Antidiabetics, Anthelmintics, Statins, and Beta-Blockers as Co-Adjuvant Drugs in Cancer Therapy

Abstract

Over the last years, repurposed agents have provided growing evidence of fast implementation in oncology treatment such as certain antimalarial, anthelmintic, antibiotics, anti-inflammatory, antihypertensive, antihyperlipidemic, antidiabetic agents. In this study, the four agents of choice were present in our patients’ daily treatment for nonmalignant-associated pathology and have known, light toxicity profiles. It is quite common for a given patient’s daily administration schedule to include two or three of these drugs for the duration of their treatment. We chose to review the latest literature concerning metformin, employed as a first-line treatment for type 2 diabetes; mebendazole, as an anthelmintic; atorvastatin, as a cholesterol-lowering drug; propranolol, used in cardiovascular diseases as a nonspecific inhibitor of beta-1 and beta-2 adrenergic receptors. At the same time, certain key action mechanisms make them feasible antitumor agents such as for mitochondrial ETC inhibition, activation of the enzyme adenosine monophosphate-activated protein kinase, amelioration of endogenous hyperinsulinemia, inhibition of selective tyrosine kinases (i.e., VEGFR2, TNIK, and BRAF), and mevalonate pathway inhibition. Despite the abundance of results from in vitro and in vivo studies, the only solid data from randomized clinical trials confirm metformin-related oncological benefits for only a small subset of nondiabetic patients with HER2-positive breast cancer and early-stage colorectal cancer. At the same time, clinical studies confirm metformin-related detrimental/lack of an effect for lung, breast, prostate cancer, and glioblastoma. For atorvastatin we see a clinical oncological benefit in patients and head and neck cancer, with a trend towards radioprotection of critical structures, thus supporting the role of atorvastatin as a promising agent for concomitant association with radiotherapy. Propranolol-related increased outcomes were seen in clinical studies in patients with melanoma, breast cancer, and sarcoma.

LOX-1 Activation by oxLDL Induces AR and AR-V7 Expression via NF-κB and STAT3 Signaling Pathways Reducing Enzalutamide Cytotoxic Effects

“…These allow us to propose LOX-1 as a target in cancer therapy or, as in our study, as a target for the prevention of the resistance to enzalutamide in CRPC. In this regard, statins, an HMG-CoA reductase inhibitor, positively prevent cancer progression [ 79 ]. Likewise, it has been determined that they prevent LOX-1 expression and that statins, such as lovastatin would directly antagonize the binding of oxLDLs to LOX-1 [ 80 ].…”

Drug Repurposing in Non-Small Cell Lung Carcinoma: Old Solutions for New Problems

“…A study by Sidorova et al, which studied the effects of beta blockers on the viability and cell colony formation of NSCLC, showed that propranolol and betaxolol are the most effective in inhibiting lung cancer cell colony formation at 90% of the EC50 value [83]. Propranolol decreases tumor angiogenesis and can stimulate the immune system [84]. Beta blockers may help treat cancer via desensitization of beta receptors to chronic beta-agonist use.…”

“…By inhibiting β-hydroxy β-methylglutaryl-CoA (HMG-CoA) reductase, an enzyme essential for synthesizing cholesterol [95], statins decrease the production of mevalonate derivatives that are essential for many growth regulatory processes such as proliferation, apoptosis, and differentiation [25]. Atorvastatin is a statin with an antitumor mechanism that inhibits Akt/mTOR and activates the MAPK pathway [84]. Atorvastatin induces apoptosis of tumor cells by depleting the isoprenoid driven growth proteins necessary for the function of cell-growth-stimulating proteins Ras, Rac, and Rho.…”

“…The experiments performed to study the effect of metformin on treating lung cancer concluded that metformin was tolerated but did not provide any oncological benefit [51]. In a lung cancer trial where 167 non-diabetic patients with unresectable stage 3 NSCLC maintained on carboplatin and paclitaxel-based chemoradiation either alone or with metformin, the metformin arm failed to provide any significant differences in the rates of survival or distant metastasis [84]. Another drug used to treat diabetes is thiazolidinediones, which functions by activating PPAR-γ (a nuclear receptor), which increases insulin sensitivity and levels of adiponectin resulting in the regulation of glucose metabolism and fatty acid storage [105].…”

Survival Outcomes of Calcium Channel Blocker Therapy in Patients With Non-Small Cell Lung Cancer Treated With Epidermal Growth Factor Receptor Inhibitors: A Retrospective Study

“… 13 Several non-cancer drugs have the potential to alter the tumor microenvironment and increase the efficacy of cancer drugs when concurrently administered. 14 , 15 To the best of our knowledge, no prospective trial to date has demonstrated the effects of CCBs on survival outcomes of patients with cancer.…”