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 Table of Contents  
REVIEW ARTICLE
Year : 2012  |  Volume : 8  |  Issue : 2  |  Page : 176-183

The pleiotropic effects and therapeutic potential of the hydroxy-methyl-glutaryl-CoA reductase inhibitors in malignancies: A comprehensive review


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 Publication26-Jul-2012

Correspondence Address:
Orlando Santana
Echocardiography Laboratory Mount Sinai Heart Institute 4300 Alton Road Miami Beach, Florida 33140
USA
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.98967

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 > Abstract 

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 2019 Sep 16];8:176-83. Available from: http://www.cancerjournal.net/text.asp?2012/8/2/176/98967


 > Introduction Top


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. [1],[2] Studies have shown that statins also possess powerful pleiotropic effects independent of their cholesterol-lowering properties in a wide range of disease processes. [3],[4],[5] 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. [6],[7] 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]. [8],[9]
Table 1: General mechanisms of statin pleiotropy

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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. [10],[11] The following is a review of the current literature regarding the potential therapeutic benefits and pleiotropic effects of statins in malignancies [Table 2].
Table 2: Clinical evidence of statin effects in malignancies (1/2,2)

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 > Materials and Methods Top


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 Top


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. [40] 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. [41],[42] 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. [43] Finally, statins have been shown to inhibit breast cancer cell proliferation, adhesion and motility, while inducing cell cycle arrest and apoptosis. [44],[45],[46]

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). [12] However, statins were only used by 7.5% of the cohort, and no information was available regarding dosage regimens. Kumar et al. [13] 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). [14] Synergistic activity of statins with previously established treatments for breast cancer has also been described. [47],[48]

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. [49] 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. [15]


 > Colon Cancer Top


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. [50] 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. [51] 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. [52],[53],[54]

A recent meta-analysis of statin use in CRC patients by Bardou et al. [16] 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. [17] 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), [18] 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. [19] 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. [20] 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. [21],[22],[23],[24]


 > Prostate Cancer Top


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] 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). [26] 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). [27] 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. [60]

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. [61] 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. [62] An elevated total prostate cancer risk was also reported among statin users by Murtola et al.; [63] 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 Top


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. [64] 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. [65],[66],[28] 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. [67],[68],[69]

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. [70] 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. [71]


 > Hepatocellular Cancer Top


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. [72],[73],[74] 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. [75],[76]

Graf et al. [29] 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. [30] 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. [31]


 > Hematologic Cancers Top


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. [77],[78] Statins also negatively effect tumor cell adhesion, migration and chemotaxis, [79],[80] and their synergism with multiple conventional anti-tumor agents has been described. [81],[82],[83],[84] 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. [85]

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. [32] 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. [33] 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. [34] 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. [35] These findings are in contrast to a phase two trial involving six multiple myeloma patients by Sondergaard et al. [86] 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. [87] 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 Top


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. [36],[37],[38],[39],[88],[89],[90]

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. [91] 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. [92] 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. [15][,61],[62],[63]

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]. [93],[94],[95],[96],[97],[98],[99],[100],[101]
Table 3: Ongoing randomized clinical trials of statin use in malignancies

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 > Conclusion Top


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.

 
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    Tables

  [Table 1], [Table 2], [Table 3]


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