ABSTRACT
Ethoxysanguinarine (ESG) is a benzophenanthridine alkaloid extracted from plants of Papaveraceae family, such as Macleaya cordata (Willd) R. Br. The anti-cancer activity of ESG has been rarely reported. In this study, we investigated the anti-breast cancer effect of ESG and its underlying mechanism. MTT assay and flow cytometry analysis showed that ESG inhibited the viability and induced apoptosis in MCF7 and MDA-MB-231 human breast cancer cells. Western blot revealed that ESG triggered intrinsic and extrinsic apoptotic pathways, as evidenced by the activation of caspase-8, caspase-9 and caspase-3. ESG attenuated breast cancer cell migration and invasion through Hakai/E-cadherin/N-cadherin. Moreover, Hakai knockdown sensitized ESG-triggered viability and motility inhibition, suggesting that Hakai mediated the anti-breast cancer effect of ESG. In addition, ESG potentiated the anti-cancer activity of docetaxel (DTX) in breast cancer cells. Overall, our findings demonstrate that ESG exhibits outstanding pro-apoptosis and anti-metastasis effects on breast cancer via a mechanism related to Hakai-related signaling pathway.
Subject(s)
Antineoplastic Agents , Breast Neoplasms , Female , Humans , Antineoplastic Agents/pharmacology , Apoptosis , Breast Neoplasms/pathology , Cell Line, Tumor , Cell Proliferation , DocetaxelABSTRACT
Dozens of hybrids of natural alkaloid evodiamine/rutaecarpine and thieno[2,3-d]pyrimidinones were synthesized in a straightforward method by condensation of substituted 2H-thieno[2,3-d][1, 3]oxazine-2,4(1H)-diones or N-methyl-2H-thieno[2,3-d][1, 3]oxazine-2,4(1H)-dione with 3,4-dihydro-ß-carbolines. In vitro cytotoxic assay discovered that compounds 9a, 10e, 11a, 11d, 11f, and 12a could induce antiproliferation against four different types of human cancer cells while compounds 10f and 12e were inactive. Notably, compound 11a displayed potent cell cytotoxicity for human non-small cell lung cancer cells A549, PC-9, human prostate cancer cells PC-3, and human breast cancer cell line MCF-7. Furthermore, compound 11a exhibited strong colony formation inhibition to A549 cells. These results unfold potential anticancer therapeutic applications of hybrids of thieno[2,3-d]pyrimidinones and quinazolinones.