Statin as a Potential Chemotherapeutic Agent: Current Updates as a Monotherapy, Combination Therapy, and Treatment for Anti-Cancer Drug Resistance

Abstract

Cancer is incurable because progressive phenotypic and genotypic changes in cancer cells lead to resistance and recurrence. This indicates the need for the development of new drugs or alternative therapeutic strategies. The impediments associated with new drug discovery have necessitated drug repurposing (i.e., the use of old drugs for new therapeutic indications), which is an economical, safe, and efficacious approach as it is emerged from clinical drug development or may even be marketed with a well-established safety profile and optimal dosing. Statins are inhibitors of HMG-CoA reductase in cholesterol biosynthesis and are used in the treatment of hypercholesterolemia, atherosclerosis, and obesity. As cholesterol is linked to the initiation and progression of cancer, statins have been extensively used in cancer therapy with a concept of drug repurposing. Many studies including in vitro and in vivo have shown that statin has been used as monotherapy to inhibit cancer cell proliferation and induce apoptosis. Moreover, it has been used as a combination therapy to mediate synergistic action to overcome anti-cancer drug resistance as well. In this review, the recent explorations are done in vitro, in vivo, and clinical trials to address the action of statin either single or in combination with anti-cancer drugs to improve the chemotherapy of the cancers were discussed. Here, we discussed the emergence of statin as a lipid-lowering drug; its use to inhibit cancer cell proliferation and induction of apoptosis as a monotherapy; and its use in combination with anti-cancer drugs for its synergistic action to overcome anti-cancer drug resistance. Furthermore, we discuss the clinical trials of statins and the current possibilities and limitations of preclinical and clinical investigations.

Keywords: anti-cancer; apoptosis; drug repurposing; resistance; statin.

Figure 1

Chemical structure of all major statins (derived from [25]).

Figure 2

Statins alone as anti-cancer agents. Statin as a monotherapy upregulates or inhibits diverse signaling cascades leading to induction of oxidative stress, cell-cycle arrest, differentiation of cancer cells, autophagy, and suppression of cancer stemness, proliferation, metastasis, angiogenesis. As a result, statin induces cell death, cytotoxicity, and apoptosis of cancer cells. Blue arrows indicate upregulation, red colored lines indicate inhibition/suppression.

Figure 3

Synergistic action of statins. Statin in combination with anti-cancer drugs such as imatinib, TRAIL, troglitazone, celecoxib, gemcitabine, cisplatin, temozolomide, PTX, dacarbazine, FLT3, sorafenib, mitotane, docetaxel, and dasatinib synergistically suppress and induce signaling cascade leading to cell-cycle arrest, cell death, apoptosis, and sensitivity. Blue arrows indicate upregulation, black colored lines indicate inhibition/suppression, and red arrows indicate the combination of statin with indicated drugs.

Figure 4

Statins for overcoming anti-cancer drug resistance. Statin overcomes the resistance developed by various anti-cancer drugs (as indicated in the figure) through the induction of cell-cycle arrest, apoptosis, cytotoxicity, and inhibition of cell growth. In most cases, statin inhibits the signaling molecules or kinases involved in cancer cell proliferation, growth, metastasis, angiogenesis, inflammation, and multi-drug resistance mechanism developed by those anti-cancer drugs. Blue arrows indicate upregulation, red colored lines indicate inhibition/suppression.