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Cancer Chemotherapy and Pharmacology

Published in:

01-04-2011 | Mini Review

Statins are logical candidates for overcoming limitations of targeting therapies on malignancy: their potential application to gastrointestinal cancers

Author: Shouji Shimoyama

Published in: Cancer Chemotherapy and Pharmacology | Issue 4/2011

Abstract

Purpose

Molecular targeting approaches have been an intensive focus of treatment strategies against advanced gastric and colorectal cancers. Recent clinical trials have demonstrated promising survival prolongation of targeted human epidermal growth factor receptors; however, patients harboring mutations in the K-Ras gene (human homolog of the Kirsten rat sarcoma-2 virus oncogene) do not derive benefit from the anti-epidermal growth factor receptor antibodies. K-Ras mutations cause a stimuli-independent activation of a large cohort of downstream effectors that permit cells to acquire a sustained growth. The perpetuated growth activation manifests resistance to molecular targeting therapies.

Methods

Literature review has been made to explore the possibilities that, given that K-Ras or downstream effector proteins require farnesyl or geranylgeranyl moiety for their activity (e.g., prenylation), statins are logical candidates to overcome the limitations of or to potentiate the effect of molecular targeting therapies as statins suppress the mevalonate pathway leading to depletion of an end product of mevalonate such as farnesylpyrophosphate and geranylgeranylpyrophosphate, which are used as substrates by their respective transferase enzyme for protein prenylation, and ultimately impair functions of K-Ras and downstream effector proteins.

Results

In the last few years, statins have gained interest in therapeutic value for anticancer treatments extending beyond their lipid-lowering effects as single agents or in combined use with other chemotherapeutic agents. This review provides insights into possible anticancer mechanisms of statins and introduces current achievements or ongoing studies of statins in the field of cancer treatment in single or combined uses. This review also offers information to help establish optimal treatment schedules of statins that overcome current limitations of molecular targeting therapies.

Conclusions

It is expected that therapeutic scope of statins will expand considerably in the future as anticancer agents in addition to their proven benefits of hyperlipidemia.

Koizumi W, Narahara H, Hara T, Takagane A, Akiya T, Takagi M, Miyashita K, Nishizaki T, Kobayashi O, Takiyama W, Toh Y, Nagaie T, Takagi S, Yamamura Y, Yanaoka K, Orita H, Takeuchi M (2008) S-1 plus cisplatin versus S-1 alone for first-line treatment of advanced gastric cancer (SPIRITS trial): a phase III trial. Lancet Oncol 9:215–221PubMedCrossRef

Glimelius B, Hoffman K, Haglund U, Nyrén O, Sjödén PO (1994) Initial or delayed chemotherapy with best supportive care in advanced gastric cancer. Ann Oncol 5:189–190PubMed

Goldberg RM, Sargent DJ, Morton RF, Fuchs CS, Ramanathan RK, Williamson SK, Findlay BP, Pitot HC, Alberts SR (2004) A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 22:23–30PubMedCrossRef

Fuchs CS, Marshall J, Mitchell E, Wierzbicki R, Ganju V, Jeffery M, Schulz J, Richards D, Soufi-Mahjoubi R, Wang B, Barrueco J (2007) Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: results from the BICC-C Study. J Clin Oncol 25:4779–4786PubMedCrossRef

Narahara H, Fujitani K, Takiuchi H, Sugimoto N, Inoue K, Uedo N, Tsukuma H, Tsujinaka T, Furukawa H, Taguchi T (2008) Phase II study of a combination of S-1 and paclitaxel in patients with unresectable or metastatic gastric cancer. Oncology 74:37–41PubMedCrossRef

Van Cutsem E, Moiseyenko VM, Tjulandin S, Majlis A, Constenla M, Boni C, Rodrigues A, Fodor M, Chao Y, Voznyi E, Risse ML, Ajani JA, V325 Study Group (2006) Phase III study of docetaxel and cisplatin plus fluorouracil compared with cisplatin and fluorouracil as first-line therapy for advanced gastric cancer: a report of the V325 Study Group. J Clin Oncol 24:4991–4997

Siena S, Sartore-Bianchi A, Di Nicolantonio F, Balfour J, Bardelli A (2009) Biomarkers predicting clinical outcome of epidermal growth factor receptor-targeted therapy in metastatic colorectal cancer. J Natl Cancer Inst 101:1308–1324PubMedCrossRef

Chan KK, Oza AM, Siu LL (2003) The statins as anticancer agents. Clin Cancer Res 9:10–19PubMed

Ciardiello F, Tortora G (2008) EGFR antagonists in cancer treatment. N Engl J Med 358:1160–1174PubMedCrossRef

10.

Graaf MR, Richel DJ, van Noorden CJ, Guchelaar HJ (2004) Effects of statins and farnesyltransferase inhibitors on the development and progression of cancer. Cancer Treat Rev 30:609–641PubMedCrossRef

11.

Ridley AJ (2001) Rho family proteins: coordinating cell responses. Trends Cell Biol 11:471–477PubMedCrossRef

12.

Rodriguez-Viciana P, Warne PH, Dhand R, Vanhaesebroeck B, Gout I, Fry MJ, Waterfield MD, Downward J (1994) Phosphatidylinositol-3-OH kinase as a direct target of Ras. Nature 370:527–532PubMedCrossRef

13.

Pruitt K, Der CJ (2001) Ras and Rho regulation of the cell cycle and oncogenesis. Cancer Lett 171:1–10PubMedCrossRef

14.

Gingras D, Lamy S, Béliveau R (2000) Tyrosine phosphorylation of the vascular endothelial-growth-factor receptor-2 (VEGFR-2) is modulated by Rho proteins. Biochem J 348(Pt 2):273–280

15.

Bryan BA, D’Amore PA (2007) What tangled webs they weave: Rho-GTPase control of angiogenesis. Cell Mol Life Sci 64:2053–2065PubMedCrossRef

16.

van Nieuw Amerongen GP, Koolwijk P, Versteilen A, van Hinsbergh VW (2003) Involvement of RhoA/Rho kinase signaling in VEGF-induced endothelial cell migration and angiogenesis in vitro. Arterioscler Thromb Vasc Biol 23:211–217PubMedCrossRef

17.

Guba M, Seeliger H, Kleespies A, Jauch KW, Bruns C (2004) Vascular endothelial growth factor in colorectal cancer. Int J Colorectal Dis 19:510–517PubMedCrossRef

18.

Iwasaki J, Nihira S (2009) Anti-angiogenic therapy against gastrointestinal tract cancers. Jpn J Clin Oncol 39:543–551PubMedCrossRef

19.

Ichikura T, Tomimatsu S, Ohkura E, Mochizuki H (2001) Prognostic significance of the expression of vascular endothelial growth factor (VEGF) and VEGF-C in gastric carcinoma. J Surg Oncol 78:132–137PubMedCrossRef

20.

Vidal O, Metges JP, Elizalde I, Valentíni M, Volant A, Molina R, Castells A, Pera M (2009) High preoperative serum vascular endothelial growth factor levels predict poor clinical outcome after curative resection of gastric cancer. Br J Surg 96:1443–1451PubMedCrossRef

21.

Takahashi Y, Kitadai Y, Bucana CD, Cleary KR, Ellis LM (1995) Expression of vascular endothelial growth factor and its receptor, KDR, correlates with vascularity, metastasis, and proliferation of human colon cancer. Cancer Res 55:3964–3968PubMed

22.

Jørgensen JT (2010) Targeted HER2 treatment in advanced gastric cancer. Oncology 78:26–33PubMedCrossRef

23.

Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, Lordick F, Ohtsu A, Omuro Y, Satoh T, Aprile G, Kulikov E, Hill J, Lehle M, Rüschoff J, Kang YK, Investigators ToGA Trial (2010) Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet 376:687–697PubMedCrossRef

24.

http://www.ClinicalTrial.gov. Accessed Aug 2010

25.

Kang Y, Ohtsu A, Van Cutsem E, Rha SY, Sawaki A, Park S, Lim H, Wu J, Langer B, Shah MA (2010) AVAGAST: a randomized, double-blind, placebo-controlled, phase III study of first-line capecitabine and cisplatin plus bevacizumab or placebo in patients with advanced gastric cancer (AGC). Proc ASCO abstr LBA 4007

26.

Cunningham D, Humblet Y, Siena S, Khayat D, Bleiberg H, Santoro A, Bets D, Mueser M, Harstrick A, Verslype C, Chau I, Van Cutsem E (2004) Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 351:337–345PubMedCrossRef

27.

Sobrero AF, Maurel J, Fehrenbacher L, Scheithauer W, Abubakr YA, Lutz MP, Vega-Villegas ME, Eng C, Steinhauer EU, Prausova J, Lenz HJ, Borg C, Middleton G, Kröning H, Luppi G, Kisker O, Zubel A, Langer C, Kopit J, Burris HA 3rd (2008) EPIC: phase III trial of cetuximab plus irinotecan after fluoropyrimidine and oxaliplatin failure in patients with metastatic colorectal cancer. J Clin Oncol 26:2311–2319PubMedCrossRef

28.

Jonker DJ, O’Callaghan CJ, Karapetis CS, Zalcberg JR, Tu D, Au HJ, Berry SR, Krahn M, Price T, Simes RJ, Tebbutt NC, van Hazel G, Wierzbicki R, Langer C, Moore MJ (2007) Cetuximab for the treatment of colorectal cancer. N Engl J Med 357:2040–2048PubMedCrossRef

29.

Van Cutsem E, Köhne CH, Hitre E, Zaluski J, Chang Chien CR, Makhson A, D’Haens G, Pintér T, Lim R, Bodoky G, Roh JK, Folprecht G, Ruff P, Stroh C, Tejpar S, Schlichting M, Nippgen J, Rougier P (2009) Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med 360:1408–1417PubMedCrossRef

30.

Bokemeyer C, Bondarenko I, Makhson A, Hartmann JT, Aparicio J, de Braud F, Donea S, Ludwig H, Schuch G, Stroh C, Loos AH, Zubel A, Koralewski P (2009) Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol 27:663–671PubMedCrossRef

31.

Van Cutsem E, Peeters M, Siena S, Humblet Y, Hendlisz A, Neyns B, Canon JL, Van Laethem JL, Maurel J, Richardson G, Wolf M, Amado RG (2007) Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol 25:1658–1664PubMedCrossRef

32.

Saltz LB, Meropol NJ, Loehrer PJ Sr, Needle MN, Kopit J, Mayer RJ (2004) Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor. J Clin Oncol 22:1201–1208PubMedCrossRef

33.

Chung KY, Shia J, Kemeny NE, Shah M, Schwartz GK, Tse A, Hamilton A, Pan D, Schrag D, Schwartz L, Klimstra DS, Fridman D, Kelsen DP, Saltz LB (2005) Cetuximab shows activity in colorectal cancer patients with tumors that do not express the epidermal growth factor receptor by immunohistochemistry. J Clin Oncol 23:1803–1810PubMedCrossRef

34.

Di Nicolantonio F, Martini M, Molinari F, Sartore-Bianchi A, Arena S, Saletti P, De Dosso S, Mazzucchelli L, Frattini M, Siena S, Bardelli A (2008) Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer. J Clin Oncol 26:5705–5712PubMedCrossRef

35.

Allegra CJ, Jessup JM, Somerfield MR, Hamilton SR, Hammond EH, Hayes DF, McAllister PK, Morton RF, Schilsky RL (2009) American society of clinical oncology provisional clinical opinion: testing for KRAS gene mutations in patients with metastatic colorectal carcinoma to predict response to anti-epidermal growth factor receptor monoclonal antibody therapy. J Clin Oncol 27:2091–2096PubMedCrossRef

36.

Jiang Y, Kimchi ET, Staveley-O’Carroll KF, Cheng H, Ajani JA (2009) Assessment of K-ras mutation: a step toward personalized medicine for patients with colorectal cancer. Cancer 115:3609–3617PubMedCrossRef

37.

Amado RG, Wolf M, Peeters M, Van Cutsem E, Siena S, Freeman DJ, Juan T, Sikorski R, Suggs S, Radinsky R, Patterson SD, Chang DD (2008) Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol 26:1626–1634PubMedCrossRef

38.

Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W, Davis N, Dicks E, Ewing R, Floyd Y, Gray K, Hall S, Hawes R, Hughes J, Kosmidou V, Menzies A, Mould C, Parker A, Stevens C, Watt S, Hooper S, Wilson R, Jayatilake H, Gusterson BA, Cooper C, Shipley J, Hargrave D, Pritchard-Jones K, Maitland N, Chenevix-Trench G, Riggins GJ, Bigner DD, Palmieri G, Cossu A, Flanagan A, Nicholson A, Ho JW, Leung SY, Yuen ST, Weber BL, Seigler HF, Darrow TL, Paterson H, Marais R, Marshall CJ, Wooster R, Stratton MR, Futreal PA (2002) Mutations of the BRAF gene in human cancer. Nature 417:949–954

39.

Riganti C, Aldieri E, Doublier S, Bosia A, Ghigo D (2008) Statins-mediated inhibition of rho GTPases as a potential tool in anti-tumor therapy. Mini Rev Med Chem 8:609–618PubMedCrossRef

40.

Stokoe D, Macdonald SG, Cadwallader K, Symons M, Hancock JF (1994) Activation of Raf as a result of recruitment to the plasma membrane. Science 264:1463–1467PubMedCrossRef

41.

Leevers SJ, Paterson HF, Marshall CJ (1994) Requirement for Ras in Raf activation is overcome by targeting Raf to the plasma membrane. Nature 369:411–414PubMedCrossRef

42.

Casey PJ (1995) Protein lipidation in cell signaling. Science 268:221–225PubMedCrossRef

43.

Rowinsky EK, Windle JJ, Von Hoff DD (1999) Ras protein farnesyltransferase: a strategic target for anticancer therapeutic development. J Clin Oncol 17:3631–3652PubMed

44.

Sepp-Lorenzino L, Ma Z, Rands E, Kohl NE, Gibbs JB, Oliff A, Rosen N (1995) A peptidomimetic inhibitor of farnesyl:protein transferase blocks the anchorage-dependent and -independent growth of human tumor cell lines. Cancer Res 55:5302–5309PubMed

45.

Kawata M, Farnsworth CC, Yoshida Y, Gelb MH, Glomset JA, Takai Y (1990) Posttranslationally processed structure of the human platelet protein smg p21B: evidence for geranylgeranylation and carboxyl methylation of the C-terminal cysteine. Proc Natl Acad Sci USA 87:8960–8964

46.

Cox AD, Hisaka MM, Buss JE, Der CJ (1992) Specific isoprenoid modification is required for function of normal, but not oncogenic, Ras protein. Mol Cell Biol 12:2606–2615

47.

Yoshida Y, Kawata M, Katayama M, Horiuchi H, Kita Y, Takai Y (1991) A geranylgeranyltransferase for rhoA p21 distinct from the farnesyltransferase for ras p21S. Biochem Biophys Res Commun 175:720–728PubMedCrossRef

48.

Rowell CA, Kowalczyk JJ, Lewis MD, Garcia AM (1997) Direct demonstration of geranylgeranylation and farnesylation of Ki-Ras in vivo. J Biol Chem 272:14093–14097PubMedCrossRef

49.

Vincent L, Chen W, Hong L, Mirshahi F, Mishal Z, Mirshahi-Khorassani T, Vannier JP, Soria J, Soria C (2001) Inhibition of endothelial cell migration by cerivastatin, an HMG-CoA reductase inhibitor: contribution to its anti-angiogenic effect. FEBS Lett 495:159–166PubMedCrossRef

50.

Bos JL (1989) Ras oncogenes in human cancer: a review. Cancer Res 49:4682–4689PubMed

51.

Andreyev HJ, Norman AR, Cunningham D, Oates JR, Clarke PA (1998) Kirsten ras mutations in patients with colorectal cancer: the multicenter “RASCAL” study. J Natl Cancer Inst 90:675–684PubMedCrossRef

52.

Fritz G, Just I, Kaina B (1999) Rho GTPases are over-expressed in human tumors. Int J Cancer 81:682–687PubMedCrossRef

53.

Liu N, Zhang G, Bi F, Pan Y, Xue Y, Shi Y, Yao L, Zhao L, Zheng Y, Fan D (2007) RhoC is essential for the metastasis of gastric cancer. J Mol Med 85:1149–1156PubMedCrossRef

54.

Liu N, Bi F, Pan Y, Sun L, Xue Y, Shi Y, Yao X, Zheng Y, Fan D (2004) Reversal of the malignant phenotype of gastric cancer cells by inhibition of RhoA expression and activity. Clin Cancer Res 10:6239–6247PubMedCrossRef

55.

Lerner EC, Qian Y, Blaskovich MA, Fossum RD, Vogt A, Sun J, Cox AD, Der CJ, Hamilton AD, Sebti SM (1995) Ras CAAX peptidomimetic FTI-277 selectively blocks oncogenic Ras signaling by inducing cytoplasmic accumulation of inactive Ras-Raf complexes. J Biol Chem 270:26802–26806PubMedCrossRef

56.

Whyte DB, Kirschmeier P, Hockenberry TN, Nunez-Oliva I, James L, Catino JJ, Bishop WR, Pai JK (1997) K- and N-Ras are geranylgeranylated in cells treated with farnesyl protein transferase inhibitors. J Biol Chem 272:14459–14464PubMedCrossRef

57.

Rao S, Cunningham D, de Gramont A, Scheithauer W, Smakal M, Humblet Y, Kourteva G, Iveson T, Andre T, Dostalova J, Illes A, Belly R, Perez-Ruixo JJ, Park YC, Palmer PA (2004) Phase III double-blind placebo-controlled study of farnesyl transferase inhibitor R115777 in patients with refractory advanced colorectal cancer. J Clin Oncol 22:3950–3957PubMedCrossRef

58.

Vogt A, Sun J, Qian Y, Hamilton AD, Sebti SM (1997) The geranylgeranyltransferase-I inhibitor GGTI-298 arrests human tumor cells in G0/G1 and induces p21(WAF1/CIP1/SDI1) in a p53-independent manner. J Biol Chem 272:27224–27229PubMedCrossRef

59.

Sun J, Blaskovich MA, Knowles D, Qian Y, Ohkanda J, Bailey RD, Hamilton AD, Sebti SM (1999) Antitumor efficacy of a novel class of non-thiol-containing peptidomimetic inhibitors of farnesyltransferase and geranylgeranyltransferase I: combination therapy with the cytotoxic agents cisplatin, Taxol, and gemcitabine. Cancer Res 59:4919–4926PubMed

60.

Lobell RB, Omer CA, Abrams MT, Bhimnathwala HG, Brucker MJ, Buser CA, Davide JP, de Solms SJ, Dinsmore CJ, Ellis-Hutchings MS, Kral AM, Liu D, Lumma WC, Machotka SV, Rands E, Williams TM, Graham SL, Hartman GD, Oliff AI, Heimbrook DC, Kohl NE (2001) Evaluation of farnesyl:protein transferase and geranylgeranyl:protein transferase inhibitor combinations in preclinical models. Cancer Res 61:8758–8768

61.

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

62.

Kaushal V, Kohli M, Mehta P, Mehta JL (2003) Potential anticancer effects of statins: fact or fiction? Endothelium 10:49–58PubMedCrossRef

63.

Wang IK, Lin-Shiau SY, Lin JK (2000) Suppression of invasion and MMP-9 expression in NIH 3T3 and v-H-Ras 3T3 fibroblasts by lovastatin through inhibition of ras isoprenylation. Oncology 59:245–254PubMedCrossRef

64.

Lee J, Lee I, Park C, Kang WK (2006) Lovastatin-induced RhoA modulation and its effect on senescence in prostate cancer cells. Biochem Biophys Res Commun 339:748–754PubMedCrossRef

65.

Collisson EA, Kleer C, Wu M, De A, Gambhir SS, Merajver SD, Kolodney MS (2003) Atorvastatin prevents RhoC isoprenylation, invasion, and metastasis in human melanoma cells. Mol Cancer Ther 2:941–948PubMed

66.

Park HJ, Kong D, Iruela-Arispe L, Begley U, Tang D, Galper JB (2002) 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors interfere with angiogenesis by inhibiting the geranylgeranylation of RhoA. Circ Res 91:143–150PubMedCrossRef

67.

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

68.

Zhao TT, Le Francois BG, Goss G, Ding K, Bradbury PA, Dimitroulakos J (2010) Lovastatin inhibits EGFR dimerization and AKT activation in squamous cell carcinoma cells: potential regulation by targeting rho proteins. Oncogene 29:4682–4692PubMedCrossRef

69.

Kato S, Smalley S, Sadarangani A, Chen-Lin K, Oliva B, Brañes J, Carvajal J, Gejman R, Owen GI, Cuello M (2010) Lipophilic but not hydrophilic statins selectively induce cell death in gynaecological cancers expressing high levels of HMGCoA reductase. J Cell Mol Med 14:1180–1193PubMed

70.

Bocci G, Fioravanti A, Orlandi P, Bernardini N, Collecchi P, Del Tacca M, Danesi R (2005) Fluvastatin synergistically enhances the antiproliferative effect of gemcitabine in human pancreatic cancer MIAPaCa-2 cells. Br J Cancer 93:319–330PubMedCrossRef

71.

Asakage M, Tsuno NH, Kitayama J, Kawai K, Okaji Y, Yazawa K, Kaisaki S, Takahashi K, Nagawa H (2004) 3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor (pravastatin) inhibits endothelial cell proliferation dependent on G1 cell cycle arrest. Anticancer Drugs 15:625–632PubMedCrossRef

72.

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

73.

Ogunwobi OO, Beales IL (2008) Statins inhibit proliferation and induce apoptosis in Barrett’s esophageal adenocarcinoma cells. Am J Gastroenterol 103:825–837PubMedCrossRef

74.

Xu XQ, McGuire TF, Blaskovich MA, Sebti SM, Romero G (1996) Lovastatin inhibits the stimulation of mitogen-activated protein kinase by insulin in HIRcB fibroblasts. Arch Biochem Biophys 326:233–237PubMedCrossRef

75.

Johnson MD, Woodard A, Okediji EJ, Toms SA, Allen GS (2002) Lovastatin is a potent inhibitor of meningioma cell proliferation: evidence for inhibition of a mitogen associated protein kinase. J Neurooncol 56:133–142PubMedCrossRef

76.

Takata M, Urakaze M, Temaru R, Yamazaki K, Nakamura N, Nobata Y, Kishida M, Sato A, Kobayashi M (2001) Pravastatin suppresses the interleukin-8 production induced by thrombin in human aortic endothelial cells cultured with high glucose by inhibiting the p44/42 mitogen activated protein kinase. Br J Pharmacol 134:753–762PubMedCrossRef

77.

Roudier E, Mistafa O, Stenius U (2006) Statins induce mammalian target of rapamycin (mTOR)-mediated inhibition of Akt signaling and sensitize p53-deficient cells to cytostatic drugs. Mol Cancer Ther 5:2706–2715PubMedCrossRef

78.

Sutter AP, Maaser K, Höpfner M, Huether A, Schuppan D, Scherübl H (2005) Cell cycle arrest and apoptosis induction in hepatocellular carcinoma cells by HMG-CoA reductase inhibitors. Synergistic antiproliferative action with ligands of the peripheral benzodiazepine receptor. J Hepatol 43:808–816PubMedCrossRef

79.

Hillyard DZ, Cameron AJ, McIntyre AH, Hadden MH, Marshall HE, Johnston N, Jardine AG (2002) Inhibition of proliferation and signalling mechanisms in human lymphocytes by fluvastatin. Clin Exp Pharmacol Physiol 29:673–678PubMedCrossRef

80.

Nishida S, Matsuoka H, Tsubaki M, Tanimori Y, Yanae M, Fujii Y, Iwaki M (2005) Mevastatin induces apoptosis in HL60 cells dependently on decrease in phosphorylated ERK. Mol Cell Biochem 269:109–114PubMedCrossRef

81.

Sekine Y, Furuya Y, Nishii M, Koike H, Matsui H, Suzuki K (2008) Simvastatin inhibits the proliferation of human prostate cancer PC-3 cells via down-regulation of the insulin-like growth factor 1 receptor. Biochem Biophys Res Commun 372:356–361PubMedCrossRef

82.

Ghosh-Choudhury N, Mandal CC, Ghosh-Choudhury N, Ghosh Choudhury G (2010) Simvastatin induces derepression of PTEN expression via NFkappaB to inhibit breast cancer cell growth. Cell Signal 22:749–758PubMedCrossRef

83.

Takeda I, Maruya S, Shirasaki T, Mizukami H, Takahata T, Myers JN, Kakehata S, Yagihashi S, Shinkawa H (2007) Simvastatin inactivates beta1-integrin and extracellular signal-related kinase signaling and inhibits cell proliferation in head and neck squamous cell carcinoma cells. Cancer Sci 98:890–899PubMedCrossRef

84.

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

85.

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

86.

Damrot J, Nübel T, Epe B, Roos WP, Kaina B, Fritz G (2006) Lovastatin protects human endothelial cells from the genotoxic and cytotoxic effects of the anticancer drugs doxorubicin and etoposide. Br J Pharmacol 149:988–997PubMedCrossRef

87.

Cho SJ, Kim JS, Kim JM, Lee JY, Jung HC, Song IS (2008) Simvastatin induces apoptosis in human colon cancer cells and in tumor xenografts, and attenuates colitis-associated colon cancer in mice. Int J Cancer 123:951–957PubMedCrossRef

88.

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

89.

Goard CA, Mather RG, Vinepal B, Clendening JW, Martirosyan A, Boutros PC, Sharom FJ, Penn LZ (2010) Differential interactions between statins and P-glycoprotein: implications for exploiting statins as anticancer agents. Int J Cancer online Mar 3

90.

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

91.

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

92.

Knox JJ, Siu LL, Chen E, Dimitroulakos J, Kamel-Reid S, Moore MJ, Chin S, Irish J, LaFramboise S, Oza AM (2005) A Phase I trial of prolonged administration of lovastatin in patients with recurrent or metastatic squamous cell carcinoma of the head and neck or of the cervix. Eur J Cancer 41:523–530PubMedCrossRef

93.

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

94.

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

95.

Lersch C, Schmelz R, Erdmann J, Hollweck R, Schulte-Frohlinde E, Eckel F, Nader M, Schusdziarra V (2004) Treatment of HCC with pravastatin, octreotide, or gemcitabine–a critical evaluation. Hepatogastroenterology 51:1099–1103PubMed

96.

Wang W, Collie-Duguid E, Cassidy J (2002) Cerivastatin enhances the cytotoxicity of 5-fluorouracil on chemosensitive and resistant colorectal cancer cell lines. FEBS Lett 531:415–420PubMedCrossRef

97.

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

98.

Feleszko W, Zagozdzon R, Golab J, Jakóbisiak M (1998) Potentiated antitumour effects of cisplatin and lovastatin against MmB16 melanoma in mice. Eur J Cancer 34:406–411PubMedCrossRef

99.

Soma MR, Pagliarini P, Butti G, Paoletti R, Paoletti P, Fumagalli R (1992) 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 52:4348–4355PubMed

100.

Huether A, Höpfner M, Baradari V, Schuppan D, Scherübl H (2005) EGFR blockade by cetuximab alone or as combination therapy for growth control of hepatocellular cancer. Biochem Pharmacol 70:1568–1578PubMedCrossRef

101.

Budman DR, Tai J, Calabro A (2007) Fluvastatin enhancement of trastuzumab and classical cytotoxic agents in defined breast cancer cell lines in vitro. Breast Cancer Res Treat 104:93–101PubMedCrossRef

102.

Cemeus C, Zhao TT, Barrett GM, Lorimer IA, Dimitroulakos J (2008) Lovastatin enhances gefitinib activity in glioblastoma cells irrespective of EGFRvIII and PTEN status. J Neurooncol 90:9–17PubMedCrossRef

103.

Dimitroulakos J, Lorimer IA, Goss G (2006) Strategies to enhance epidermal growth factor inhibition: targeting the mevalonate pathway. Clin Cancer Res 12(14 Pt 2):4426s–4431s

104.

Shimoyama S. Statins and gastric cancer risk. Hepatogastroenterology (in press)

105.

Dale KM, Coleman CI, Henyan NN, Kluger J, White CM (2006) Statins and cancer risk: a meta-analysis. JAMA 295:74–80PubMedCrossRef

Title: Statins are logical candidates for overcoming limitations of targeting therapies on malignancy: their potential application to gastrointestinal cancers
Author: Shouji Shimoyama
Publication date: 01-04-2011
Publisher: Springer-Verlag
Published in: Cancer Chemotherapy and Pharmacology / Issue 4/2011
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-011-1583-2

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