Abstract
Abstract Background: The aim of this study was to evaluate the anticancer activity of a natural product Noscapine (Nos) and Camptothecin (CMP) combination (Nos+CMP) against non-small cell lung cancer (NSCLC) and to elucidate the underlying mechanism of action. Methods: A549 cells were treated with Nos, CMP or their combination and combination index (CI) values were calculated using isobolographic method. The apoptotic proportion of the cells and cell cycle effects were analyzed using flow cytometry. The expression of apoptotic proteins was detected by western blot analysis such as anti-apoptotic protein Bcl2, cell survival marker survivin, extracellular matrix proteins like MMP-2, MMP-9 and cell cycle regulatory proteins like p21 and cyclin dependent kinase 2 (CDK2). Results: The CI values (<0.61) were suggestive of synergistic behavior between Nos and CMP. To investigate the underlying mechanism of the Nos antiproliferative effect, cell cycle-analysis was conducted with A549 cells. Nos+CMP treatment group induced G2/M phase arrest (using the the fluorescence-activated cell sorting analysis) and the number of apoptotic cells were also increased significantly in a dose-dependent manner compared to Nos and CMP alone and control treatments. Furthermore, western blot analysis revealed that Nos+CMP treatment significantly upregulated 0.9 fold (p<0.05) the expression of tumor suppressor protein p21 Waf1/Cip1 (suggesting inhibition of cell cycle progression) compared to single agent treated and control groups. Expression of CDK2 (an important component of cell machinery) and cyclin D1 (another important regulator of cell cycle progression) was significantly downregulated 1.03 fold (p<0.05) and 0.7 fold (p<0.05) respectively in Nos+CMP compared to other groups. Also, expression of Bcl2, survivin, MMP-2 and MMP-9 was significantly downregulated in Nos+CMP treated cells (p<0.05). Further, investigations are currently being conducted to evaluate the synergistic anticancer effect of Nos and CMP in lung tumor xenografts in nude mice. Conclusion: Nos potentiated the anticancer activity of CMP in an additive to synergistic manner against lung cancer via cell cycle and apoptotic pathways. These findings suggest potential benefit for use of Nos+CMP in treatment of lung cancer. Citation Format: Ravi Doddapaneni, Ketan Patel, Mandip Singh. Synergistic anticancer effect of Noscapine and Camptothecin is mediated through apoptosis and cell cycle arrest in A549 lung cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2619. doi:10.1158/1538-7445.AM2015-2619
Published Version
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