Statins: a repurposed drug to fight cancer

Abstract

As competitive HMG-CoA reductase (HMGCR) inhibitors, statins not only reduce cholesterol and improve cardiovascular risk, but also exhibit pleiotropic effects that are independent of their lipid-lowering effects. Among them, the anti-cancer properties of statins have attracted much attention and indicated the potential of statins as repurposed drugs for the treatment of cancer. A large number of clinical and epidemiological studies have described the anticancer properties of statins, but the evidence for anticancer effectiveness of statins is inconsistent. It may be that certain molecular subtypes of cancer are more vulnerable to statin therapy than others. Whether statins have clinical anticancer effects is still an active area of research. Statins appear to enhance the efficacy and address the shortcomings associated with conventional cancer treatments, suggesting that statins should be considered in the context of combined therapies for cancer. Here, we present a comprehensive review of the potential of statins in anti-cancer treatments. We discuss the current understanding of the mechanisms underlying the anti-cancer properties of statins and their effects on different malignancies. We also provide recommendations for the design of future well-designed clinical trials of the anti-cancer efficacy of statins.

Recent Advances of WEE1 Inhibitors and Statins in Cancers With p53 Mutations

“…Co-targeting of Wee1 and the DNA damage response kinase ATM was shown to downregulate PD-L1 expression in pancreatic cancer ( 15 ). Wee1 inhibition was found to sensitize cancer cells to immunotherapy via PD-1 checkpoint blockade in oral cavity carcinoma, melanoma and colon adenocarcinoma with variable Tp53 mutations, which provide a pre-clinical rationale for the combination of agents that target cell cycle checkpoints and activate anti-tumor immunity and simultaneously support the clinical trials of Wee1 inhibitor in combination with immunotherapy ( 16 ). The effect of the combination of Wee1 inhibitor ZN-c3 with PD1 inhibitor Pembrolizumab will also be studied in patients with solid tumors with advanced or metastatic disease at the clinical trial NCT04158336.…”

“…It was later determined that knockout of mevalonate kinase (MVK) has the same effect as reducing mevalonate 5-phosphate, suggesting that the disruption of mutp53 functions may be brought about through targeting and manipulating different parts of the mevalonate pathway ( 18 ). In addition to its effects on mevalonate 5-phosphate, statins inhibit HMG-CoA (HMGCR) reductase activity, which mediates the synthesis of cholesterol and the inhibition of the biosynthesis of selenoproteins (such as GPX4) and CoQ10, and thus enhance ferroptosis ( 11 , 16 , 17 ). Several groups have reported that Hsp90, Hsp40, CHIP and MDM2 play critical roles to stabilize mutant p53 via the HSP chaperone system, which suggests a possible synergism between HSP chaperone system inhibitors and statins in tandem ( 22 , 24 , 25 , 30 ).…”

“…Mevalonate-5-phosphate (MVP) promotes mutp53 stabilization by increasing the interaction between mutp53 and KSP40/DNAJA1 and inhibiting CHIP-mediated ubiquitination and proteasomal degradation of mutp53 ( 11 ). The mevalonate pathway inhibition can also sensitize cancer cells to ferroptosis by depleting CoQ10 and the biosynthesis of GPX4 by inhibiting tRNA isopentenylation via TRIT1 ( 12 – 16 ). In cancers with GOF Mutp53, statins can inhibit tumor growth by inducing mutp53 degradation, inhibiting prenylation of oncogenes and cholesterol synthesis, as well as inducing ferroptosis by inhibiting the biosynthesis of GPX4 and CoQ10 ( 16 – 18 ).…”

“…The mevalonate pathway inhibition can also sensitize cancer cells to ferroptosis by depleting CoQ10 and the biosynthesis of GPX4 by inhibiting tRNA isopentenylation via TRIT1 ( 12 – 16 ). In cancers with GOF Mutp53, statins can inhibit tumor growth by inducing mutp53 degradation, inhibiting prenylation of oncogenes and cholesterol synthesis, as well as inducing ferroptosis by inhibiting the biosynthesis of GPX4 and CoQ10 ( 16 – 18 ). The function of Wee1, as well as the progress of Wee1 inhibitors, statins and effect on immunotherapy in cancer with p53 mutations, will thus be discussed.…”

Mevastatin in colon cancer by spectroscopic and microscopic methods - Raman imaging and AFM studies

“…An important observation of great importance for cancer therapy is that statins have an apoptotic effect mainly in the case of neoplastic cells. This means that statins are not destructive in normal cells, as is the case with most drugs used to treat cancer [23][24][25].…”