Statins and prostate cancer—hype or hope? The epidemiological perspective

Abstract

Background Men using cholesterol-lowering statin medications have been found to have lower risks of both advanced and fatal prostate cancer in multiple registry-based studies and prospective cohort studies. Statin use has also been associated with longer survival among men already diagnosed with prostate cancer. Mechanisms responsible for purported anti-cancer effects of statins are not well understood but may offer insight into prostate cancer biology. Methods We summarise epidemiological data from studies of statins and prostate cancer and discuss to what extent these findings can be interpreted as causal. Additionally, lipid-mediated and non-lipid-mediated mechanisms that may contribute to potential anti-cancer effects of statins are reviewed. Finally, we consider treatment settings and molecular subgroups of men who might benefit more than others from statin use in terms of prostate cancer-specific outcomes. Results Data from prospective observational studies generally reported a lower risk of fatal prostate cancer among statin users. There is some evidence for serum cholesterol-lowering as an indirect mechanism linking statins with advanced and fatal prostate cancer. Window-of-opportunity clinical trials show measurable levels of statins in prostate tissue highlighting potential for direct effects, whilst observational data suggest possible statin-driven modulation of prostate microenvironment inflammation. Additionally, emerging data from registry studies support a potential role for statins within the context of androgen deprivation therapy and anti-androgen treatment. Conclusion Prospective and registry-based studies support a lower risk of advanced and fatal prostate cancer in statin users relative to non-users, as well as better outcomes among prostate cancer patients. The few randomised-controlled trials conducted so far have short follow-up, lack identified molecular subgroups, and do not provide additional support for the observational results. Consequently, additional evidence is required to determine which men may experience greatest benefit in terms of prostate cancer-specific outcomes and how statin effects may vary according to molecular tumour characteristics.

Incidence and risk factors of prostate cancer among the Northern and Eastern parts of the United Arab Emirates population

“…This finding is consistent with a study by Craig et al, which reported a 20% reduction in the risk of advanced PCa with statin use. 41 Furthermore, we found that UTIs exhibited a lower risk of PCa and were associated with a higher incidence of BPH (Figure 2).…”

Statin drugs enhance responses to immune checkpoint blockade in head and neck cancer models

“…5 6 Numerous epidemiological studies in different cancer types have shown improved survival outcomes in patients taking statins, versus patients not taking these drugs. [7][8][9][10][11][12] In head and neck cancer patients, the use of statins is associated with improved survival outcomes, 11 12 lower incidence of cisplatin-induced hearing loss, 13 and reversal of radiation-induced fibrosis, 14 by mechanisms that are not currently understood. The potential benefit of statins in WHAT IS ALREADY KNOWN ON THIS TOPIC ⇒ Cholesterol may impact antitumor immune responses, and a few prior studies suggest that statin drugs may increase responses to immune checkpoint blockade.…”

Pharmacological Efficacy of Repurposing Drugs in the Treatment of Prostate Cancer

“…So, it is known that androgen deprivation therapy, the standard treatment for PC, inhibits androgen synthesis in testicles and, consequently, decreases the levels of systemic androgens, but despite the low availability of circulating androgens, tumor progression continues, because there is an intratumoral synthesis of androgens from the existing cholesterol [ 11 ]. Thus, statins are antidyslipidemic drugs that inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and block mevalonate production, which is a cholesterol precursor that allows for controlling the synthesis of androgens from cholesterol, which could explain the synergistic effect of statins in androgen deprivation therapy [ 2 , 5 , 10 , 11 ]. On the other hand, it is known that the metabolic pathway of mevalonate is associated with Yes-Associated Protein (YAP) and Tafazzin protein (TAZ), which are related to tumor growth and tumor progression.…”

“…Thus, statins will eventually act on both serum cholesterol and intratumoral cholesterol, which is an advantage, because men with high serum cholesterol seem to have a higher risk of developing more aggressive PC and higher mortality rates. On the other hand, significant amounts of statins were detected in the prostate tissue of several patients, which allows us to conclude that statins have a direct effect on prostate cells, and after a four-week treatment with statins, it is already possible to detect them in prostatic tissue [ 11 ].…”

“…Moreover, dipyridamole, an antiplatelet agent, when administered in combination with fluvastatin, reduces the amount of fluvastatin needed to induce the death of PC cells. Concerning simvastatin, it is known that it can resensitize PC cell lines that have developed resistance to enzalutamide (a second-generation non-steroidal antiandrogen that competes with androgens for binding sites in the prostate) and that acts through apoptosis caused by cholesterol depletion and inhibition of the Protein Kinase B (Akt) signaling pathway [ 5 , 10 , 11 , 12 , 13 , 14 ]. On the other hand, it also prevents tumor growth, reduces PSA levels and, when administered in combination with irinotecan, suppression of tumor growth and induction of apoptosis caused by inhibition of the MCL-1 protein occur [ 12 ].…”