Abstract
Abstract
Naturally occurring terpenoid compounds are diverse active constituent in several plants and known of their potential anticancer activities. Camptothecin (CPT) is a topoisomerase inhibitor agent with well documented anti-neoplastic activity against several types of tumors. The purpose of this study is to investigate the potential chemotherapeutic effects of some terpenoid compounds isolated from Salvia africana lutea, Stachys aegyptiaca, Tanacetum sinaicum. Terpenoid compounds with promising anticancer profile has been further investigated for potential chemomodulatory effects to CPT against different tumor cell types. Cytotoxicity of the isolated terpenoids were assessed against human breast adenocarcinoma (MCF7), human colorectal cancer (HCT116 and LS174T) and human hepatocellular carcinoma (HepG2) cells using sulpharhodamine-B assay after cell exposure for 72 h. Cytotoxic parameters (IC50 and R-fraction) were calculated from cell viability after fitting to Emax mathematical model. The tetrahydrofuran type terpenoid, (R,E)-6-hydroxy-6-methyl-2-((2S,5R)-methyl-5-vinyltetrahydrofuran-2-yl)hept-4-en-3-one (TSS-7), isolated from Tanacetum sinaicum showed considerable cytotoxicity with IC50 ranging from 49 to 70 μM in all tested cell lines. On the other hand, IC50 of CPT ranged from 0.13 to 1.5 μM in the same cell lines under investigation. Combination index analysis (CI-value) for TSS-7 with CPT showed synergistic relationship in MCF7, HCT116 and HepG2 (CI-values were 0.17, 0.17 and 0.39 respectively). However, the same combination of TSS-7 and CPT against LS174T cells showed antagonistic relationship (CI-value of 1.2). Further investigation for apoptosis/necrosis assessment using annexin-V/PI staining was undertaken for single and combination treatment of CPT and TSS-7. In HCT116 cells, TSS-7 combination with CPT significantly increased apoptotic and necrotic cells compared to CPT treatment alone. However, in LS174T cells, TSS-7 combination with CPT significantly decreased apoptotic and necrotic cells compared to CPT treatment alone. Cell cycle analysis using DNA cytometry showed strong G2/M arrest induced by CPT treatment. Yet, TSS-7 increased cell population in S-phase and to a lesser extend in G2/M-phase which might be the reason for temporal synergism/antagonism of TSS-7 and CPT in different cell lines. In conclusion, TSS-7 could be considered promising anticancer chemomodulatory terpenoid compound which requires further molecular investigations to elucidate its sub-cellular molecular target.
Citation Format: Eman M. Atiya, Fahad A. Al-Abbasi, Mohamed-Elamir F. Hegazy, Ali M. El-Halawany, Ahmed M. Al-Abd. Chemotherapeutic and chemomodulatory effects of naturally occurring tetrahydrofuran type terpenoid. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4846.