goniothalamin and Breast-Neoplasms

Combination of natural products with chemically synthesised biomaterials as cancer therapy has attracted great interest lately. Hence, this study is aimed at investigating the combined effects of goniothalamin and bioactive glass 45S5 (GTN-BG) and evaluating their anticancer properties on human breast cancer cells MCF-7.. The BG 45S5 was prepared using the sol-gel process followed by characterisation using PSA, BET, SEM/EDS, XRD, and FTIR. The effects of GTN-BG on the proliferation of MCF-7 were assessed by MTT, PrestoBlue, and scratch wound assays. The cell cycle analysis, Annexin-FITC assay, and activation of caspase-3/7, caspase-8, and caspase-9 assays were determined to further explore its mechanism of action.. The anticancer effect of GTN in MCF-7 cells was improved when combined with BG. The findings provide significant insight into the mechanism of GTN-BG against MCF-7 cells, which can potentially be used as a novel anticancer therapeutic approach.

Topics: Apoptosis; Breast Neoplasms; Caspase 8; Caspase 9; Cell Cycle Checkpoints; Cell Proliferation; Ceramics; Female; Glass; Humans; MCF-7 Cells; Pyrones

Topics: Anoikis; Antineoplastic Agents; Biomarkers; Breast Neoplasms; Calcium; Caspases; Cell Line, Tumor; Cytosol; Epithelial-Mesenchymal Transition; ErbB Receptors; Female; Focal Adhesion Kinase 1; Humans; Necroptosis; Pyrones; Reactive Oxygen Species; Signal Transduction; src-Family Kinases

The molecular basis of anticancer and apoptotic effects of R-goniothalamin (GON), a plant secondary metabolite was studied. We show that induction of oxidative stress and reactivation of mutant p53 underlie the strong cytotoxic effects of GON against the breast cancer cells. While GON was not toxic to the MCF10a breast epithelial cells, the SKBR3 breast cancer cells harboring an R175H mutant p53 were highly sensitive (IC50 = 7.3 µM). Flow cytometry and other pertinent assays showed that GON-induced abundant reactive oxygen species (ROS), glutathione depletion, protein glutathionylation and activation of apoptotic markers. GON was found to conjugate with glutathione both in vitro and in cells and the product was characterized by mass spectrometry. We hypothesized that the redox imbalance induced by GON may affect the structure of the R175H mutant p53 protein, and account for greater cytotoxicity. Using the SKBR3 breast cancer and p53-null H1299 lung cancer cells stably expressing the R175H p53 mutant protein, we demonstrated that GON triggers the appearance of a wild-type-like p53 protein by using conformation-specific antibodies, immunoprecipitation, DNA-binding assays and target gene expression. p53 restoration was associated with a G2/M arrest, senescence, reduced cell migration, invasion and increased cell death. GON elicited a highly synergistic cytotoxicity with cisplatin in SKBR3 cells. In SKBR3 xenografts developed in nude mice, there was a marked tumor growth delay by GON alone and GON + cisplatin combination. Our studies highlight the impact of tumor redox-stress generated by GON in activating the mutant p53 protein for greater antitumor efficacy.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast; Breast Neoplasms; Cell Line, Tumor; Cell Movement; Cisplatin; Female; G2 Phase Cell Cycle Checkpoints; Glutathione; Humans; MCF-7 Cells; Mice; Mice, Nude; Neoplasm Invasiveness; Oxidation-Reduction; Oxidative Stress; Pyrones; Reactive Oxygen Species; Tumor Suppressor Protein p53; Xenograft Model Antitumor Assays

Goniothalamin, a plant bioactive styrly-lactone, possesses many biological activities. In the present study, the anticancer effect of goniothalamin on human breast cancer cell line SK-BR-3 was investigated. The results showed that goniothalamin induced nuclear condensation, DNA fragmentation, apoptotic bodies and mitochondrial dysfunction as determined by JC-1 staining. Goniothalamin also increased the Bax/Bcl-2 ratio and expression of cleaved caspase-7, cleaved caspase-9 and cleaved PARP, but decreased Bcl-2 expression. In addition, goniothalamin induced apoptosis via p-JNK1/2 and p-p38 upregulation and inhibited cell survival via p-ERK1/2 and p-Akt downregulation. Notably, goniothalamin induced autophagy through upregulation of Atg7, Atg12-Atg5 conjugation and LC3II. The increased p-p38 and p-JNK1/2 and decreased p-Akt may lead to autophagy induction. Therefore, goniothalamin promoted apoptosis associated with autophagy induction in SK-BR-3 cells through p-p38 and p-JNK1/2 upregulation and p-Akt downregulation. The present study indicated that goniothalamin may be further used as a potential therapeutic candidate or may offer an alternative treatment for breast cancer.

Topics: Antineoplastic Agents; Apoptosis; Autophagy; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Drug Screening Assays, Antitumor; Female; Humans; MAP Kinase Signaling System; Membrane Potential, Mitochondrial; Proto-Oncogene Proteins c-akt; Pyrones

Topics: Antineoplastic Agents; Apoptosis; Breast Neoplasms; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Goniothalamus; Humans; Lactones; Pyrones; TCF Transcription Factors; Transcription, Genetic; Wnt Signaling Pathway

Cancer is one of the major health problems worldwide and its current treatments have a number of undesired adverse side effects. Natural compounds may reduce these. Currently, a few plant products are being used to treat cancer. In this study, goniothalamin, a natural occurring styryl-lactone extracted from Goniothalamus macrophyllus, was investigated for cytotoxic properties against cervical cancer (HeLa), breast carcinoma (MCF-7) and colon cancer (HT29) cells as well as normal mouse fibroblast (3T3) using MTT assay. Fluorescence microscopy showed that GTN is able to induce apoptosis in HeLa cells in a time dependent manner. Flow cytometry further revealed HeLa cells treated with GTN to be arrested in the S phase. Phosphatidyl serine properties present during apoptosis enable early detection of the apoptosis in the cells. Using annexin V/PI double staining it could be shown that GTN induces early apoptosis on HeLa cells after 24, 48 and 72 h. It could be concluded that goniothalamin showing a promising cytotoxicity effect against several cancer cell lines including cervical cancer cells (HeLa) with apoptosis as the mode of cell death induced on HeLa cells by Goniothalamin was.

Topics: Animals; Apoptosis; Blotting, Western; Breast Neoplasms; Cell Proliferation; Cells, Cultured; Colonic Neoplasms; Female; Fibroblasts; Flow Cytometry; HeLa Cells; Humans; In Vitro Techniques; Mice; Plant Extracts; Plant Roots; Pyrones; S Phase

The mechanism of action for alpha,beta-unsaturated lactones can be explained by their Michael acceptor properties. They have the potential of being covalently binding inhibitors by accepting nucleophiles from target proteins. In this work, Michael addition reactions of ethanethiol with 6-bicycloaryl substituted 5,6-dihydro-2H-pyran-2-ones were studied to explore the existence of such interactions. Three of the Michael addition products were isolated and tested over PC3 (human prostate cancer) and MCF-7 (human breast adenocarcinoma) cancer cell lines and no cytotoxicity was observed. It was revealed that biological activity depends on the existence of a Michael acceptor, but potency probably depends upon the 3D structure of the substituent on lactone ring. The primary chemical-quantum properties of the lactones were also calculated using the Spartan'08 computer program.

Topics: Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Female; Humans; Lactones; Male; Molecular Conformation; Prostatic Neoplasms; Pyrones; Sulfhydryl Compounds

(R)- and (S)-Goniothalamin (1) and analogues 2-9 were efficiently prepared in high overall yield and enantiomeric purity, and their cytotoxic activities were evaluated against eight human cancer cell lines. A structure-activity relationship study (SAR) allowed us to establish the relevant structural features for the cytotoxic activity of goniothalamin analogues. In addition, we have identified non-natural form of goniothalamin (S)-1 and analogue 5 as the highest and more selective cytotoxic compounds against kidney cancer cell growth (786-0) with IC50 = 4 and 5 nM, respectively, and compound 8 (IC50 = 4 nM) as the more potent against breast cancer cells with resistance phenotype for adryamycin (NCI.ADR).

Topics: Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Doxorubicin; Drug Resistance, Neoplasm; Female; Humans; Kidney Neoplasms; Magnetic Resonance Spectroscopy; Male; Neoplasms; Pyrones; Stereoisomerism; Structure-Activity Relationship