Cancer Management and Research (Feb 2019)
Apoptotic and antimetastatic activities of betulin isolated from Quercus incana against non-small cell lung cancer cells
Abstract
Binte Zehra,1,* Ayaz Ahmed,1,* Rizwana Sarwar,2 Ajmal Khan,3 Umar Farooq,2 Syed Abid Ali,4 Ahmed Al-Harrasi3 1Dr Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, Pakistan; 2Department of Chemistry, COMSATS University Islamabad Abbottabad Campus, Abbottabad, Pakistan; 3Natural and Medical Sciences Research Center, University of Nizwa, Nizwa, Sultanate of Oman; 4Hussain Ebrahim Jamal Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, Pakistan *These authors contributed equally to this work Background: Globally, the prevalence and mortality rates of lung cancer have been escalated with the increasing trend of tobacco smoking. The toxicity and irresponsive nature of the available drugs for lung cancer treatment demands an alternative approach.Methods: In this study, four known compounds namely, cirsimaritin (4′,5, -dihydroxy-6,7-dimethoxyflavone) (1), eupatorin (5,3′-dihydroxy-6,7,4′-trimethoxyflavone) (2), betulin (Lup-20 (29)-ene-3, 28-diol) (3), and β-amyrin acetate (12-Oleanen-3yl acetate) (4) have been isolated from the leaves extract of Quercus incana. Preliminary screening of these natural compounds (1–4) was performed against non-small cell lung carcinoma (NCI-H460) and normal mouse fibroblast (NIH-3T3) cell lines.Results: The compounds were found to be antiproliferative against cancer cells with wide therapeutic index in comparison to the normal cells. Effects of betulin (3) on cell migration, invasion, apoptosis, and expression of important apoptosis- and metastasis-related markers were observed at different concentrations. The results showed significant dose-dependent induction of apoptosis after the treatment with betulin (3) followed by increased expression of the caspases family (ie, caspase-3, -6, and -9), proapoptotic genes (BAX and BAK), and inhibiting anti-apoptotic genes (BCL-2L1 and p53). Furthermore, wound healing and transwell invasion assays suggested that betulin (3) could also regulate metastasis by inhibiting MMP-2/-9. Osteopontin, a central regulator of apoptosis and metastasis was also inhibited in a dose-dependent manner.Conclusion: The present findings suggest that betulin (3) can be an attractive chemotherapeutic target for treating resistant lung cancers. Keywords: Quercus incana, betulin, cirsimaritin, eupatorin, b-amyrin acetate, non-small cell lung carcinoma, metastasis, MMP-2, MMP-9, apoptosis, caspases, osteopontin
