harmine and Breast-Neoplasms

Topics: Animals; Breast Neoplasms; Carbolines; Carcinogens, Environmental; Cattle; Colonic Neoplasms; Cooking; Food; Harmine; Head and Neck Neoplasms; Humans; Imidazoles; Male; Meat; Mutagens; Neoplasms; Nitrates; Nitrites; Nitrosamines; Prostatic Neoplasms

Breast cancer remains a serious threaten to the women's health, discovery of potent treatment would help to improve the outcomes of breast cancer patients. Harmine extracted from Peganum harmala L , has been reported to exert tumor suppressive activity in several malignancies. Our objective was to demonstrate the effects of harmine on the malignant phenotypes of breast cancer cells. Breast cancer cell lines (MDA-MB-231, SKBR3, and MCF-7) and human normal breast cell line MCF-10A were employed in the present study. The MTT and colony formation assays were applied to the detection of cell viability and proliferation. Wound healing and transwell assays were performed to evaluate the alterations of cell migration and invasion after harmine treatment. Flow cytometry was applied to assess the effect of harmine in inducing cell apoptosis. Furthermore, western blotting assay was used to detect the biomarkers of epithelial-mesenchymal transition and phosphatidylinositol 3 kinase (PI3K) signaling pathway. The tumorigenesis ability was detected by subcutaneous implantation. Harmine dose-dependently suppressed the viability and proliferative capacity of breast cancer cells. Flow cytometry showed that harmine induced apoptosis in MCF-7 and MDA-MB-231 cells. In addition, harmine effectively inhibited the migration and invasion abilities of breast cancer cells. Western blotting indicated harmine significantly promoted E-cadherin and PTEN expression, while suppressed N-cadherin, vimentin, PI3K, p-mTOR, and AKT levels. Interfering the PTEN expression by siRNA partly rescued the activity of PI3K signaling pathway. Moreover, harmine injection also suppressed the tumorigenesis of breast cancer cells. Our results suggested that Hermine could suppress multiple malignant phenotypes and inhibit PI3K signaling, which supports that harmine might be a potential tumor-suppressive natural compound against breast cancer.

Topics: Apoptosis; Breast Neoplasms; Carcinogenesis; Cell Line, Tumor; Cell Movement; Cell Proliferation; Female; Harmine; Humans; Phenotype; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt

To prepare hyaluronic acid-loaded Harmine polymeric micelles with CD. The carboxyl group on hyaluronic acid is coupled to the amino group on 3,5-bis(trifluoromethyl)benzylamine by an amidation reaction. And the polymeric micelles self-assemble to encapsulate the Harmine in a hydrophobic core, characterized the polymer micelles by IR,. The prepared polymer micelles had a uniform particle size of about 200 nm, good dispersion, PDI < 0.3, encapsulation rate up to 87%, drug loading of 4.12±0.03%, and negative charge. Hyaluronidase has a good enzymatic effect on polymeric micelles, with a hemolysis rate of less than 1%. It showed some dose-dependent toxicity to both MDA-MB-231 and MCF-7, with increased uptake of polymer micelles by CD

Topics: Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Female; Harmine; Hemolysis; Humans; Hyaluronic Acid; MCF-7 Cells; Micelles; Polymers

Topics: Antineoplastic Agents; Apoptosis; Breast Neoplasms; Carbolines; Cell Line, Tumor; Cell Proliferation; DNA; DNA Breaks, Double-Stranded; Drug Design; Drug Screening Assays, Antitumor; G2 Phase Cell Cycle Checkpoints; Humans; Molecular Structure; Nitric Oxide Donors; Oxadiazoles; Reactive Oxygen Species; Structure-Activity Relationship; Sulfones

Breast cancer (BC) is one of the most common causes of death among women worldwide. Recently, interest in novel approaches for BC has increased by developing new drugs derived from natural products with reduced side effects. This study aimed to treat BC cells with harmine hydrochloride (HMH) to identify its anticancer effects and mechanisms. HMH treatment suppressed cell growth, migration, invasion, and colony formation in MCF-7 and MDA-MB-231 cells, regardless of the hormone signaling. It also reduced the phosphorylation of PI3K, AKT, and mTOR and increased FOXO3a expression. Additionally, HMH treatment increased p38 phosphorylation in MCF-7 cells and activated c-Jun N-terminal kinase (JNK) phosphorylation in MDA-MB-231 cells in a dose-dependent manner, where activated p38 and JNK increased FOXO3a expression. Activated FOXO3a increased the expression of p53, p21, and their downstream proteins, including p-cdc25, p-cdc2, and cyclin B1, to induce G2/M cell cycle arrest. Furthermore, HMH inhibited the PI3K/AKT/mTOR pathway by significantly reducing p-AKT expression in combination with LY294002, an AKT inhibitor. These results indicate that mitogen-activated protein kinases (MAPKs) and AKT/FOXO3a signaling pathways mediate the induction of cell cycle arrest following HMH treatment. Therefore, HMH could be a potential active compound for anticancer bioactivity in BC cells.

Topics: Breast Neoplasms; Cell Line, Tumor; Cell Movement; Cell Proliferation; Female; Forkhead Box Protein O3; G2 Phase Cell Cycle Checkpoints; Harmine; Humans; Mitogen-Activated Protein Kinases; Molecular Structure; Proto-Oncogene Proteins c-akt; Signal Transduction

Breast cancer is the leading cause of cancer-related deaths in the United States. The majority of deaths (90%) in breast cancer patients is caused by invasion and metastasis-two features related to the epithelial-to-mesenchymal transition (EMT). Twist1 is a key transcription factor that promotes the EMT, which leads to cell migration, invasion, cancer metastasis, and therapeutic resistance. Harmine is a beta-carboline alkaloid found in a variety of plants and was recently shown to be able to induce degradation of Twist Family BHLH Transcription Factor 1 (Twist1) in non-small cell lung cancer cells (NSCLC). In this study, we show that harmine can inhibit migration and invasion of both human and mouse breast cancer cells in a dose-dependent manner. Further study shows that this inhibition is most likely achieved by inducing a proteasome-dependent Twist1 degradation. At the concentrations tested, harmine did not affect the viability of cells significantly, suggesting that its inhibition of cancer cell migration and invasion is largely independent of its cytotoxicity, but due to its ability to affect regulators of EMT such as Twist1. This result may facilitate the development of strategies that target Twist1 to treat metastatic breast cancer, as Twist1 is expressed at a high level in metastatic breast cancer cells but not in normal cells.

Topics: Animals; Breast Neoplasms; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Movement; Dose-Response Relationship, Drug; Epithelial-Mesenchymal Transition; Harmine; Humans; Mice; Neoplasm Invasiveness; Proteolysis; Twist-Related Protein 1; Wound Healing

Harmine (HM) is a β‑carboline alkaloid found in multiple medicinal plants. It has been used in folk medicine for anticancer therapy; however, the molecular mechanism of HM on human breast cancer remains unclear. Transcriptional co‑activator with PDZ‑binding motif (TAZ), also known as WW domain‑containing transcription regulator 1, serves an important role in the carcinogenesis and progression of breast cancer. The aim of the present study was to elucidate the potential anticancer activity and mechanism of HM in breast cancer, in vitro and in vivo. Cell proliferation was measured using a CCK‑8 assay, apoptotic activity was detected by flow cytometry and DAPI staining, and cell migration was examined using a wound healing assay. The expression of proteins, including extracellular signal‑regulate kinase (Erk), phosphorylated (p‑) Erk, protein kinase B (Akt), p‑Akt, B‑cell lymphoma 2 (Bcl‑2) and Bcl‑2‑associated X protein (Bax), were determined by western blotting. The mRNA expression of TAZ was detected using reverse transcription‑quantitative polymerase chain reaction analysis. The expression of proteins in mouse tumor tissues were examined by immunohistochemistry. HM significantly suppressed cellular proliferation and migration, promoted apoptosis in vitro and inhibited tumor growth in vivo. In addition, HM significantly decreased the expression of TAZ, p‑Erk, p‑Akt and Bcl‑2, but increased that of Bax. The overexpression of TAZ in breast cancer cells inhibited the antitumor effect of HM. In conclusion, HM was found to induce apoptosis and prevent the proliferation and migration of human breast cancer cell lines, possibly via the downregulation of TAZ.

Topics: Antineoplastic Agents, Phytogenic; Breast Neoplasms; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cell Survival; Female; Gene Expression Regulation, Neoplastic; Harmine; Humans; Intracellular Signaling Peptides and Proteins; MCF-7 Cells; Signal Transduction; Trans-Activators; Transcription Factors; Transcriptional Coactivator with PDZ-Binding Motif Proteins; Xenograft Model Antitumor Assays

JKA97, a benzylidene analog of harmine, has been found to be a promising drug candidate for human cancer therapy, although the underlying molecular mechanisms have not been fully demonstrated. In this study, we evaluated the effects of JKA97 on human breast cancer cells in vitro and in vivo. JKA97 inhibited the growth and proliferation of MCF7 (p53 wild-type), MCF7 (p53 knockdown), and MDA-MB-468 (p53 mutant) cells in a dose-dependent manner. Treatment with JKA97 arrested breast cancer cells in G1 phase and induced apoptosis. JKA97 also significantly suppressed the growth of MCF7 and MDA-MB-468 xenograft tumors. It regulated the expression levels of G1 phase regulators, such as p21, p27, cyclinE, and cylinD1. JKA97 activated p21 transcription, independent of p53, but had little effect on p21 protein stability/degradation. In summary, our results suggest that JKA97 inhibits human breast cancer cell growth through activating p21, independent of p53, which provides a basis for developing this compound as a novel drug for human breast cancer therapy.

Topics: Antineoplastic Agents; Apoptosis; Benzylidene Compounds; Breast Neoplasms; Carbolines; Cell Line, Tumor; Cell Proliferation; Cyclin-Dependent Kinase Inhibitor p21; Dose-Response Relationship, Drug; Female; G1 Phase Cell Cycle Checkpoints; Gene Expression Regulation; Harmine; Humans; In Vitro Techniques; Styrenes

beta-Carbolines, harman (1-methyl-9H-pyrido[3,4-b]indole) and norharman (9H-pyrido[3,4-b]indole) and gamma-carbolines, 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) and 3-amino-4-methyl-5H-pyrido[4,3-b]indole (Trp-P-2), are present in cooked foods and cigarette smoke. We studied the effects of these heterocyclic amines on the activity of DNA topoisomerases. Trp-P-1 and Trp-P-2 inhibited topoisomerase I (topo I) activity with ED50 values of 1.48 and 1.55 micrograms/ml, respectively, in a relaxation assay. Harman and norharman inhibited topo I activity but with much higher ED50 values, 23.8 and 34.4 micrograms/ml, respectively. Trp-P-1 and Trp-P-2 also inhibited topoisomerase II (topo II) activity at about 50 micrograms/ml, in a decatenation assay. Harman and norharman showed a much lower inhibitory effect on topo II activity. None of these compounds stabilized the cleavable complex mediated by topo II. Trp-P-1 and Trp-P-2 intercalated into DNA at concentrations inhibitory to topoisomerases. We considered that the intercalation with DNA and the inhibition of DNA topoisomerases by heterocyclic amines might be partly related to their inhibition of DNA excision repair and their enhancing effect on UV- or chemically induced mutagenic activity.

Topics: Breast Neoplasms; Carbolines; Carcinoma, Small Cell; Cell Line; Enzyme Inhibitors; Female; Harmine; Humans; Kinetics; Mutagens; Topoisomerase I Inhibitors; Topoisomerase II Inhibitors; Tumor Cells, Cultured