Int J Cancer 1993 53: 302–307

    Article  CAS  PubMed  Google Scholar 

  163. Bernhard EJ, McKenna WG, Hamilton AD, Sebti SM, Qian Y, Wu JM, Muschel RJ . Inhibiting Ras prenylation increases the radiosensitivity of human tumor cell lines with activating mutations of ras oncogenes Cancer Res 1998 58: 1754–1761

    CAS  PubMed  Google Scholar 

  164. Shack S, Gorospe M, Fawcett TW, Hudgins WR, Holbrook NJ . Activation of the cholesterol pathway and Ras maturation in response to stress Oncogene 1999 18: 6021–6028

    Article  CAS  PubMed  Google Scholar 

  165. Mevacor (Lovastatin, MSD); Merck, Sharp and Dohme, Montreal, Quebec, Canada

  166. Zocor (Simvastatin, MSD); Merck, Sharp and Dohme, Montreal, Quebec, Canada

  167. Pravachol (Pravastatin sodium, MSD); Bristol Meyers Squibb, Princelton, NJ, USA

  168. Lescol (Fluvastatin sodium, MSD); Novartis, Basel, Switzerland

  169. Lipitor (Atorvastatin calcium, MSD); Parke-Davis, Ann Arbor, MI, USA

  170. Baycol/Lipobay (Cerivastatin sodium, MSD); Bayer, Wuppertal, Germany

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Acknowledgements

We wish to thank our colleagues who generously contributed data prior to publication. We also thank the Penn Lab for critical review of the manuscript. We apologize to those whose contributions have not been cited due to space constraints. Support from the Canadian Institutes of Health Research (formerly the Medical Research Council of Canada) for an operating grant (LZP), doctoral research award (WWW) and postdoctoral fellowship (JD) and the Leukemia Lymphoma Society (formerly the Leukemia Society of America) for a translational research program grant (LZP and MDM) is gratefully acknowledged.

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Wong, WL., Dimitroulakos, J., Minden, M. et al. HMG-CoA reductase inhibitors and the malignant cell: the statin family of drugs as triggers of tumor-specific apoptosis. Leukemia 16, 508–519 (2002). https://doi.org/10.1038/sj.leu.2402476

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