mangostin and Breast-Neoplasms

α-Mangostin (AMG) is a potent anticancer xanthone that was discovered in mangosteen (

Topics: Animals; Breast Neoplasms; Carcinogenesis; Cell Death; Cell Line, Tumor; Female; Humans; Nanoparticles; Signal Transduction; Xanthones

According to cancer stem cell theory, only a limited number of self-renewing and cloning cells are responsible for tumor relapse after a period of remittance. The aim of the present study was to investigate the effects of Doxorubicin and α-Mangostin, two antiproliferative drugs, on both tumor bulk and stem cells in multicellular tumor spheroids originated from the luminal MCF-7 breast cancer cell line. A new and original fluorimetric assay was used to selectively measure the activity of the retinaldehyde-dependent isoenzymes of aldehyde dehydrogenase (RALDH), which are markers of a subpopulation of breast cancer stem cells. The administration of 5 μg/ml (12.2 μM) α-Mangostin for 48 h provoked: i) a marked disaggregation of the spheroids, leading to a doubling of their volume (p < 0.01), ii) a 40 % decrease in cell viability (p < 0.01), evaluated by the acid phosphatase assay, and iii) a reduction by more than 90 % of RALDH activity. By contrast, Doxorubicin given for 48 h in the range of 0.1-40 μM did not significantly reduce cell viability and caused only a modest modification of the spheroid morphology. Moreover, 40 μM Doxorubicin increased RALDH activity 2.5-fold compared to the untreated sample. When the two drugs were administered together using 5 μg/ml α-Mangostin, the IC

Topics: Aldehyde Dehydrogenase; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cell Survival; Dose-Response Relationship, Drug; Doxorubicin; Female; Humans; Inhibitory Concentration 50; MCF-7 Cells; Neoplastic Stem Cells; Retinaldehyde; Spheroids, Cellular; Xanthones

Alpha-mangostin, a natural xanthonoid, has been reported to possess the anti-cancer property in various types of human cancer. However, its effects and mechanism of α-mangostin in cervical cancer remain unclear. We found that α-mangostin effectively inhibited cell viability, resulted in loss of mitochondrial membrane potential (MMP), release of cytochrome C, increase of Bax, decrease of Bcl-2, and activation of caspase-9/caspase-3 cascade in cervical cancer cells. Alpha-mangostin elevated the contents of reactive oxygen species (ROS) to activate p38. Disrupting ASK1/p38 signaling pathway by a specific inhibitor of p38, or by the siRNAs against ASK1, MKK3/6, or p38, significantly abolished α-mangostin-induced cell death and apoptotic responses. Moreover, α-mangostin also repressed tumor growth in accordance with increased levels of p-ASK1, p-p38, cleaved-PARP and cleaved-caspase-3 in the tumor mass from the mouse xenograft model of cervical cancer. In the current study, we provided first evidence to demonstrate that dietary antioxidant α-mangostin could inhibit the tumor growth of cervical cancer cells through enhancing ROS amounts to activate ASK1/p38 signaling pathway and damage the integrity of mitochondria and thereby induction of apoptosis in cervical cancer cells.

Topics: Animals; Antineoplastic Agents; Apoptosis; Breast Neoplasms; Cell Line, Tumor; Cytochromes c; Disease Models, Animal; Female; Humans; MAP Kinase Kinase Kinase 5; Matrix Metalloproteinases; Membrane Potential, Mitochondrial; Mice; Mitochondria; Models, Biological; p38 Mitogen-Activated Protein Kinases; Protein Kinase Inhibitors; Reactive Oxygen Species; Signal Transduction; Xanthones; Xenograft Model Antitumor Assays

α-Mangostin extracted from mangosteen, Garcinia mangostana Linn. is known as 'queen of fruits'. The anticancer activity of α-mangostin through apoptosis induction and related signaling pathways in human breast cancer T47D cells was investigated. Human epidermal growth factor receptor 2 (HER2) and mitogen-activated protein kinase (MAPK) signaling have been shown to play important roles in apoptosis. The results showed that α-mangostin induced cell proliferation inhibition, DNA fragmentation, nuclear condensation, increased cleaved caspase-3 and cleaved caspase-9, but decreased Bcl-2 and Mcl-1 expression. Mitochondrial dysfunction and cytochrome c release were also detected. In addition, phosphorylation of ERα, HER2, PI3K, Akt and ERK1/2 were downregulated whereas p-JNK1/2 and p-p38 were upregulated. These results indicated that α-mangostin induced apoptosis associated with HER2/PI3K/Akt and MAPK signaling pathways suggesting that α-mangostin may be used as food supplement or a potential therapeutic compound for breast cancer.

Topics: Antineoplastic Agents; Apoptosis; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Cell Survival; DNA Fragmentation; Female; Gene Expression Regulation, Neoplastic; Humans; MAP Kinase Signaling System; Membrane Potential, Mitochondrial; Phosphorylation; Receptor, ErbB-2; Xanthones

Tumor necrosis-factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF-superfamily that selectively induces apoptosis through death receptors (DRs) 4 and/or 5 in cancer cells. These receptors are expressed on the cancer cell surface, without affecting normal cells. Unfortunately, many clinical studies have shown that cancer cells acquire TRAIL-resistance and finally avoid TRAIL-induced apoptosis. The detailed mechanisms of this resistance are not well understood. In the current study, we established a TRAIL-resistant human colon cancer DLD-1 cell line to clarify the mechanisms of TRAIL-resistance and developed agents to cancel its machinery. Also, we found that cancer stem-like cells from breast epithelial proliferating MCF10A cells were also sensitive to TRAIL-induced apoptosis. The enforced expression of DR5 in both TRAIL-resistant cells partially recovered the sensitivity to the TRAIL ligand, which was judged by the activation of caspase-8. As a result, we newly found that the mechanisms of TRAIL-resistance comprised co-existence of a decrease in the expression level of DR5 along with malfunction of its recruitment to the cell surface, as evidenced by Western blot and immunocytological analysis, respectively. Interestingly, α-mangostin, which is a xanthone derivative, canceled the resistance by increasing the expression level of DR5 through down-regulation of miR-133b and effectively induced the translocation of DR5 to the cancer cell surface membrane in TRAIL-resistant DLD-1 cells. These findings indicate that α-mangostin functioned as a sensitizer of TRAIL-induced apoptosis and may thus serve as a possible adjuvant compound for cytokine therapy to conquer TRAIL-resistance.

Topics: Antineoplastic Agents; Apoptosis; Breast Neoplasms; Caspase 8; Cell Line, Tumor; Cell Proliferation; Colonic Neoplasms; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Enzyme Activation; Female; Gene Expression Regulation, Neoplastic; Humans; MicroRNAs; Neoplastic Stem Cells; Protein Transport; Receptors, TNF-Related Apoptosis-Inducing Ligand; RNA Interference; Signal Transduction; TNF-Related Apoptosis-Inducing Ligand; Transfection; Xanthones

In this study, we evaluated the effects of α-mangostin on cell growth inhibition and induction of apoptosis in MCF-7 ERα-positive human breast cancer cells. Our results showed that α-mangostin inhibited MCF-7 cell proliferation whereas ERα-negative MDA-MB-231 cells were less sensitive to the agent. Additionally, α-mangostin effectively induced apoptosis as evidenced by the appearance of apoptotic nuclei observed with Hoechst 33258 staining and evaluation of sub-G1 DNA contents by flow cytometry. α-Mangostin also activated caspases-8, -9, and -7; increased the protein levels of Bax, p53, and cytosolic cytochrome c; and induced PARP cleavage while reducing Bid and Bcl-2 protein expression. In addition, apoptosis-inducing factor (AIF) was transported from mitochondria to the cytosol after α-mangostin treatment. α-mangostin also induced apoptosis in 17-β-estradiol (E2)-stimulated MCF-7 cells in parallel with the non-stimulated cells. Moreover, treatment with 10μM α-mangostin for 48h specifically decreased the expression of ERα and pS2, an estrogen-responsive gene, in MCF-7 cells. Furthermore, knockdown of ERα expression in MCF-7 cells with siRNA attenuated α-mangostin-induced cell growth inhibition and caspase-7 activation. These results suggest that ERα is required for α-mangostin-induced growth inhibition and apoptosis in human breast cancer cells. Therefore, α-mangostin may be used to prevent and treat of ER-positive breast cancer.

Topics: Animals; Apoptosis; Breast Neoplasms; Estrogen Receptor alpha; Humans; MCF-7 Cells; Rats; Xanthones

Mangosteen has been used in traditional medicine for treatment of many diseases. Recent studies have reported the active constituents isolated from this plant. In this study, purified α-mangostin, a major component and partially purified water-soluble fraction found in fruit pericarps, was carefully isolated, and their biological activity was compared, i.e. antioxidative activity and cytotoxic effect in breast cancer cells: SKBR3.. Antioxidative activity was determined using the 1,1-diphenyl-2-picrylhydrazyl radicals (DPPH) assay and reactive oxygen species (ROS) assay, whereas the cytotoxic effect was evaluated by the MTT assay and morphological changes by fluorescence staining.. The DPPH scavenging capacities of α-mangostin and water-soluble extract were obtained, the IC50 at 183.95 and 54.57 μg/ml, respectively. Meanwhile, the intracellular ROS level was significantly decreased after treatment with α-mangostin and water-soluble extraction at 20 and 200 μg/ml, respectively. α-mangostin exhibited the cytotoxicity at ED50 8.21 μg/ml, while the water-soluble extract was non-toxic to cells at ED50 higher than 160 μg/ml. Both constituents showed antioxidative activity by chemical assay and in cells, but α-mangostin expressed strong cytotoxicity and showed apoptotic bodies.. The different isolated constituents would be further studied for future possible use as chemotherapy in cancer and chemoprevention in Alzheimer's disease.

Topics: Antineoplastic Agents, Phytogenic; Antioxidants; Breast Neoplasms; Cell Line, Tumor; Female; Fruit; Garcinia mangostana; Humans; Plant Extracts; Reactive Oxygen Species; Xanthones

Cratoxylum arborescens is an equatorial plant belonging to the family Guttiferae. In the current study, α-Mangostin (AM) was isolated and its cell death mechanism was studied. HCS was undertaken to detect the nuclear condensation, mitochondrial membrane potential, cell permeability, and the release of cytochrome c. An investigation for reactive oxygen species formation was conducted using fluorescent analysis. To determine the mechanism of cell death, human apoptosis proteome profiler assay was conducted. In addition, using immunofluorescence and immunoblotting, the levels of Bcl-2-associated X protein (Bax) and B-cell lymphoma (Bcl)-2 proteins were also tested. Caspaces such as 3/7, 8, and 9 were assessed during treatment. Using HCS and Western blot, the contribution of nuclear factor kappa-B (NF-κB) was investigated. AM had showed a selective cytotoxicity toward the cancer cells with no toxicity toward the normal cells even at 30 μg/mL, thereby indicating that AM has the attributes to induce cell death in tumor cells. The treatment of MCF-7 cells with AM prompted apoptosis with cell death-transducing signals. This regulated the mitochondrial membrane potential by down-regulation of Bcl-2 and up-regulation of Bax, thereby causing the release of cytochrome c from the mitochondria into the cytosol. The liberation of cytochrome c activated caspace-9, which, in turn, activated the downstream executioner caspace-3/7 with the cleaved poly (ADP-ribose) polymerase protein, thereby leading to apoptotic alterations. Increase of caspace 8 had showed the involvement of an extrinsic pathway. This type of apoptosis was suggested to occur through both extrinsic and intrinsic pathways and prevention of translocation of NF-κB from the cytoplasm to the nucleus. Our results revealed AM prompt apoptosis of MCF-7 cells through NF-κB, Bax/Bcl-2 and heat shock protein 70 modulation with the contribution of caspaces. Moreover, ingestion of AM at (30 and 60 mg/kg) significantly reduced tumor size in an animal model of breast cancer. Our results suggest that AM is a potentially useful agent for the treatment of breast cancer.

Topics: Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Breast Neoplasms; Cell Proliferation; Cells, Cultured; Clusiaceae; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Female; HSP70 Heat-Shock Proteins; Humans; Mammary Neoplasms, Animal; MCF-7 Cells; Molecular Structure; NF-kappa B; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Structure-Activity Relationship; Xanthones

The development of molecularly targeted drugs has greatly advanced cancer therapy, despite these drugs being associated with some serious problems. Recently, increasing attention has been paid to the anticancer effects of natural products. α-Mangostin, a xanthone isolated from the pericarp of mangosteen fruit, has been shown to induce apoptosis in various cancer cell lines and to exhibit antitumor activity in a mouse mammary cancer model. In this study, we investigated the influence of α-mangostin on apoptosis and cell cycle in the human breast cancer cell line MDA-MB231 (carrying a p53 mutation, and HER2, ER, and PgR negative) in order to elucidate its anticancer mechanisms. In α-mangostin-treated cells, induction of mitochondria-mediated apoptosis was observed. On cell-cycle analysis, G1-phase arrest, increased p21(cip1) expression and decreases in cyclins, cdc(s), CDKs and PCNA were observed. In conclusion, α-mangostin may be useful as a therapeutic agent for breast cancer carrying a p53 mutation and having HER2- and hormone receptor-negative subtypes.

Topics: Apoptosis; BH3 Interacting Domain Death Agonist Protein; Breast Neoplasms; Caspases; Cell Cycle; Cell Cycle Proteins; Cell Line, Tumor; Cell Shape; Cell Survival; Cytochromes c; Female; Fruit; Garcinia mangostana; Humans; Plant Extracts; Xanthones