Involvement of GSK-3β, NF-κB, PPARγ, and apoptosis in amlodipine's anticancer effect in BALB/c mice

Abstract

Lung cancer is the primary cause of death due to cancer all over the world despite the decrease in the mortality rates from cancer in general. While chemotherapy is a commonly employed treatment for lung cancer, its efficacy is limited due to poor tissue selectivity, inadequate delivery to tumor sites, and associated side effects. The present work aims to assess the potential anti-cancer effectiveness of amlodipine, a calcium channel blocker, on murine lung cancer via modulating GSK-3β, NF-κB, PPARγ, and apoptosis. Lung cancer was induced in BALB/c mice by intraperitoneal injection of 1.5 g/kg in two doses of urethane: once on the 1st and the second on the 60th day of the experiment. Amlodipine was administered orally at a dose of 10 mg/kg/day for the last 28 days of experiment. Relative to urethane group, amlodipine mitigated urethane-induced histopathological abnormalities. It restored oxidant/antioxidant balance by normalizing MDA, GSH, and SOD. Furthermore, it exerted a marked anti-inflammatory effect through downregulating lung MPO, ICAM-1, IL-6, TNF-α, and NF-қB expressions. Amlodipine enhanced apoptosis of cancer cells as evidenced by increasing Bax and decreasing Bcl-2 expression. The anticancer effect of amlodipine was suggested to be mediated through increasing PPARγ and reducing GSK3β and p-GSK3β signaling. Collectively, these results suggest that amlodipine could exert a promising anticancer effect against lung cancer through modulating GSK-3β, NF-κB, PPARγ, and apoptosis. Our findings could be highly significant in clinical settings, offering a valuable adjuvant option for managing lung carcinoma, particularly in patients with cardiovascular disorders.