Statins are competing inhibitors of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase; lower cholesterol blood levels, and risk evolving cardiovascular diseases and associated complications. In addition to this principal activity; statins show pleiotropic results such as antioxidant; anti-inflammatory and antiproliferative characteristics; with applications in various pathologies. Based on their antiproliferative features; in vitro and in vivo studies have examined their effects on numerous types of cancer like breast cancer; prostate cancer; colorectal cancer; ovarian cancer; lung cancer with many genetic and molecular characteristics. Investigations obtained many positive results, but they were profoundly dependent on the physicochemical properties of the statins; their dose, and therapy period. Combined therapies of statins and cytotoxic medications have also been experimented with, and synergistic or additive effects were observed.
Further; observational studies conducted on patients who used statins for various pathologies revealed that statins decreased the risk of developing multiple cancers and improved the outcomes for cancer patients. Recently; many ongoing clinical trials directed at exploring the potential of statins to reduce mortality and the disease-recurrence risk. All these outcomes are the foundation of novel treatment directions in cancer therapy.
Statins are the prime cholesterol-lowering agents discovered. Due to their significant potential to reduce cholesterol blood levels; international guidelines declare statins as a first-line treatment for hypercholesterolemia. By blocking the synthesis of cholesterol and its metabolites; statins have presented antiproliferative effects in various types of cancer. Plenty of observational studies reported a risk mitigation in the onset of cancer; or improvements in the consequences of cancer; in statin users. The variable effect of different statins is related to their other physiochemical properties and the duration of treatment. Several in vitro and in vivo studies on various cancers underlined the molecular mechanisms through which statins hinder cancer cell proliferation and metastasis. These mechanisms were regarded as the basis for introducing statins in cancer treatment and cancer prevention. The antiproliferative effects of statins result from both repression of the mevalonate pathway and their pleiotropic products; i.e.; antioxidant; anti-inflammatory, and immune-modulatory properties; significantly impacting patient survival and cancer recurrence.
MECHANISM OF ACTION
Cholesterol; along with isoprenoid intermediates; is manufactured through the mevalonate pathway. In this method; 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) is transformed into mevalonate via HMG-CoA reductase. Due to their structural similarity to HMG-CoA; statins are competitive inhibitors of HMG-CoA reductase and thereby have the capacity to suppress cholesterol synthesis. The affinity of statins for HMG-CoA reductase is in the nanomolar scale; compared to the natural substrate; whose strength needs to be in the micromolar range. Statins primarily act in the liver; where they induce overexpression of low-density lipoprotein (LDL) receptors at the exterior of hepatocytes; thereby improving the uptake of circulating LDL. By this mechanism; statins reduce lipoprotein blood levels and reduce the risk of developing cardiovascular diseases and related difficulties.
ANTICANCER EFFECTS OF STATINS
Following the first reports in the late 1990s on the efficacy of statins to influence cancer progression; their anticancer properties have been widely documented in a wide range of cancer cell lines and tumor-bearing animal models. Numerous preclinical studies establish the anticancer effects of statins against different types of tumors; including liquid tumors such as myeloma and leukemia and solid tumors. The potential underlying mechanisms that estimate the anticancer effects have been published in numerous in vitro studies. It has been revealed that their anticancer properties emerge from the suppression of tumor growth; initiation of apoptosis and autophagy; repression of cell migration and invasion; and repression of angiogenesis.
Statins have a high potential in preventing PC progression; as some researches have shown that statin use is linked with a reduction in PC risk. On the other hand; the onset of PC is tightly correlated with risk factors like obesity; hypertension; raised testosterone; race; and family history. As earlier mentioned in this review; these risk factors are also connected to cardiovascular diseases and their associated complications. At present; the most effective therapy for PC is androgen deprivation. This therapy is based on the strength of PC cells to synthesize androgen hormones de novo due to the high circulating cholesterol levels and the de novo synthesis of cholesterol. Since cholesterol is a precursor in androgen synthesis; statin therapy was considered a potential strategy to improve the results in PC by inhibiting this pathway. In cancer; cholesterol is connected with the synthesis of sexual hormones and is also responsible for cell growth; progression; proliferation; and migration. Thus; statins can improve the outcomes of PC therapy by increasing the survival rate and decreasing the progression and recurrence of the tumor. Additionally; due to their anti-inflammatory properties; statins can hinder the overexpression of androgen receptors; leading to the suppression of cell growth.
BC is the most commonly encountered cancer among women, and the number of clinical trials evaluating the putative clinical advantage of statins in BC is growing. Recently; a direct connection between cholesterol blood levels and the incidence of BC was seen. A high level of LDL raises BC cell proliferation and causes gene changes that are not beneficial for the prognosis of BC. A 72% risk loss in the onset of BC was seen among statin users; particularly in estrogen-negative BC cases. This decision has been reported in long-term statin treatment. In addition; statins were given to reduce BC patient death, but the benefit seems to be dependent on statin class and follow-up time. Thus; lipophilic statins conferred a more substantial protective effect in BC patients; indicated by a significantly increased recurrence-free durability and improved overall durability.
On the other hand; hydrophilic statins only somewhat improved all-cause mortality. Moreover; the shielding effect was observed only in groups with less than four years of follow-up. Also; it has been shown that statins did not improve the risk of BC.
Gathering evidence suggests that statins may have a part in CRC prevention and treatment; but relations between individual statin features; their doses and CRC have not yet been determined. Rho and Ras proteins are overexpressed in this kind of cancer, and by hindering their synthesis through the mevalonate pathway; cancer propagation and invasion are contained.
In various studies; statin use was linked with a 30% to 50% risk reduction in developing CRC.
It has been confirmed that in interest to its significant implication in promoting cardiovascular diseases; cholesterol also plays a vital role in the onset of cancer. These findings suggest; statins; the potent inhibitors of HMG-CoA reductase; utilized as first-line medication in the treatment of hypercholesterolemia; were also examined for cancer treatment.