Ethoxysanguinarine Induces Apoptosis, Inhibits Metastasis and Sensitizes cells to Docetaxel in Breast Cancer Cells through Inhibition of Hakai.

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.

Celastrol inhibits the migration and invasion and enhances the anti-cancer effects of docetaxel in human triple-negative breast cancer cells.

The molecular mechanism of anti-metastatic effect of celastrol is not fully understood in breast cancer cells. Herein, we investigated the activity and molecular mechanism of celastrol in triple-negative breast cancer (TNBC) cells, which is a more aggressive subtype of breast cancer. The results of wound healing assay and trans-well assay revealed that celastrol inhibited cell migration and invasion under sub-cytotoxic concentrations in MDA-MB-231 and MDA-MB-468 TNBC cells. Molecular data showed that the effect of celastrol on TNBC cells might be mediated via up-regulation of E-cadherin, a key protein involved in epithelial-mesenchymal transition (EMT). In addition, Hakai, an E3 ligase responsible for E-cadherin complex ubiquitination and degradation, was down-regulated under celastrol treatment. Hakai partially contributed to celastrol-induced anti-invasive effect. In addition, celastrol and docetaxel could synergistically inhibit growth and metastasis of MDA-MB-231 cells. Our results showing anti-migratory/anti-invasive effects of celastrol and associated mechanisms provide new evidence for the development of celastrol as a potential anti-metastatic compound against highly aggressive breast cancer, and celastrol in combination with docetaxel might potentially be used as a novel regimen for the treatment of TNBC.

A novel 8-hydroxyquinoline derivative induces breast cancer cell death through paraptosis and apoptosis.

Chemotherapy represents one of the main conventional therapies for breast cancer. However, tumor cells develop mechanisms to evade chemotherapeutic-induced apoptosis. Thus, it is of great significance to induce non-apoptotic cell death modes, such as paraptosis, in breast cancer. Herein, a novel 8-hydroxyquinoline derivative, 5,7-dibromo-8-(methoxymethoxy)-2-methylquinoline (HQ-11), was obtained and its potential anti-breast cancer mechanisms were investigated. Our results showed that extensive cytoplasmic vacuoles derived from the endoplasmic reticulum (ER) and mitochondria were appeared in MCF7 and MDA-MB-231 breast cancer cells by HQ-11 incubation, and pretreatment of cycloheximide was able to inhibit this vacuolation and HQ-11-induced cell death, showing the characteristics of paraptosis. ER stress was involved in HQ-11-caused paraptosis evidenced by the increase of glucose-regulated protein 78, C/EBP homologous protein and polyubiquitinated proteins. Molecular docking analysis revealed a favorable binding mode of HQ-11 in the active site of the chymotrypsin-like ß5 subunit of the proteasome, indicative of proteasome dysfunction under HQ-11 treatment, which might result in further aggravated ER stress. Furthermore, treatment of HQ-11 resulted in increased phosphorylation of extracellular signal-regulated kinase (ERK) and c-Jun NH2-terminal kinase, and inhibition of ERK with U0126 significantly attenuated HQ-11-induced ER stress and paraptosis. In addition, exposure to HQ-11 also caused apoptosis in breast cancer cells partially through activation of ERK pathway. All these results conclusively indicate that HQ-11 triggers two distinct cell death modes via inhibition of proteasome and activation of ERK pathway in breast cancer cells, providing a promising candidate in future anti-breast cancer therapy.