Fixed-Dose Combinations of Pioglitazone and Metformin for Lung Cancer Prevention

Abstract

Combination treatment with pioglitazone and metformin are utilized clinically in the treatment of type II diabetes. Treatment with this drug combination reduced the development of aerodigestive cancers in this patient population. Our goal is to expand this treatment into clinical lung cancer chemoprevention. We hypothesized that dietary delivery of metformin/pioglitazone would prevent lung adenoma formation in A/J mice in a B[a]P-induced carcinogenesis model while modulating chemoprevention and anti-inflammatory biomarkers in residual adenomas. We found metformin (500 & 850 mg/kg/day) and pioglitazone (15 mg/kg/day) produced statistically significant decreases in lung adenoma formation both as single agent treatments and in combination, compared to untreated controls, after 15 weeks. Treatment with metformin alone and in combination with pioglitazone resulted in statistically significant decreases in lung adenoma formation at both early and late stage interventions. Pioglitazone alone resulted in significant decreases in adenoma formation only at early treatment intervention. We conclude oral metformin is a viable chemopreventive treatment at doses ranging from 500 to 1000 mg/kg/day. Pioglitazone at 15 mg/kg/day is a viable chemopreventive agent at early stage interventions. Combination metformin and pioglitazone performed equal to metformin alone and better than pioglitazone at 15 mg/kg/day. Since the drugs are already FDA approved, rapid movement to human clinical studies is possible.

Chloride intracellular channel 1 regulates the antineoplastic effects of metformin in gallbladder cancer cells

“…Recent studies have shown that metformin exerts multiple antitumor effects in vivo and in vitro . However, these antitumor effects as well as the related underlying mechanisms vary among different cancer cells.…”

“…Recent studies have shown that metformin exerts multiple antitumor effects in vivo and in vitro. (24)(25)(26) However, these antitumor effects as well as the related underlying mechanisms vary among different cancer cells. In colorectal cancer, metformin suppresses colonic epithelial proliferation by inhibiting the mTOR pathway via AMPK activation.…”

Metformin partially reverses the carboplatin-resistance in NSCLC by inhibiting glucose metabolism

“…Recent research demonstrates that the use of metformin in patients with diabetes may reduce the occurrence of cancers [ 9 ]. Furthermore, metformin treatment is reported to prevent lung adenoma formation and induce growth inhibition and cell cycle arrest in renal cancer cells [ 10 , 11 ]. For adjuvant therapy of cancer, studies have indicated that metformin may reverse the resistance of breast cancer cells to doxorubicin by reducing the drug efflux [ 12 ].…”

Assessing the Current State of Lung Cancer Chemoprevention: A Comprehensive Overview

“…Although some preclinical data suggested the potential benefit of mTOR inhibitors [162,163], significant side effects associated with their use prevented the development of clinical trials with this class of drugs. Metformin, another inhibitor of mTOR [157], has shown some potential for chemoprevention in in vivo models [164], further supported by some meta-analytical and epidemiologic studies in type-2 diabetic patients [165][166][167][168][169][170][171]. However, selected studies report no effect of metformin on the development of several types of cancers, including lung cancer, in diabetic patients [172].…”