Alternariol ameliorates lung carcinoma via reprogramming cytokine signaling associated with PI3K/Akt cascade in vitro and in vivo

Abstract

Objectives: The lung cancer is most frequently diagnosed cancer incidence worldwide. A large number of populations are heavily affected to this every year with poor prognosis. Methods: Our study investigated the anticancer effect of alternariol, a secondary metabolite, on A549 lung cancer cell line and benzo-α-pyrene induced lung carcinoma model on balb/c mice. The cytotoxicity assay, DAPI staining and the flow cytometry was performed to assess the anticancer efficacy of alternariol in A549 lung cancer cell. For in vivo study the toxicity study was performed. The lung cancer was developed in the animals via intraperitoneal administration of benzo-α-pyrene and subsequently 2 weeks later alternariol treatment was carried out for 24 weeks. The chemotherapeutic effect of alternariol was assessed through histopathological analysis, followed by immunohistochemistry and in vivo antioxidant study. Results: The in vitro data suggested a significant percentage of early and late apoptotic events in A549 cells with G0/G1 phase arrest which ultimately caused apoptosis followed by alternariol therapy. The in vivo study showed that alternariol therapy decreased the pulmonary fibrosis and formation of granuloma in lung tissue and restored the normal histopathological characteristics of lung. Furthermore, alternariol treatment downregulated the expression of PI3K, Akt and inflammatory mediators such as IL-6, TNF-α and increased the expression of apoptotic markers, p53. Conclusion: In conclusion, the treatment with alternariol effectively decreased the progression of lung cancer through the inhibition of carcinogenic markers by reprogramming the p53/PI3K/Akt pathway and IL-6/TNF-α mediated cytokine signaling in mice.