Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Cancer Chemotherapy and Pharmacology
Published in: Cancer Chemotherapy and Pharmacology 4/2014

01-04-2014 | Original Article

Simvastatin suppresses head and neck squamous cell carcinoma ex vivo and enhances the cytostatic effects of chemotherapeutics

Authors: Matthaeus Stoehr, Christian Mozet, Andreas Boehm, Achim Aigner, Andreas Dietz, Gunnar Wichmann

Published in: Cancer Chemotherapy and Pharmacology | Issue 4/2014

Login to get access

Abstract

Purpose

Simvastatin (Sim) is approved as lipid-controlling drug in patients with cardiovascular risk to reduce hypercholesterolemia. Recent publications indicate possible inhibitory effects of Sim on tumor cell lines, and epidemiological data suggest activity in cancer patients. Still, its therapeutic efficacy, particularly in head and neck squamous cell carcinoma (HNSCC), remains to be elucidated. This study analyzes the effects of Sim on HNSCC cell lines (KB, HN5, FaDu) and on a larger set of primary HNSCC cells by employing a short-time ex vivo colony formation test (FLAVINO assay). Possible additive or synergistic effects of Sim combinations with established chemotherapeutics are determined as well.

Methods

Biopsies of 49 HNSCC were tested in the FLAVINO assay with Sim alone or in combination with cisplatin (Cis) or docetaxel (DTX). Cell lines were studied for reference. Epithelial HNSCC cells were stained by Cy2-labeled anti-cytokeratin antibodies facilitating the detection of colony formation (CF) by immunofluorescence. Drug combinations were analyzed regarding their interaction.

Results

Sim alone acted suppressive on tested cell lines and increased the cytostatic efficacy of Cis and DTX. 18/49 HNSCC qualified for FLAVINO-based dose-response analyses, and Sim significantly suppressed CF in 18/18 primary HNSCC. Moreover, Sim increased cytotoxic effects of Cis and DTX, primarily in an additive mode of action.

Conclusions

The ex vivo tumor cell inhibition of Sim and its additive effects upon combination with established cytostatics provide the basis for epidemiological and clinical studies on statins, potentially directed toward co-medication in future treatment regimens.
Literature
1.
Ridker PM, MacFadyen JG, Fonseca FAH, Genest J, Gotto AM, Kastelein JJP et al (2009) Rosuvastatin to prevent vascular events in men and women with elevated c-reactive protein. Circ Cardiovasc Qual Outcomes 2:616–623PubMedCrossRef
2.
Emberson JR, Kearney PM, Blackwell L, Newman C, Reith C, Bhala N et al (2012) Lack of effect of lowering LDL cholesterol on cancer: meta-analysis of individual data from 175,000 people in 27 randomised trials of statin therapy. PLoS One 7:e29849PubMedCrossRef
3.
Jakobisiak M, Golab J (2003) Potential antitumor effects of statins (review). Int J Oncol 23:1055–1069PubMed
4.
Fritz G (2009) Targeting the mevalonate pathway for improved anticancer therapy. Curr Cancer Drug Targets 9:626–638PubMedCrossRef
5.
Fritz G (2005) HMG-CoA reductase inhibitors (statins) as anticancer drugs (review). Int J Oncol 27:1401–1409PubMed
6.
Zeichner S, Mihos CG, Santana O (2012) The pleiotropic effects and therapeutic potential of the hydroxy-methyl-glutaryl-CoA reductase inhibitors in malignancies: a comprehensive review. J Cancer Res Ther 8:176–183PubMedCrossRef
7.
Kim WS, Kim MM, Choi HJ, Yoon SS, Lee MH, Park K et al (2001) Phase II study of high-dose lovastatin in patients with advanced gastric adenocarcinoma. Invest New Drugs 19:81–83PubMedCrossRef
8.
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
9.
Sacks FM, Pfeffer MA, Moye LA, Rouleau JL, Rutherford JD, Cole TG et al (1996) The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and recurrent events trial investigators. N Engl J Med 335:1001–1009PubMedCrossRef
10.
Schachter M (2005) Chemical, pharmacokinetic and pharmacodynamic properties of statins: an update. Fundam Clin Pharmacol 19:117–125PubMedCrossRef
11.
Nielsen SF, Nordestgaard BG, Bojesen SE (2012) Statin use and reduced cancer-related mortality. N Engl J Med 367:1792–1802PubMedCrossRef
12.
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
13.
Yanae M, Tsubaki M, Satou T, Itoh T, Imano M, Yamazoe Y et al (2011) Statin-induced apoptosis via the suppression of ERK1/2 and Akt activation by inhibition of the geranylgeranyl-pyrophosphate biosynthesis in glioblastoma. J Exp Clin Cancer Res 30:74PubMedCentralPubMedCrossRef
14.
Ogunwobi OO, Beales ILP (2008) Statins inhibit proliferation and induce apoptosis in Barrett’s esophageal adenocarcinoma cells. Am J Gastroenterol 103:825–837PubMedCrossRef
15.
Cho S, Kim JS, Kim JM, Lee JY, Jung HC, Song S (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
16.
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 22:749–758PubMedCentralPubMedCrossRef
17.
Kato S, Smalley S, Sadarangani A, Chen-Lin K, Oliva B, Brañes J et al (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
18.
Takeda I, Maruya S, Shirasaki T, Mizukami H, Takahata T, Myers JN et al (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
19.
Dietz A, Boehm A, Horn I, Kruber P, Bechmann I, Golusinski W et al (2010) Assay-based response evaluation in head and neck oncology: requirements for better decision making. Eur Arch Otorhinolaryngol 267:483–494PubMedCrossRef
20.
Dietz A (2009) Method and kit for the ex vivo evaluation of the response of a tumor to conditions to be tested. International publication number WO 2009/124997, PCT/EP2009/054297
21.
Schrader C, Boehm A, Reiche A, Dietz A, Mozet C, Wichmann G (2012) Combined effects of lapatinib and cisplatin on colony formation of head and neck squamous cell carcinoma. Anticancer Res 32:3191–3199PubMed
22.
Horvat S, McWhir J, Rozman D (2011) Defects in cholesterol synthesis genes in mouse and in humans: lessons for drug development and safer treatments. Drug Metab Rev 43:69–90PubMedCrossRef
23.
24.
Edison RJ, Muenke M (2004) Central nervous system and limb anomalies in case reports of first-trimester statin exposure. N Engl J Med 350:1579–1582PubMedCrossRef
25.
Mozet C, Stoehr M, Dimitrova K, Dietz A, Wichmann G (2013) Hedgehog targeting by cyclopamine suppresses head and neck squamous cell carcinoma and enhances chemotherapeutic effects. Anticancer Res 33:2415–2424PubMed
26.
27.
Sobin LH, Gospodarowicz MK, Wittekind C (2010) TNM classification of malignant tumours. International union against cancer, 7th edn. Wiley, Chichester
28.
Desoize B, Berthiot G, Manot L, Coninx P, Dumont P (1996) Evaluation of a prediction model of cisplatin dose based on total platinum plasma concentration. Eur J Cancer 32A:1734–1738PubMedCrossRef
29.
Bissett D, Setanoians A, Cassidy J, Graham MA, Chadwick GA, Wilson P et al (1993) Phase I and pharmacokinetic study of taxotere (RP 56976) administered as a 24-hour infusion. Cancer Res 53:523–527PubMed
30.
Jin Z (2004) About the evaluation of drug combination. Acta Pharmacol Sin 25:146–147PubMed
31.
Graaf MR, Beiderbeck AB, Egberts ACG, Richel DJ, Guchelaar H (2004) The risk of cancer in users of statins. J Clin Oncol 22:2388–2394PubMedCrossRef
32.
Ahern TP, Pedersen L, Tarp M, Cronin-Fenton DP, Garne JP, Silliman RA et al (2011) Statin prescriptions and breast cancer recurrence risk: a Danish nationwide prospective cohort study. J Natl Cancer Inst 103:1461–1468PubMedCentralPubMedCrossRef
33.
Chae YK, Valsecchi ME, Kim J, Bianchi AL, Khemasuwan D, Desai A et al (2011) Reduced risk of breast cancer recurrence in patients using ACE inhibitors, ARBs, and/or statins. Cancer Invest 29:585–593PubMedCrossRef
34.
Farwell WR, D’Avolio LW, Scranton RE, Lawler EV, Gaziano JM (2011) Statins and prostate cancer diagnosis and grade in a veterans population. J Natl Cancer Inst 103:885–892PubMedCrossRef
35.
Singh PP, Singh S (2013) Statins are associated with reduced risk of gastric cancer: a systematic review and meta-analysis. Ann Oncol 24:1721–1730PubMedCrossRef
36.
Knox JJ, Siu LL, Chen E, Dimitroulakos J, Kamel-Reid S, Moore MJ et al (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
37.
Ziviani L, Da Ros L, Squassante L, Milleri S, Cugola M, Iavarone LE (2001) The effects of lacidipine on the steady/state plasma concentrations of simvastatin in healthy subjects. Br J Clin Pharmacol 51:147–152PubMedCentralPubMedCrossRef
38.
Goard CA, Mather RG, Vinepal B, Clendening JW, Martirosyan A, Boutros PC et al (2010) Differential interactions between statins and P-glycoprotein: implications for exploiting statins as anticancer agents. Int J Cancer 127:2936–2948PubMedCrossRef
39.
Clendening JW, Penn LZ (2012) Targeting tumor cell metabolism with statins. Oncogene 31:4967–4978PubMedCrossRef
40.
Dimitrova K, Stoehr M, Dehghani F, Dietz A, Wichmann G, Bertolini J et al (2013) Overexpression of the Hedgehog signalling pathway in head and neck squamous cell carcinoma. Onkologie 36:279–286PubMedCrossRef
41.
Incardona JP, Gaffield W, Kapur RP, Roelink H (1998) The teratogenic Veratrum alkaloid cyclopamine inhibits sonic hedgehog signal transduction. Development 125:3553–3562PubMed
42.
Schneider S, Thurnher D, Kloimstein P, Leitner V, Petzelbauer P, Pammer J et al (2011) Expression of the sonic hedgehog pathway in squamous cell carcinoma of the skin and the mucosa of the head and neck. Head Neck 33:244–250PubMedCrossRef
43.
Wang Y, Chang C, Lin C, Chang S, Chu P, Tai S et al (2012) Expression of hedgehog signaling molecules as a prognostic indicator of oral squamous cell carcinoma. Head Neck 34:1556–1561PubMedCrossRef
Metadata
Title
Simvastatin suppresses head and neck squamous cell carcinoma ex vivo and enhances the cytostatic effects of chemotherapeutics
Authors
Matthaeus Stoehr
Christian Mozet
Andreas Boehm
Achim Aigner
Andreas Dietz
Gunnar Wichmann
Publication date
01-04-2014
Publisher
Springer Berlin Heidelberg
Published in
Cancer Chemotherapy and Pharmacology / Issue 4/2014
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI
https://doi.org/10.1007/s00280-014-2412-1

Other articles of this Issue 4/2014

Cancer Chemotherapy and Pharmacology 4/2014 Go to the issue

Short Communication

The interactions of lenalidomide with human uptake and efflux transporters and UDP-glucuronosyltransferase 1A1: lack of potential for drug–drug interactions

Original Article

A phase II study of capecitabine plus docetaxel in gemcitabine-pretreated metastatic pancreatic cancer patients: CapTere

Original Article

Salvage chemotherapy with docetaxel and pegylated liposomal doxorubicin in pretreated patients with platinum- and taxane-sensitive ovarian cancer: a multicenter phase II trial of the Hellenic Oncology Research Group (HORG)

Original Article

Phase I dose-escalation and pharmacokinetic study (TED 11576) of cabazitaxel in Japanese patients with castration-resistant prostate cancer

Original Article

Population pharmacokinetics of afatinib, an irreversible ErbB family blocker, in patients with various solid tumors

Review Article

Therapy resistance mechanisms in Ewing’s sarcoma family tumors
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits