Abstract 3193: Apoptotic effect of a single compound derived from natural product in Gefitinib-resistant non-small cell lung cancer cells (2014)

Abstract Lung cancer is the leading cause of cancer death worldwide. Non-small cell lung cancer (NSCLC) accounts for over 80% of all the lung cancer cases. The application of advanced gene sequencing technology has identified several specific driver genetic mutations in NSCLC, such as EGFR, KRAS and EML4-ALK etc. The most common types of EGFR activating mutation are L858R substitution mutation on exon 21 and in-flame deletion mutation on exon 19. It leads to the high demand of using small molecule tyrosine kinase inhibitors specific to these mutations as a new anti-cancer strategy. For example, Gefitinib is used for treating NSCLC with EGFR activating mutation. Despite the great achievement in the initial response of Gefitinib treatment, drug resistance remains an unresolved problem. The discovery of new inhibitors or drugs targeting the molecules responsible to Gefitinib resistant is urgent needed. The application of natural products to achieve therapeutic properties has been tried for a long time along human civilization. Plants, animals and mineral products are the main sources of the natural drugs. In this study, we have found a single compound, designated as MUST-1, which is purified from a Chinese medicine herb, is a potential anti-cancer compound in Gefitinib resistant NSCLC. MUST-1, which is a natural alkaloid, is isolated from a commonly used Chinese medicinal herb, which has been utilized clinically to treat inflammatory diseases, anti-microbe, anti-inflammation and anti-oxidation functions traditionally. Quantitative analysis using flow cytometer of the control and the MUST-1-treated cells after Annexin V/PI staining showed that MUST-1 significantly induced apoptosis in NSCLC cells after 24 hours treatment, the effect is especially effective in those NSCLC cell lines with EGFR mutation(s) and resisted to Gefitinib treatment. Western blot analysis demonstrated that MUST-1 initially activated c-Jun-N-terminal kinase (JNK) and p38 phosphorylation, triggered EGFR degradation and suppressed the EGFR downstream anti-apoptotic AKT signaling. Moreover, NF-κB pathway suppression was also observed. JC-1 staining was used to prove the change in mitochondrial membrane potentials, our result showed that mitochondrial disruption plays an important role in the MUST-1-mediated apoptosis. Further Western blot analysis showed that Caspases-3/7 was activated during apoptosis. Treatment with pan-caspases inhibitor can attenuate the apoptotic effect of MUST-1, suggesting that apoptosis induced by MUST-1 is Caspases-dependent. Overall, our data suggest that MUST-1 is particularly effective in Gefitinib-resistant NSCLC. It may potentially be developed as an alternative treatment option for the NSCLC patients who have developed Gefitinib resistance. Citation Format: Xing-Xing Fan, Maria Pik Wong, Zhi-Wei Cao, Na Li, Jin-Lin Wu, Hua Zhou, Zhi-Hong Jiang, Liang Liu, Elaine Lai-Han Leung. Apoptotic effect of a single compound derived from natural product in Gefitinib-resistant non-small cell lung cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3193. doi:10.1158/1538-7445.AM2014-3193