|Year : 2012 | Volume
| Issue : 2 | Page : 176-183
The pleiotropic effects and therapeutic potential of the hydroxy-methyl-glutaryl-CoA reductase inhibitors in malignancies: A comprehensive review
Simon Zeichner1, Christos G Mihos2, Orlando Santana1
1 Department of Internal Medicine, Mount Sinai Medical Center, Miami Beach, Florida, USA
2 Columbia University Division of Cardiology at Mount Sinai Heart Institute, Miami Beach, Florida, USA
|Date of Web Publication||26-Jul-2012|
Echocardiography Laboratory Mount Sinai Heart Institute 4300 Alton Road Miami Beach, Florida 33140
Source of Support: None, Conflict of Interest: None
The hydroxy-methyl-glutaryl-CoA reductase inhibitors (statins) are used extensively in the treatment of hyperlipidemia. They have also demonstrated a benefit in a variety of other disease processes via actions known as pleiotropic effects. Our paper serves as a focused review of pre-clinical investigations and published clinical data regarding the pleiotropic effects of statins in malignancies and emphasizes the importance of randomized, placebo-controlled trials to further elucidate this interesting phenomenon.
Keywords: Cancer, HMG-CoA-reductase, malignancies, pleiotropic effects, statins
|How to cite this article:|
Zeichner S, Mihos CG, Santana O. The pleiotropic effects and therapeutic potential of the hydroxy-methyl-glutaryl-CoA reductase inhibitors in malignancies: A comprehensive review. J Can Res Ther 2012;8:176-83
|How to cite this URL:|
Zeichner S, Mihos CG, Santana O. The pleiotropic effects and therapeutic potential of the hydroxy-methyl-glutaryl-CoA reductase inhibitors in malignancies: A comprehensive review. J Can Res Ther [serial online] 2012 [cited 2022 Jan 28];8:176-83. Available from: https://www.cancerjournal.net/text.asp?2012/8/2/176/98967
| > Introduction|| |
The use of statins is essential in the treatment of hyperlipidemia as well as for the primary and secondary prevention of coronary artery disease and stroke. , Studies have shown that statins also possess powerful pleiotropic effects independent of their cholesterol-lowering properties in a wide range of disease processes. ,, This includes the upregulation of endothelial nitric oxide synthase and decreased production of nicotinamide adenine dinucleotide phosphate-oxidase, which enhances vascular endothelial function, reduces the amount of reactive oxidant species, and improves pathophysiologic response. , Downregulation of proinflammatory cytokines, immunomodulation, plaque stabilization, normalization of sympathetic outflow, decreased activation of the blood coagulation cascade, and inhibition of platelet aggregation have also been proposed as likely mechanisms for statin pleiotropy [Table 1]. ,
Mounting evidence has begun to suggest that statins may play an important role in the prevention and treatment of a variety of malignancies, as they have been shown to possess anti-tumor proliferating properties and promote tumor cell apoptosis, among other effects. , The following is a review of the current literature regarding the potential therapeutic benefits and pleiotropic effects of statins in malignancies [Table 2].
| > Materials and Methods|| |
A comprehensive search of PubMed for published literature addressing the use of statins in malignancies was performed. All study types were considered for inclusion if they contained robust data on statin effects in preclinical models of cancer or on statins as therapeutic agents in cancer patients. Studies were excluded if they were published in abstract form only, or were not available in English. Studies were identified using appropriate subject headings and the text words "statins," "hydroxyl-methyl-glutaryl-CoA reductase inhibitors," "cancer," "malignancy" and/or "pleiotropic." SZ, CGM and OS independently screened and assessed the citations.
| > Breast Cancer|| |
Statins have shown marked activity against breast cancer cells at the molecular level. The Rho family guanine triphosphatases are promoters of countless cellular functions, including tumor cell migration and invasion. They are frequently overexpressed in breast cancer cells, and have been shown to be inhibited by statins via the downregulation of RhoA and RhoC proteins.  Statins have also been shown to inhibit Ras and nuclear factor kappa-B (NF-kappaB), two proteins responsible for breast cancer cell invasiveness. This inhibition of NF-kappaB attenuates the expression of anti-apoptotic protein Bcl-xl, while simultaneously increasing the expression of the tumor suppressor protein PTEN. , Furthermore, tumor-specific expression in breast cancer cells of the statin rate-limiting enzyme hydroxy-methyl-glutaryl-CoA reductase has been associated with tumors that are small, low grade and low proliferating, while harboring estrogen positivity.  Finally, statins have been shown to inhibit breast cancer cell proliferation, adhesion and motility, while inducing cell cycle arrest and apoptosis. ,,
Data has generally shown a positive effect of statins on breast cancer in terms of disease prevention and increased patient survival. The largest cohort study to report on the association between statin use and invasive breast cancer analyzed 156,351 postmenopausal, cancer-free women enrolled in the Women's Health Initiative. Over an average follow-up period of nearly 7 years, hydrophobic statin use (simvastatin, lovastatin, fluvastatin) was associated with an 18% reduction in breast cancer (P = 0.02).  However, statins were only used by 7.5% of the cohort, and no information was available regarding dosage regimens. Kumar et al.  retrospectively analyzed 2141 patients in the Kaiser Permanente Northern California Cancer Registry, and found a 37% reduction in the development of estrogen receptor/progesterone receptor-negative breast cancer in patients with at least 1 year of statin use prior to diagnosis (P = 0.02), with those developing breast cancer having a greater likelihood of low-grade or less-invasive tumors. Analysis of a central database in this study allowed for accruement of accurate data regarding total patient exposure to statins. In the Life After Cancer Epidemiology (LACE) study, 1945 early-stage breast cancer survivors were shown to have a 33% decreased risk of breast cancer recurrence with postdiagnosis statin use, an effect that was magnified with increasing duration of statin use (P = 0.02).  Synergistic activity of statins with previously established treatments for breast cancer has also been described. ,
While statins are showing promise as possible preventative agents for breast cancer, it is important to note that some studies have also demonstrated a neutral or negative effect in this population. A meta-analysis of seven randomized controlled trials and nine observational studies revealed that statin use did not significantly affect breast cancer risk, findings that are tempered by the short-term patient follow-up of 5 years.  A small, hospital-based, case-control study involving 95 overweight, postmenopausal women who were newly diagnosed with cancer found no overall association between statin use and breast cancer. However, the specific use of hydrophobic statins (simvastatin, lovastatin, fluvastatin) was associated with a four-fold increased risk of developing progesterone receptor-negative breast cancer. 
| > Colon Cancer|| |
In vitro studies have proven that hydroxy-methyl-glutaryl-CoA reductase and low-density lipoprotein (LDL) receptors are present in higher levels in colorectal cancer (CRC) cells as compared with normal mucosa, prompting investigation into the potential effects that statins may exert on CRC cells.  Simvastatin has been shown to augment capsase-3 activity and downregulate the anti-apoptotic gene Bcl-2, leading to suppression of CRC cell angiogenesis while promoting tumor cell death.  Additionally, treatment of CRC cells with statins decreases the levels of several proinflammatory cytokines and downregulates special AT-rich sequence binding protein (SATB1), a molecule that regulates the expression of cancer cells and has been implicated in tumor metastasis. ,,
A recent meta-analysis of statin use in CRC patients by Bardou et al.  included 34 trials, 11 of which were randomized controlled studies. The authors found that statin use was associated with an 8% reduction in the risk of CRC, which supported an earlier meta-analysis that cited a 9% reduction in the risk of CRC among statin users.  In both studies, secondary analyses revealed that the protective effects were present only in case-control studies, and the authors noted that many of the studies analyzed were not designed to assess cancer incidence and survival, especially among the randomized controlled trials. Furthermore, while a retrospective analysis of 2626 statin users showed a 49% reduction in adenomatous polyp recurrence 3-5 years post initial polypectomy (P < 0.01), as well as a smaller number of polyps (P = 0.002), smaller polyp size (P = 0.03) and lower incidence of advanced polyps (P = 0.03),  other studies have suggested that long-term statin use may be associated with increased risk of developing colorectal adenomas. In a secondary analysis of 2035 adenoma patients enrolled in the Adenoma Prevention with Celecoxib (APC) trial, Bertagnolli et al.  found a 39% increased risk of newly detected adenomas in patients taking statins for at least 3 years (P = 0.024). Similar results were reported by Eddi et al.  who found a 54% increased risk of new colorectal adenomas in type-two diabetics on statins, who had a prior history of colorectal adenomas (P = 0.007).
While the efficacy of statins in the prevention of CRC remains controversial, strong evidence exists to support a synergistic effect with concomitant chemotherapeutic or anti-inflammatory treatment. In vitro treatment of CRC cells with statins has been shown to: (1) increase the amount of apoptosis from treatment with 5-fluorouracil and cisplatin, (2) reduce proliferation of KRas mutant tumor cells treated with cetuximab, (3) increase the efficacy of doxorubicin by enhancing its effects on the NF-kappaB pathway and upregulating nitric oxide synthase expression, and (4) suppress the expression of the tumor promoter caveolin-1, an integral membrane protein implicated in aggressive tumor metastasis, in cells concomitantly treated with celecoxib. ,,,
| > Prostate Cancer|| |
Various mechanisms have been suggested for the effects of statins on the natural progression of prostate cancer. The purported decreases in prostate cancer cell viability, as well as induction of cancer cell apoptosis and cell cycle disruption, likely result from: (1) suppression of RhoA protein, which leads to the activation of several caspase cysteine proteases responsible for cellular apoptosis, (2) downregulation of the Akt signaling pathway, which results in the inhibition of tumor cell migration, invasion, colony formation and proliferation, (3) increased proteolysis of androgen receptors while decreasing their expression and androgen sensitivity in cancer cells, and (4) induction of autophagy via the inhibition of posttranslational protein modification. [55-59]
A retrospective review of 4204 men who underwent prostate biopsy at the Cleveland Clinic,  25% of whom were taking statins, revealed that statin use was associated with an 8%, 24% and 16% reduced risk of prostate cancer, high-grade cancer and high-volume disease, respectively. In a separate retrospective analysis, 691 men with prostate adenocarcinoma treated with radiotherapy were followed-up at a median of 50 months posttreatment. Statin use was found to confer improved freedom from biochemical failure (P < 0.001), freedom from salvage androgen deprivation therapy (P = 0.001) and relapse-free survival (P < 0.001).  Additionally, after adjusting for nonsteroidal anti-inflammatory drug prescriptions, statin use among 236 men undergoing radical prostactectomy was shown to be associated with a 69% reduction in intratumoral inflammation (P = 0.047).  This suggests that statins may help prevent the development of advanced carcinoma, as the presence of imflammatory prostatic infiltrate has been shown to strongly correlate with prostate cancer outcomes. 
The true efficacy of statins in improving patient outcomes and preventing prostate cancer development has been questioned by several studies, with some suggesting that statins may promote the development of prostate malignancy. A meta-analysis by Bonovas et al.  of six randomized, placebo-controlled trials and 13 observational studies, which included nearly 900,000 male patients, sought to assess the relationship between statin use and the incidence of total and advanced prostate cancer. While statins were shown to offer no protection against total prostate cancer, they were associated with a 23% risk reduction in advanced carcinoma. A retrospective case-control study involving 388 first-time prostate cancer patients aged 50 years or older, matched to 1552 controls, found that ever-use of statins was associated with a 55% increased risk in total prostate cancer.  An elevated total prostate cancer risk was also reported among statin users by Murtola et al.;  however, they did observe a 39% decreased risk of advanced disease in users of atorvastatin, lovastatin and simvastatin. The main limitation of these studies is the lack of data concerning prostate-specific antigen testing and medical visits, which could possibly skew any protective effects of statins on prostate cancer due to clinical detection of disease.
| > Lung Cancer|| |
The standard of care for the treatment of lung cancer typically involves a form of adjuvant chemotherapy and radiation. With this in mind, statins are being investigated as possible therapeutic agents utilizing lung cancer cell lines. Park et al.  have demonstrated that in human nonsmall cell lung cancer cells with a Kras mutation, gefitinib treatment in combination with lovastatin can help overcome chemotherapy-induced resistance by downregulating Ras protein thus blunting tumor growth pathway activation. Additionally, statins may sensitize lung cancer cells to the effects of chemotherapy and ionizing radiation by impairing various growth factors and inducing the apoptosis of cancer cells via the inhibition of the Akt pathway, which plays a major role in tumor cell proliferation, survival and invasiveness. ,, Other in vitro studies have shown that statins modulate the activity of tumor suppressors, proinflammatory proteases and cell cycle regulatory proteins, inhibiting the formation of lung cancer cells. ,,
Clinical data regarding the use of statins as anti-tumor or therapeutic agents in lung cancer is limited. In a retrospective case-control study involving 483,733 patients enrolled in the Veterans Integrated Service Network, Khurana et al.  found that patients using statins for greater than 6 months had a 55% reduction in the development of lung cancer (P < 0.01). While the protective effect was observed in smokers, other risk factors for the development of lung carcinoma, such as environmental exposures and underlying parenchymal lung disease, were not analyzed. Conversely, a phase two trial consisting of 61 patients with untreated extensive-disease small-cell lung cancer, who were given 40 mg of simvastatin daily along with irinotecan and cisplatin chemotherapy, failed to show any benefit in 1-year survival. 
| > Hepatocellular Cancer|| |
In addition to its anti-inflammatory effects on hepatocellular carcinoma (HCC) cells, researchers have proposed several unique mechanisms by which statins induce apoptosis and cell cycle arrest in vitro, including (1) breakdown of HCC cell mitochondrial membrane potential, while simultaneously activating caspases and promoting nuclear degradation, (2) downregulation of cell cycle regulators such as cyclin-dependant kinases and cyclins and upregulation of cell cycle inhibitors, and (3) decreased phosphorylation of the proto-oncogenic transcription factor Myc. ,, The addition of statins to various HCC cell lines in vitro has been shown to diminish tumor cell growth and induce apoptosis, particularly when combined with other anti-tumor agents such as doxorubicin. ,
Graf et al.  prospectively evaluated 183 HCC patients undergoing palliative transarterial chemoembolization (TAE), 131 of who underwent TAE solely, and 52 who were also given 20-40 mg of pravastatin daily. Over a maximum follow-up of 5 years, the median survival was significantly longer in patients treated with TAE and pravastatin versus TAE alone (20.9 versus 12.0 months, P = 0.003). Similar results were reported by Kawata et al.  who randomized 83 patients undergoing TAE and taking 5-fluorouracil for unresectable HCC to either 40 mg of pravastatin daily (n = 42) or placebo (n = 41). At a mean follow-up of 16.5 ± 9.8 months, survival was significantly prolonged in the pravastatin group compared with the placebo group (18 versus 9 months, P = 0.006). Finally, a matched case-control study of diabetic HCC patients compared 1303 patients with 5212 control subjects, and found a 37% reduction in HCC among patients who took statin medications over a 2.5-year period and had no previous liver disease. 
| > Hematologic Cancers|| |
The pleiotropic effects of statins in hematologic malignancies are thought to be the result of apoptotic and anti-inflammatory mechanisms. Notably, in vitro studies have shown that statins prevent prenylation and geranylgeranylation of several target proteins, including Ras, RhoA and ERK 1 and 2. This results in altered membrane localization of these proteins and inhibits their function of downstream signal transduction, leading to tumor cell apoptosis. , Statins also negatively effect tumor cell adhesion, migration and chemotaxis, , and their synergism with multiple conventional anti-tumor agents has been described. ,,, However, statins have also been implicated in interfering with the detection of CD20 and disrupting the anti-lymphoma activity of rituximab in lymphoma cell lines, leading to speculation regarding their true clinical potential. 
In the Environmental Exposures and Lymphoid Neoplasms (EPILYMPH) study, which included 2362 patients with B- and T-cell lymphoma matched to 2206 controls, Fortuny et al.  found a 39% decrease in the incidence of lymphomas among regular statin users, irrespective of treatment duration. This was a transnational study with a large sample size, in which detailed interviews were conducted at diagnosis regarding family history and risk factors for lymphoma. Statin use at diagnosis and treatment initiation for follicular lymphoma was shown by Nowakowski et al.  to be associated with a 55% improvement in event-free survival (P = 0.001), with a 7% greater benefit in those whose regimens contained rituximab (P = 0.04). A phase two trial in six patients with multiple myeloma resistant to two cycles of bortezomib or bendamustine revealed that 80 mg of simvastatin daily, when admininstered concomitantly with two further cycles of chemotherapy, reduced drug resistance without causing significant drug toxicity.  A separate study involving 179 incidental multiple myeloma cases and 691 controls showed that statin use was associated with a 60% decreased risk for developing multiple myeloma in women.  These findings are in contrast to a phase two trial involving six multiple myeloma patients by Sondergaard et al.  who administered simvastatin (15 mg/kg/day) in addition to conventional therapy for 1 week, followed by 3 weeks of no statin treatment, for two successive 4-week cycles. No benefit on bone turnover was observed, and statin treatment may actually have been detrimental due to increased osteoclast activity. A case-control study by Iwata et al.  included 221 incident cases of lymphoid malignancies matched with 442 and 437 orthopedic and otorhinolaryngolic patients, respectively. A greater than two-fold increase in statin use among patients with lymphoma or multiple myeloma was observed when compared with patients with orthopedic (P = 0.009) or otorhinolaryngolic (P = 0.001) malignancies.
| > Discussion|| |
The therapeutic potential of statins in the prevention and treatment of malignancies has been observed in patients with breast, colon, prostate, lung, hepatocellular and hematologic cancer. Data continues to emerge, suggesting that statin pleiotropy may extend to a larger number of malignancies, as evidenced by (1) induction of cancer cell apoptosis and chemotherapeutic drug synergism by statins in patients with ovarian cancer, (2) an observed 67% reduction in the risk of pancreatic cancer with at least 6 months of statin use (P < 0.01), which increases to 80% if prescribed for more than 4 years (P < 0.01), (3) significant reduction in melanoma cell migration and metastasis in murine models treated with statins, as well as a 19% reduction in Breslow thickness (P = 0.03) in statin users with melanoma, (4) a nearly 50% reduction in the risk of renal cell carcinoma with statin use observed across different gender and age groups, and (5) sensitization of glioblastoma cells to gefitinib treatment, as well as decreased tumor size and increased survival in pediatric patients with brain stem tumors treated with statins and conventional chemotherapeutic regimens. ,,,,,,
While a large amount of data exists supporting the possible use of statins in malignancies, it is important to note that several studies have conversely shown that statins may in fact promote the development of cancer. A metaanalysis of 42 studies, which included 17 randomized trials, by Kuoppala et al.  revealed that while statin use had no overall effect on the incidence of cancer, there was a weak association between statins and increased incidence of melanoma and nonmelanoma skin cancer over a median follow-up of 4 years. In a large population-based case-controlled study comparing 88,125 primary cancer cases and 362,254 matched controls, Vinogradova et al.  also observed no effect of statin use on overall cancer risk. However, greater than 4 years of statin use was associated with a 23% increased risk of colorectal cancer, 29% increased risk of bladder cancer and 18% increased risk of lung cancer. Evidence also exists suggesting an association between statins and breast and prostate cancer. [,61],,
Although a substantial amount of evidence suggests that there may be role for statins as preventative agents or as an adjuvant treatment option in cancer patients, recommendations and guidelines on their use in malignancies do not exist. Several randomized controlled trials are currently taking place to further elucidate the link between statins and malignancies [Table 3]. ,,,,,,,,
|Table 3: Ongoing randomized clinical trials of statin use in malignancies|
Click here to view
| > Conclusion|| |
The major limitations that temper conclusions regarding statin use in the treatment and prevention of malignancies stem from the observational or retrospective nature of the majority of the studies as well as the generally small sample sizes. Large, randomized, placebo-controlled trials will be pivotal in corroborating or repudiating the numerous in vitro and in vivo studies supporting the use of statins in malignancies, as well as clarifying data that exists on potential links between statins and cancer development. Future studies will need to identify the specific populations that may benefit from statin use and address the variability that exists among published studies with respect to methodology, design and determination of primary end points. Ultimately, the development of recommendations or guidelines for the use of statins as preventative agents or as an adjuvant treatment option in selected malignancies will help guide clinical practice, and is of utmost importance.
| > References|| |
Pignone M, Phillips C, Mulrow C. Use of lipid lowering drugs for primary prevention of coronary heart disease: Meta-analysis of randomized trials. BMJ 2000;321:983-5.
Tonkin A, Aylward P, Colquhoun D, Glasziou P, Harris P, Huntet D, et al
. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) study group. N Engl J Med 1998;339:1349-57.
Mihos CG, Santana O. Pleiotropic effects of the HMG-CoA reductase inhibitors. Int J Gen Med 2011;4:261-71.
Mihos CG, Salas MJ, Santana O. The pleiotropic effects of the hydroxy-methyl-glutaryl-CoA reductase inhibitors in cardiovascular disease: A comprehensive review. Cardiol Rev 2010;18:298-304.
Mihos CG, Artola RT, Santana O. The pleiotropic effects of the hydroxy-methyl-glutaryl-CoA reductase inhibitors in rheumatologic disorders: A comprehensive review. Rheumatol Int 2012;32:287-94.
Endres M. Statins and stroke. J Cereb Blood Flow Metab 2005;25:1093-110.
Liao JK. Beyond lipid lowering: The role of statins in vascular protection. Int J Cardiol 2002;86:5-18.
Li J, Li JJ, He JG, Nan JL, Guo YL, Xiong CM. Atorvastatin decreases C-reactive protein-induced inflammatory response in pulmonary artery smooth muscle cells by inhibiting nuclear factor-kappa B pathway. Cardiovasc Ther 2010;28:8-14.
Tandon V, Bano G, Khajuria V, Parihar A, Gupta S. Pleiotropic effects of statins. Indian J Pharmacol 2005;37:77-85.
Li YC, Park MJ, Ye SK, Kim CW, Kim YN. Elevated levels of cholesterol-rich lipid rafts in cancer cells are correlated with apoptosis sensitivity induced by cholesterol-depleting agents. Am J Pathol 2006;168:1107-18.
Dulak J, Józkowicz A. Anti-angiogenic and anti-inflammatory effects of statins: Relevance to anti-cancer therapy. Curr Cancer Drug Targets 2005;5:579-94.
Cauley JA, McTiernan A, Rodabough RJ, LaCroix A, Bauer DC, Margolis KL, et al
. Statin use and breast cancer: Prospective results from the Women's Health Initiative. J Natl Cancer Inst 2006;98:700-7.
Kumar AS, Benz CC, Shim V, Minami CA, Moore DH, Esserman LJ. Estrogen receptor-negative breast cancer is less likely to arise among lipophilic statin users. Cancer Epidemiol Biomarkers Prev 2008;17:1028-33.
Kwan ML, Habel LA, Flick ED, Quesenberry CP, Caan B. Post-diagnosis statin use and breast cancer recurrence in a prospective cohort study of early breast cancer survivors. Breast Cancer Res Treat 2008;109:573-9.
Eaton M, Eklof J, Beal JR, Sahmoun AE. Statins and breast cancer in postmenopausal women without hormone therapy. Anticancer Res 2009;29:5143-8.
Bardou M, Barkun A, Martel M. Effect of statin therapy on colorectal cancer. Gut 2010;59:1572-85.
Bonovas S, Filioussi K, Flordellis CS, Sitaras NM. Statins and the risk of colorectal cancer: A meta-analysis of 18 studies involving more than 1.5 million patients. J Clin Oncol 2007 10;25:3462-8.
Siddiqui AA, Nazario H, Mahgoub A, Pandove S, Cipher D, Spechler SJ. The long term use of statins is associated with a decrease incidence of adenomatous colon polyps. Digestion 2009;79:17-22.
Bertagnolli MM, Hsu M, Hawk ET, Eagle CJ, Zauber AG. Statin use and colorectal adenoma risk: Results from the adenoma prevention with celecoxib trial. Cancer Prev Res (Phila) 2010;3:588-96.
Eddi R, Karki A, Shah A, DeBari VA, DePasquale JR. Association of type 2 diabetes and colon adenomas. J Gastrointest Cancer. 2012;43(1):87-92.
Agarwal B, Bhendwal S, Halmos B, Moss SF, Ramey WG, Holt PR. Lovastatin augments apoptosis induced by chemotherapeutic agents in colon cancer cell. Clin Cancer Res 1999;5:2223-9.
Lee J, Lee I, Han B, Park JO, Jang J, Park C. Effect of simvastatin on cetuximab resistance in human colorectal cancer with KRAS mutations. J Natl Cancer Inst 2011;103:674-88.
Riganti C, Doublier S, Costamagna C, Aldieri E, Pescarmona G, Ghigo D. Activation of nuclear factor-kappa B pathway by simvastatin and RhoA silencing increases doxorubicin cytotoxicity in human colon cancer HT29 cells. Mol Pharmacol 2008;72:476-84.
Guruswamy S, Rao CV. Synergistic effects of lovastatin and celecoxib on caveolin-1 and its down-stream signaling molecules: Implications for colon cancer prevention. Int J Oncol 2009;35:1037-43.
Tan N, Klein EA, Li J, Moussa AS, Jones JS. Statin use and risk of prostate cancer in a population of men who underwent biopsy. J Urol 2011;186:86-90.
Gutt R, Tonlaar N, Kunnavakkam R, Karrison T, Weichselbaum RR, Liauw SL. Statin use and risk of prostate cancer recurrence in men treated with radiation therapy. J Clin Oncol 2010;28:2653-9.
Bañez LL, Klink JC, Jayachandran J, Lark AL, Gerber L, Hamilton RJ, et al
. Association between statins and prostate tumor inflammatory infiltrate in men undergoing radical prostatectomy. Cancer Epidemiol Biomarkers Prev 2010;19:722-8.
Hwang KE, Na KS, Park DS, Choi KH, Kim BR, Shim H, et al
. Apoptotic induction by simvastatin in human lung cancer A549 cell via Akt signaling dependent down-regulation of surviving. Invest New Drugs 2010;29:945-52.
Graf H, Jüngst C, Straub G, Dogan S, Hoffmann RT, Jakobs T, et al
. Chemoembolization combined with pravastatin improves survival in patients with hepatocellular carcinoma. Digestion 2008;78:34-8.
Kawata S, Yamasaki E, Nagase T, Inui Y, Ito N, Matsuda Y, et al
. Effect of pravastatin on survival in patients with advanced hepatocellular carcinoma. A randomized controlled trial. Br J Cancer 2001;84:886-91.
El-Serag HB, Johnson ML, Hachem C, Morgana RO. Statins associated with a reduced risk of hepatocellular carcinoma in a large cohort of patients with diabetes. Gastroenterology 2009;136:1601-8.
Fortuny J, de Sanjosé S, Becker N, Maynadié M, Cocco PL, Staines A, et al
. Statin use and risk of lymphoid neoplasms: Results from the European Case-control study EPILYMPH. Cancer Epidemiol Biomarkers Prev 2006;15:921-5.
Nowakowski GS, Maurer MJ, Habermann TM, Ansell SM, Macon WR, Ristow KM, et al
. Statin use and prognosis in patients with diffuse larger B-cell lymphoma and follicular lymphoma in the rituximab era. J Clin Oncol 2010;28:412-7.
Landgren O, Zhang Y, Zahm SH, Inskip P, Zheng T, Baris D. Risk of multiple myeloma following medication use and medical conditions: A case-control study in Connecticut women. Cancer Epidemiol Biomarkers Prev 2006;15:2342-7.
Schmidmaier R, Baumann P, Bumeder I, Meinhardt G, Straka C, Emmerich B. First clinical experience with simvastatin to overcome drug resistance in refractory multiple myeloma. Eur J Haematol 2007;79:240-3.
Khurana V, Sheth A, Caldito G, Barkin JS. Statins reduce the risk of pancreatic cancer in human: A case-control study of a half a million veterans. Pancreas 2007;34:260-5.
Koomen ER, Joosse A, Herings RM, Casparie MK, Bergman W, Nijsten T, et al
. Is statin use associated with a reduced incidence, a reduced Breslow thickness or delayed metastasis of melanoma of the skin? Eur J Cancer 2007;43:2580-9.
Khurana V, Caldito G, Ankem M. Statins might reduce risk of renal cell carcinoma in human: A case control study of 500,000 veterans. Urology 2008;71:118-22.
López-Aguilar E, Sepúlveda-Vildósola AC, Betanzos-Cabrera Y, Rocha-Moreno YG, Gascón-Lastiri G, Rivera-Márquez H, et al
. Phase II study of metronomic chemotherapy with thalidomide, carboplatin-vincristine-fluvastatin in the treatment of brain stem tumors in children. Arch Med Res 2008;39:665-2.
Kusama T, Mukai M, Tatsuta M, Nakamura H, Inoue M. Inhibition of transendothelial migration and invasion of human breast cancer cells by preventing geranylation of Rho. Int J Oncol 2006;29:217-23.
Denoyelle C, Vasse M, Körner M, Mishal Z, Ganné F, Vannier JP, et al
. 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;22:1139-48.
Ghosh-Choudhury N, Mandal CC, Ghosh-Choudhury N, Ghosh Choudhury G. Simvastatin induces derepression of PTEN expression via NFkappaB to inhibit breast cancer cell growth. Cell Signal 2010;22:749-55.
Borgquist S, Jögi A, Pontén F, Rydén L, Brennan DJ, Jirström K. Prognostic impact of tumour-specific HMG-CoA reductase expression in primary breast cancer. Breast Cancer Res 2008;10:R79.
Muck AO, Seeger H, Wallwiener D. Inhibitory effect of statins on the proliferation of human breast cancer cells. Int J Clin Pharmacol Ther 2004;42:695-700.
Sánchez CA, Rodríguez E, Varela E, Zapata E, Páez A, Massó FA, et al
. Statin-induced inhibition of MCF-7 breast cancer cell proliferation is related to cell cycle arrest and apoptotic and necrotic cell death mediated by an enhanced oxidative stress. Cancer Invest 2008;26:698-707.
Farina HG, Bublik DR, Alonso DF, Gomez DE. Lovastatin alters cytoskeleton organization and inhibits experimental metastasis of mammary carcinoma cells. Clin Exp Metastasis 2002;19:551-9.
Kozar K, Kaminski R, Legat M, Kopec M, Nowis D, Skierski JS, et al
. Cerivastatin demonstrates enhanced antitumor activity against human breast cancer cell lines when used in combination with doxorubicin or cisplatin. Int J Oncol 2004;24:1149-57.
Budman DR, Tai J, Calabro A. Fluvastatin enhancement of trastuzumab and classical cytotoxic agents in defined breast cancer cell lines in vitro
. Breast Cancer Res Treat 2007;104:93-101.
Bonovas S, Filioussi K, Tsavaris N, Sitaras NM. Use of statins and breast cancer: A meta-analysis of seven randomized clinical trials and nine observational studies. J Clin Oncol 2005;1;23:8606-12.
Notarnicola M, Messa C, Pricci M, Guerra V, Altomare DF, Montemurro S, et al
. Up-regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity in left sided human colon cancer. Anticancer Res 2004;24:3887-42.
Cho SJ, Kim JS, Kim JM, Lee JY, Jung HC, Song IS. Simvastatin induces apoptosis in human colon cancer cells and in tumor xenografts, and attenuates colitis-associated colon cancer in mice. Int J Cancer 2008;123:951-7.
Malicki S, Winiarski M, Matlok M, Kostarczyk W, Guzdek A, Konturek PC. IL-6 and IL-8 responses of colorectal cancer in vivo
and in vitro
cancer cells subjected to simvastatin. J Physiol Pharmacol 2009;60:141-6.
Bergman M, Salman H, Djaldetti M, Bessler H. Statins as modulators of colon cancer cells induced cytokine secretion by human PBMC. Vascul Pharmacol 2011;54:88-92.
Lakshminarayana Reddy CN, Vyjayanti VN, Notani D, Galande S, Kotamraju S. Down-regulation of the global regulator SATB1 by statins in COLO205 colon cancer cell. Mol Med Report 2010;3:857-61.
Hoque A, Chen H, Xu XC. Statin induces apoptosis and cell growth arrest in prostate cancer cells. Cancer Epidemiol Biomarkers Prev 2008;17:88-94.
Kochuparambil ST, Al-Husein B, Goc A, Soliman S, Somanath PR. Anticancer efficacy of simvastatin on prostate cancer cells and tumor xenografts is associated with inhibition of Akt and reduced prostate-specific antigen expression. J Pharmacol Exp Ther 2011;336:496-505.
Yokomizo A, Shiota M, Kashiwagi E, Kuroiwa K, Tatsugami K, Inokuchi J, et al
. Statins reduce the androgen sensitivity and cell proliferation by decreasing the androgen receptor protein in prostate cancer cells. Prostate 2011;71:298-304.
Yang L, Egger M, Plattner R, Klocker H, Eder IE. Lovastatin causes diminished PSA secretion by inhibiting AR expression and function in LNCaP prostate cancer cells. Urology 2011;77:1508.e1-7.
Parikh A, Childress C, Deitrick K, Lin Q, Rukstalis D, Yang W. Statin-induced autophagy by inhibition of geranylgeranyl biosynthesis in prostate cancer PC3 cells. Prostate 2010;70:971-81.
Irani J, Goujon JM, Ragni E, Peyrat L, Hubert J, Saint F, et al
. Pathologist Multi Center Study Group. High-grade inflammation in prostate cancer as a prognostic factor for biochemical recurrence after radical prostatectomy. Urology 1999;54:467-72.
Bonovas S, Filioussi K, Sitaras NM. Statin use and the risk of prostate cancer: A meta-analysis of six randomized clinical trials and 13 observational studies. Int J Cancer 2008;123:889-904.
Chang CC, Ho SC, Chiu HF, Yang CY. Statins increase the risk of prostate cancer: A population-based case control study. Prostate 2011;71:1818-24.
Murtola TJ, Tammela TL, Lahtela J, Auvinen A. Cholesterol-lowering drugs and prostate cancer risk: A population-based case-control study. Cancer Epidemiol Biomarkers Prev 2007;16:2226-32.
Park IH, Kim JY, Jung JI, Han JY. Lovastatin overcomes gefitinib resistance in human non-small cell lung cancer cells with K-ras mutations. Invest New Drugs 2010;28:791-9.
Khanzada UK, Pardo OE, Meier C, Downward J, Seckl MJ, Arcaro A. Potent inhibition of small cell lung cancer cell growth by simvastatin reveals selective functions of ras isoforms in growth factor signaling. Oncogene 2006;25:877-87.
Sanli T, Liu C, Rashid A, Hopmans SN, Tsiani E, Schultz C, et al
. Lovastatin sensitizes lung cancer cells to ionizing radiation: Modulation of molecular pathways of radiosensitive and tumor suppression. J Thorac Oncol 2011;6:439-50.
Hanai JI, Doro N, Sasaki AT, Kobayashi S, Cantley LC, Seth P, et al
. Inhibition of lung cancer growth: ATP citrate lyase knockdown and statin treatment leads to dual blockade of mitogen activated protein kinase and phosphatidylinositol-3-kinase (PI3K)/AKT pathways. J Cell Physiol 2012;227(4):1709-20.
Maksimova E, Yie TA, Rom WN. In vitro
mechanisms of lovastatin on lung cancer cell lines as a potential chemopreventive agent. Lung 2008:186:45-54.
Yao CJ, Lai GM, Chan CF, Cheng AL, Yang YY, Chuang SE. Dramatic synergistic anticancer effect of clinically achievable doses of lovastatin and troglitazone. Int J Cancer 2006;118:773-9.
Khurana V, Bejjanki HR, Caldito G, Owens MW. Statins reduce risk of lung cancer in human: A large case control study of US veterans. Chest 2007;131:1282-8.
Han JY, Lim KY, Yu SY, Yun T, Kim HT, Lee JS. A phase 2 study of irinotecan, cisplatin, and simvastatin for untreated extensive-disease small cell lung cancer. Cancer 2011;117:2178-85.
Sutter AP, Maaser K, Höpfner M, Huether A, Schuppan D, Scherübl H. Cell cycle arrest and apoptosis in hepatocellular carcinoma cells by HMG-CoA reductase inhibitors. Synergistic antiproliferative action with ligands of the peripheral benzodiazepine receptor. J Hepatol 2005;43:808-16.
Relja B, Meder F, Wilhelm K, Henrich D, Marzi I, Lehnert M. Simvastatin inhibits cell growth and induce apoptosis and G0/G1 cell cycle arrest in hepatic cancer cells. Int J Mol Med 2010;26:735-41.
Cao Z, Fan-Minogue H, Bellovin DI, Yevtodiyenko A, Arzeno J, Yang Q, et al
. MYC phosphorylation, activation, and tumorigenic potential in hepatocellular carcinoma are regulated by HMG-CoA reductase. Cancer Res 2011;71:2286-97.
Montero J, Morales A, Llacuna L, Lluis JM, Terrones O, Basañez G, et al
. Mitochondrial cholesterol contributes to chemotherapy resistance in hepatocellular carcinoma. Cancer Res 2008;68:5246-56.
Kim W, Yoon JH, Kim JR, Jang IJ, Bang YJ, Kim YJ, et al
. Synergistic anti-tumor efficacy and protein kinase C-beta inhibitor in hepatocellular carcinoma. Cancer Chemother Pharmacol 2009;64:497-507.
Wu J, Wong WW, Khosravi F, Minden MD, Penn LZ. Blocking the Raf/MEK/ERK pathway sensitizes acute myelogenous leukemia cells to lovastatin-induced apoptosis. Cancer Res 2004;64:6461-8.
Cafforio P, Dammacco F, Gernone A, Silvestris F. Statins activate the mitochondrial pathway of apoptosis in human lymphoblasts and myeloma cells. Carcinogenesis 2005;26:883-91.
Infante E, Heasman SJ, Ridley AJ. Statins inhibit T-acute lymphoblastic leukemia cell adhesion and migration through Rap1b. J Leukoc Biol 2011;89:577-86.
Katano H, Pesnicak L, Cohen JI. Simvastatin induces apoptosis of Epstein-Barr virus (EBV)-transformed lymphoblastoid cell lines and delays development of EBV lymphomas. Proc Natl Acad Sci USA 2004;101:4960-5.
Sassano A, Katsoulidis E, Antico G, Altman JK, Redig AJ, Minucci S, et al
. Suppressive effects of statins on acute promyelocytic leukemia cells. Cancer Res 2007;67:4524-32.
Van der Weide K, de Jonge-Peeters SD, Kuipers F, de Vries EG, Vellenga E. Combining simvastatin with the farnesyltransferase inhibitor tipifarnib results in an enhanced cytotoxic effect in a subset of primary CD34+ acute myeloid leukemia samples. Clin Cancer Res 2009;15:3076-83.
Calabro A, Tai J, Allen SL, Budman DR. In-vitro
synergism of m-TOR inhibitors, statins, and classical chemotherapy: Potential implications in acute leukemia. Anticancer Drugs 2008;19:705-12.
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 Investig Med 2001;49:319-24.
Winiarska M, Bil J, Wilczek E, Wilczynski GM, Lekka M, Engelberts PJ, et al
. Statins impair antitumor effects of rituximab by inducing conformational changes of CD20. PLoS Med 2008;5:e64.
Sondergaard TE, Pedersen PT, Andersen TL, Søe K, Lund T, Ostergaard B, et al
. A phase II clinical trial does not show that high dose simvastatin has beneficial effect on markers of bone turnover in multiple myeloma. Hematol Oncol 2009;27:17-22.
Iwata H, Matsuo K, Hara S, Takeuchi K, Aoyama T, Murashige N, et al
. Use of hydroxyl-methyl-glutaryl coenzyme A reductase inhibitors is associated with risk of lymphoid malignancies. Cancer Sci 2006;97:133-8.
Martirosyan A, Clendening JW, Goard CA, Penn LZ. Lovastatin induces apoptosis of ovarian cancer cells and synergizes with doxorubicin: Potential therapeutic relevance. BMC Cancer 2010;10:103.
Kidera Y, Tsubaki M, Yamazoe Y, Shoji K, Nakamura H, Ogaki M, et al
. Reduction of lung metastasis, cell invasion, and adhesion in mouse melanoma by statin-induced blockade of the Rho/Rho-associated coiled-coil-containing protein kinase pathway. J Exp Clin Cancer Res 2010;29:127.
Cemeus C, Zhao TT, Barrett GM, Lorimer IA, Dimitroulakos J. Lovastatin enhances gefitinib activity in glioblastoma cells irrespective of EGFRvIII and PTEN status. J Neurooncol 2008;90:9-17.
Kuoppala J, Lamminpää A, Pukkala E. Statins and cancer: A systematic review and meta-analysis. Eur J Cancer 2008;44:2122-32.
Vinogradova Y, Coupland C, Hippisley-Cox J. Exposure to statins and risk of common cancers: A series of nested case-control studies. BMC Cancer 2011;11:409.
Wood M. Statins and breast cancer biomarkers. Vermont Cancer Center at University of Vermont and Fletcher Allen Health Care; United States of America: Clinicaltrial gov NCT00914017.
Wolmark N. Statin polyp prevention trial in patients with resected colon cancer. Clinicaltrial gov NCT01011478.
Bujanda L. Randomized Controlled Study to Evaluate the Efficacy of Pravastatin on Survival and Recurrence of Advanced Gastroesophageal Cancer. Department of Gastroenterology at Hospital; Spain: Clinicaltrial gov NCT01038154.
Limburg PJ. Randomized phase II trial of atorvastatin, RAFTILOSE?
Synergy1, and sulindac among patients at increased risk for sporadic colorectal neoplasia. Mayo Clinic Cancer Center; United States of America: Clinicaltrial gov NCT00335504.
Jouve JL, Denis J. Randomized phase III Trial sorafenib-pravastatin versus sorafenib alone for the palliative treatment of Child-Pugh A hepatocellular carcinoma. Hospital Du Bocage; France: Clinicaltrial gov NCT01075555.
Seckl MJ. A multicentre phase III randomized double blind placebo controlled trial of pravastatin added to first-line standard chemotherapy in patients with small lung cancer. Charing Cross Hospital; England: Clinicaltrial gov NCT00433498.
Kang WK. Placebo-controlled, double-blinded phase III trial of XP (Capecitabine/CDDP) simvastatin in advanced gastric cancer patients. Samsung Medical Center; South Korea: Clinicaltrial gov NCT01099085.
Park YS, Kim YH. Randomized double-blinded, placebo-controlled phase II trial of simvastatin and gemcitabine in advanced pancreatic cancer patients. Samsung Medical Center; South Korea: Clinicaltrial gov NCT00944463.
Meyskens FL. A randomized double-blind, placebo-controlled phase II clinical trial of lovastatin for various endpoints of melanoma pathobiology. Chao Family Comprehensive Cancer Center at University of California Irvine Medical Center; United States of America: Clinicaltrial gov NCT00462280.
[Table 1], [Table 2], [Table 3]
|This article has been cited by|
||The Role of Structure and Biophysical Properties in the Pleiotropic Effects of Statins
| ||Christopher Murphy, Evelyne Deplazes, Charles G. Cranfield, Alvaro Garcia |
| ||International Journal of Molecular Sciences. 2020; 21(22): 8745 |
|[Pubmed] | [DOI]|
||Statin and Cancer Mortality and Survival: An Umbrella Systematic Review and Meta-Analysis
| ||Gwang Hun Jeong, Keum Hwa Lee, Jong Yeob Kim, Michael Eisenhut, Andreas Kronbichler, Hans J. van der Vliet, Jae Il Shin, Gabriele Gamerith |
| ||Journal of Clinical Medicine. 2020; 9(2): 326 |
|[Pubmed] | [DOI]|
||Simvastatin suppresses head and neck squamous cell carcinoma ex vivo and enhances the cytostatic effects of chemotherapeutics
| ||Matthaeus Stoehr,Christian Mozet,Andreas Boehm,Achim Aigner,Andreas Dietz,Gunnar Wichmann |
| ||Cancer Chemotherapy and Pharmacology. 2014; 73(4): 827 |
|[Pubmed] | [DOI]|
||Statin use and risk of liver cancer: an update meta-analysis
| ||M. Shi,H. Zheng,B. Nie,W. Gong,X. Cui |
| ||BMJ Open. 2014; 4(9): e005399 |
|[Pubmed] | [DOI]|
||Chemically induced mouse liver tumors are resistant to treatment with atorvastatin
| ||Albert Braeuning,Philip Bucher,Ute Hofmann,Albrecht Buchmann,Michael Schwarz |
| ||BMC Cancer. 2014; 14(1): 766 |
|[Pubmed] | [DOI]|
||Efficient Use of Exogenous Isoprenols for Protein Isoprenylation by MDA-MB-231 Cells Is Regulated Independently of the Mevalonate Pathway
| ||Fredrick Onono, Thangaiah Subramanian, Manjula Sunkara, Karunai Leela Subramanian, H. Peter Spielmann, Andrew J. Morris |
| ||Journal of Biological Chemistry. 2013; 288(38): 27444 |
|[Pubmed] | [DOI]|
||Efficient use of exogenous isoprenols for protein isoprenylation by MDA-MB-231 cells is regulated independently of the mevalonate pathway
| ||Onono, F., Subramanian, T., Sunkara, M., (...), Peter Spielmann, H., Morris, A.J. |
| ||Journal of Biological Chemistry. 2013; 288(38): 27444-27455 |
||Dietary-suppression of hepatic lipogenic enzyme expression in intact male transgenic mice
| ||Notarnicola, M., Caruso, M.G., Tafaro, A., (...), Minoia, M., Francavilla, A. |
| ||World Journal of Gastroenterology. 2013; 19(46): 8671-8677 |
||The pleiotropic effects and therapeutic potential of the hydroxy-methyl-glutaryl-CoA reductase inhibitors in gastrointestinal tract disorders: A comprehensive review
| ||Cortes-Bergoderi, M. and Pineda, A.M. and Santana, O. |
| ||Journal of Gastrointestinal and Liver Diseases. 2013; 22(2): 199-204 |
||Beyond cholesterol reduction, the pleiotropic effects of statins: Is their use in cancer prevention hype or hope?
| ||Barkas, F. and Rizzo, M. and Dinicolantonio, J.J. and Liberopoulos, E. |
| ||Clinical Lipidology. 2013; 8(3): 273-277 |