130 Poster - The synergistic action of isolated sesquiterpene with cisplatin against non-small cell lung cancer cells

Abstract

Non-small cell lung carcinoma (NSCLC) is the most frequently diagnosed and heterogenous subtype of lung cancer, contributing to 85% of new lung cancer cases worldwide. The prevalence of lung cancer especially NSCLC in Pakistan is also on the rise due to tobacco smoking and chewing as well as air pollution. The asymptomatic and poor prognostic nature of the disease usually results in advanced stage metastatic lung cancer and development of resistance against available treatment modalities. This obviates the extensive need for significant improvements in disease management strategies and its therapeutics. This study was designed to evaluate the synergistic properties of isolated natural sesquiterpene i.e. Compound 3 isolated from the aerial parts of Polygonum barbatum, with cisplatin an FDA approved anticancer drugs against NSCLC NCI-H460 cells. The combinatorial efficacy of compound 3 and cisplatin was evaluated for anti proliferation, apoptosis induction and anti metastatic potential by using MTT, wound healing, invasion assays, zymography, FACS analysis, gene and protein expression assays. The results showed that a strong synergistic interaction between Cisplatin and Compound 3, leading to anti-cancer effects at much lower doses than the individual drugs alone. Furthermore, combined drug dose also triggered apoptosis as demonstrated through Yo-Pro-1 assay and deregulated metastasis in H460 cells, as found by transwell invasion and cell migration assays. The drug combination significantly downregulated inhibitory apoptotic markers, i.e. BCL-2L1 and p53 and upregulated apoptogenic BAK, BAX and caspases family proteins. On the other hand, the metastatic markers: MMP-2/-9, VEGF, and COX-2 were also downregulated with the subsequent treatment of combined dose of Cisplatin/Compound 3. The common regulator of apoptosis and metastasis, osteopontin, was also subjected to analysis and found to be regulated suppressively to manage the tumor progression and spread. These results suggest that compound 3 being anticancer itself also has capabilities to sense and synergize cisplatin which can be helpful to minimize cisplatin related toxicity and resistance development.