baohuoside-i and Breast-Neoplasms

A series of Icariside II (ICS II) derivatives were synthesized, and their structure-activity relationships (SARs) were studied in this paper. The in vitro antitumor activities towards human breast cancer cell lines (MCF-7) were evaluated by Cell Counting Kit-8 (CCK-8 kit). Preliminary results showed that, compared with ICS II, most of the derivatives displayed good micromole level activities. Among the series of derivatives, the S27, which totally acetylated hydroxyl of ICS II, possessed highest cytotoxicity, with IC

Topics: Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Female; Flavonoids; Humans; Molecular Structure; Structure-Activity Relationship

Breast cancer is the most common malignancy in women and metastasis is the leading cause of breast cancer-related deaths. Our previous studies have shown that XIAOPI formula, a newly approved drug by the State Food and Drug Administration of China (SFDA), can dramatically inhibit breast cancer metastasis by modulating the tumor-associated macrophages/C-X-C motif chemokine ligand 1 (TAMs/CXCL1) pathway. However, the bioactive compound accounting for the anti-metastatic effect of XIAOPI formula remains unclear.. This study was designed to separate the anti-metastatic bioactive compound from XIAOPI formula and to elucidate its action mechanisms.. TAMs/CXCL1 promoter activity-guided fractionation and multiple chemical structure identification approaches were conducted to screen the bioactive compound from XIAOPI formula. Breast cancer cells and TAMs were co-cultured in vitro or co-injected in vivo to simulate their coexistence. Multiple molecular biology experiments, zebrafish breast cancer xenotransplantation model and mouse breast cancer xenografts were applied to validate the anti-metastatic activity of the screened compound.. Bioactivity-guided fractionation identified baohuoside I (BHS) as the key bioactive compound of XIAOPI formula in inhibiting TAMs/CXCL1 promoter activity. Functional studies revealed that BHS could significantly inhibit the migration and invasion as well as the expression of metastasis-related proteins in both human and mouse breast cancer cells, along with decreasing the proportion of breast cancer stem cells (CSCs). Furthermore, BHS could suppress the M2 phenotype polarization of TAMs and therefore attenuate their CXCL1 expression and secretion. Notably, mechanistic investigations validated TAMs/CXCL1 as the crucial target of BHS in suppressing breast cancer metastasis as exogenous addition of CXCL1 significantly abrogated the anti-metastatic effect of BHS on breast cancer cells. Moreover, BHS was highly safe in vivo as it exhibited no observable embryotoxicity or teratogenic effect on zebrafish embryos. More importantly, BHS remarkably suppressed breast cancer metastasis and TAMs/CXCL1 activity in both zebrafish breast cancer xenotransplantation model and mouse breast cancer xenografts.. This study not only provides novel insights into TAMs/CXCL1 as a reliable screening target for anti-metastatic drug discovery, but also suggests BHS as a promising candidate drug for metastatic breast cancer treatment.

Topics: Animals; Breast Neoplasms; Cell Line, Tumor; Chemokine CXCL1; Coculture Techniques; Down-Regulation; Drug Screening Assays, Antitumor; Drugs, Chinese Herbal; Embryo, Nonmammalian; Female; Flavonoids; Humans; Macrophages; Mice, Inbred BALB C; Neoplasm Metastasis; Neoplastic Stem Cells; Xenograft Model Antitumor Assays; Zebrafish

The biggest challenge for the treatment of multidrug resistant cancer is to deliver a high concentration of anticancer drugs to cancer cells. Icariside II is a flavonoid from Epimedium koreanum Nakai with remarkable anticancer properties, but poor solubility and significant efflux from cancer cells limited its clinical use. In our previous study, a self-assembled mixture of micelles (TPGS-Icariside II-phospholipid complex) was successfully constructed, which could substantially increase the solubility of Icariside II and inhibit the efflux on Caco-2 cells. In this study, we evaluate the anticancer effect of the mixed micelles encapsulating Icariside II (Icar-MC) on MCF-7/ADR, a multidrug-resistant breast cancer cell line. The cellular uptake of the micelles was confirmed by fluorescent coumarin-6-loaded micelles. The IC50 of Icar-MC in MCF-7/ADR was 2-fold less than the free drug. The in vitro study showed Icar-MC induced more apoptosis and lactate dehydrogenase release. Intravenous injection of Icar-MC into nude mice bearing MCF-7/ADR xenograft resulted in a better antitumor efficacy compared with the administration of free drug, without causing significant body weight changes in mice. The antitumor effect was further verified by magnetic resonance imaging and immunohistochemical assays for Ki-67, a proliferative indicator. Moreover, Icar-MC treatment also elevated Bax/Bcl-2 ratio and the expressions of cleaved caspase-3, -8, -9 and AIFM1 in tumors. This study suggests that phospholipid/TPGS mixed micelles might be a suitable drug delivery system for Icariside II to treat multidrug resistant breast cancer.

Topics: Animals; Antineoplastic Agents; Apoptosis; Apoptosis Inducing Factor; bcl-2-Associated X Protein; Breast Neoplasms; Caco-2 Cells; Caspases; Cell Line, Tumor; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Female; Flavonoids; Humans; MCF-7 Cells; Mice; Mice, Nude; Micelles; Phospholipids; Proto-Oncogene Proteins c-bcl-2; Vitamin E

More than 90 percent of cancer-mediated deaths are due to metastasis, but the mechanisms that control metastasis remain poorly understood. Thus, the therapy targeting this process has been challenged constantly, but no therapy has yet been approved. CXC chemokine receptor 4 (CXCR4), a Gi protein-coupled receptor for the CXC chemokine ligand (CXCL) 12/stromal cell derived factor (SDF) 1α, is known to be expressed in various tumors. Recently, the CXCL12/CXCR4 axis has emerged as a key mediator of tumor metastasis; therefore, the possibility that identification of CXCR4 inhibitors can be a promising strategy for abrogating metastasis has been considered. In this report, we investigate baohuoside I, a component of Epimedium koreanum, as a regulator of CXCR4 expression as well as function in cervical cancer and breast cancer cells. We observed that baohuoside I downregulated CXCR4 expression in a dose- and time-dependent manner in HeLa cells. Treatment with a pharmacological proteasome and lysosomal inhibitors did not have a substantial effect on baohuoside I's ability to suppress CXCR4 expression. When we investigated the molecular mechanism of action, it was observed that the suppression of CXCR4 expression occurred at the level of mRNA. The decrease in the level of CXCR4 expression caused by baohuoside I was correlated with inhibition of the CXCL12-induced invasion of both cervical and breast cancer cells. Overall, our results show that baohuoside I exerts its antimetastatic effect through the downregulation of CXCR4 expression and, thus, has the potential to play a role in the suppression of cancer metastasis.

Topics: Antineoplastic Agents, Phytogenic; Breast Neoplasms; Cell Line, Tumor; Dose-Response Relationship, Drug; Down-Regulation; Epimedium; Female; Flavonoids; HeLa Cells; Hep G2 Cells; Humans; Neoplasm Invasiveness; Receptors, CXCR4; RNA, Messenger; RNA, Neoplasm; Uterine Cervical Neoplasms

The anti-tumor effect of Icariside II (IcaS), a natural prenylated flavonol glycoside, was studied on human breast cancer MCF7 cells to unveil the underlying mechanisms involved. IcaS in MCF7 cells produced a loss of mitochondrial membrane potential and release of cytochrome c and apoptosis-inducing factor (AIF), and activation of caspase-9 revealed the involvement of the intrinsic apoptosis pathway. In contrast, IcaS enhanced the expression level of Fas and the Fas-associated death domain (FADD), and activated caspase-8, suggesting the involvement of the extrinsic apoptosis pathway. IcaS also increased the expression of Bax and BimL without affecting the expression status of Bcl-2 and Bid, suggesting that the apoptosis induced by IcaS was related to Bcl-2 family protein regulation. IcaS thus induced apoptosis in MCF7 cells involving both the intrinsic and extrinsic signaling pathways. Its potential as a candidate for an anti-cancer agent warrants further investigation.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Apoptosis Inducing Factor; Breast Neoplasms; Carcinoma; Caspase 8; Caspase 9; Cell Line, Tumor; Cytochromes c; fas Receptor; Fas-Associated Death Domain Protein; Female; Flavonoids; Gene Expression Regulation, Neoplastic; Humans; Membrane Potential, Mitochondrial; Mitochondria; Proto-Oncogene Proteins c-bcl-2; Signal Transduction