Commentary (Lao/Brenner): The Role of Statins in Cancer Prevention and Treatment

Increasing epidemiologic data have emerged to support an association between 3-hydroxy-3-methylglutaryl- coenzyme A (HMG-CoA) reductase inhibitor (statin) use and the prevention or delay in the development of invasive cancer. The inhibition of HMG-CoA reductase results in the depletion of mevalonate, a precursor of cholesterol, but also of geranylgeranyl pyrophosphate and farnesyl pyrophosphate, both of which are critical for the isoprenylation of important cellular signaling proteins. Alterations in function and expression of these signaling proteins- particularly Ras and Rho- have been implicated in malignant transformation and proliferation. Furthermore, the epidemiologic data are being surpassed by preclinical data supporting the concept that inhibition of critical signaling pathways by statins can lead to increased cell death and prevent the proliferation of malignant cells. Stamm and Ornstein have written an excellent review that addresses some of these data and the potential role of statins in cancer therapy and prevention. It is unclear where statins might find a niche, but the use of these agents is of great interest to the prevention community, and we propose that statins may play a more important role in this area. Cancer Treatment
We agree with Stamm and Ornstein that the future role of statins in cancer therapy will likely be in the adjuvant setting, particularly for tumors for which these agents can be mechanistically linked to promotion and progression and for which treatment remains controversial (eg, stage III melanoma and resected hepatocellular and pancreatic cancer). Clinical trial data for statins in cancer treatment are limited, and considerable clinical trial investigation will be required to determine the appropriate dose, schedule, duration, and specific type of statin to use. Given various molecular and cellular effects beyond the effect on protein prenylation, statins are excellent agents for cancer treatment and prevention. However, such attributes create more difficult challenges to the study of statin therapy in humans because of limitations in short-term valid end points. In this regard, statins may be passed over for newer smallmolecule, "targeted" agents, such as farnesyl transferase inhibitors (eg, R115777, tipifarnib [Zarnestra]), B-Raf inhibitors (eg, BAY 43-9006 [Sorafenib]), and vascular endothelial growth factor (VEGF) inhibitors (eg, bevacizumab [Avastin]) in the treatment of cancer. Cancer Prevention
With the rapidly advancing knowledge about carcinogenesis and the development of relatively nontoxic agents that affect pathways important in transformation as well as in proliferation and metastasis, the line between prevention and treatment is becoming blurred. This has lead to debates as to whether such agents are treating early-stage, microscopic disease, or preventing or delaying carcinogenesis progression. Thus, the use of agents such as statins for both treatment and prevention ("convergence") is likely to develop in the future. While Stamm and Ornstein recognize the importance of statins for cancer prevention, a more thorough review of statin preclinical prevention literature reveals that these agents synergistically delay or prevent cellular transformation in multiple tissue targets. For example, there is increasing evidence that statins are synergistic with other chemopreventive agents. Agarwal et al[1] demonstrated that lovastatin and sulindac induced a fivefold increase in apoptosis in colon cancer cells above sulindac alone and caused a significant decrease in aberrant crypt formation in a rat model, compared to either agent alone. The primary mechanism appeared to involve its effect on geranylgeranylation of small GTPases of the Rho family[2] working synergistically with the known modulation of the arachidonate pathway by sulindac. Experience in designing and implementing prevention studies with combination agents is growing, and we anticipate that statins will be included in similar studies in the future. The future of cancer prevention interventions is likely in the use of combination agents (eg, aspirin or sulindac with difluoromethylornithine [DFMO]) with complementary or synergistic mechanisms that can account for redundant signal transduction pathways. Impact of Adverse Events
The vast experience with this class of agents supports the safety of its chronic administration. However, as we have learned, implementation of prevention interventions to healthy individuals with modest benefits will require minimal if any side effects. Even the need to monitor for myositis or liver dysfunction might be an issue for otherwise healthy individuals. In contrast, side effects and risks associated with cancer treatment are often readily accepted. Some adverse effects are dose-dependent, and the maximal effective or tolerable dose of a single agent vs combination agents might be significantly different. Thus, determining an optimal dose and duration of use for a specific indication within a clinical trial will be essential. Conclusions
Considerable data support the concept of statin use for cancer prevention and treatment. As we have learned from studies of agents that were supported by epidemiologic and preclinical data (eg, finasteride,[3] betacarotene,[ 4] and rofecoxib[5,6]), prospective clinical trials should always be performed to adequately determine the balance between the risks and benefits of such agents. The increased cancer incidence reported in some studies emphasizes the importance of scientifically sound, prospective, randomized clinical trials prior to any recommendations regarding statin use.

Disclosures:

The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

1. Agarwal B, Rao CV, Bhendwal S, et al: Lovastatin augments sulindac-induced apoptosis in colon cancer cells and potentiates chemopreventive effects of sulindac. Gastroenterology 117:838-847,1999.
2. Agarwal B, Bhendwal S, Halmos B, et al: Lovastatin augments apoptosis induced by chemotherapeutic agents in colon cancer cells. Clin Cancer Res 5:2223-2229,1999.
3. Thompson IM, Goodman PJ, Tangen CM, et al: The influence of finasteride on the development of prostate cancer. N Engl J Med 349:215-224,2003.
4. Goodman GE, Thornquist MD, Balmes J, et al: The Beta-Carotene and Retinol Efficacy Trial: Incidence of lung cancer and cardiovascular disease mortality during 6-year follow-up after stopping beta-carotene and retinol supplements. J Natl Cancer Inst 96:1743- 1750,2004.
5. Mukherjee D, Nissen SE, Topol EJ: Risk of cardiovascular events associated with selective COX-2 inhibitors. JAMA 286:954-959,2001.
6. Bombardier C, Laine L, Reicin A, et al: Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group. N Engl J Med 343:1520-1528, 2000.