gambogic-acid and Neoplasm-Metastasis

Integrins are cell-matrix adhesion molecules providing both mechanical engagement of cell to extracellular matrix, and generation of cellular signals that are implicated in cancer malignancies. The concept that integrins play important roles in cell survival, proliferation, motility, differentiation, and ensuring appropriate cell localization, leads to the hypothesis that inhibition of certain integrins would benefit cancer therapy. In lung cancer, integrins αv, α5, β1, β3, and β5 have been shown to augment survival and metastatic potential of cancer cells. This review presents data suggesting integrins as molecular targets for anti-cancer approaches, and the mechanisms through which integrins confer resistance of lung cancer to chemotherapeutics and metastasis. The better understanding of these key molecules may benefit the discovery of anti-cancer drugs and strategies.

Topics: Antineoplastic Agents; Cell Adhesion; Cell Differentiation; Cell Proliferation; Cell Survival; Curcumin; Disease Progression; Extracellular Matrix; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Integrins; Lung Neoplasms; Neoplasm Metastasis; Ouabain; Phloretin; Xanthones

Gambogic acid (GA) is a caged xanthone that is derived from Garcinia hanburyi and functions as a strong apoptotic inducer in many types of cancer cells. The distinct effectiveness of GA has led to its characterization as a novel anti-cancer agent. There is an increasing number of research studies focused on elucidating the molecular mechanisms of GA-induced anti-cancer effects, and several critical signaling pathways have been reported to be influenced by GA treatment. In this review, we summarize the multiple functional effects of GA administration in cancer cells including the induction of apoptosis, the inhibition of proliferation and the prevention of cancer metastasis and tumor angiogenesis.

Topics: Antineoplastic Agents, Phytogenic; Biological Products; Cell Proliferation; Garcinia; Humans; Neoplasm Metastasis; Neoplasms; Neovascularization, Pathologic; Xanthones

Poor targeting and penetration of chemotherapy drugs in solid tumors, and the development of resistance to chemotherapeutic agents are currently hindering the therapy of breast cancer; meanwhile, breast cancer metastasis is one of the leading causes of death in breast cancer patients. With the development of nanotechnology, nanomaterials have been widely used in tumor therapy.. A multi-functional nano-platform containing gambogic acid (GA) and paclitaxel (PTX) was characterized by a small size, high encapsulation efficiency, slow release, long systemic circulation time in vivo, showed good targeting and penetrability to tumor tissues and tumor cells, and exhibited higher anti-tumor effect and lower systemic toxicity in BALB/c mice bearing 4T1 tumor. GA not only overcame the multidrug resistance of PTX by inhibiting P-glycoprotein (P-gp) activity in MCF-7/ADR cells, but also inhibited MDA-MB-231 cells migration and invasion, playing a crucial role in preventing and treating the lung metastasis of breast cancer caused by PTX; meanwhile, the synergistic anti-tumor effect of GA and PTX has also been verified in vitro and in vivo experiments.. Our data described the better recognition and penetration of tumor cells of R9dGR-modified versatile nanosystems containing GA and PTX, which exerted one stone three birds clinical therapeutic efficacy of multifunctionality.

Topics: Animals; Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; Breast Neoplasms; Cell Line, Tumor; Drug Delivery Systems; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Drug Therapy, Combination; Female; Humans; MCF-7 Cells; Mice; Mice, Inbred BALB C; Mice, Nude; Nanoparticles; Neoplasm Metastasis; Paclitaxel; Particle Size; Pharmaceutical Preparations; Wound Healing; Xanthones; Xenograft Model Antitumor Assays

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cell Survival; Extracellular Signal-Regulated MAP Kinases; Humans; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Melanoma; Melanoma, Cutaneous Malignant; Mice; Neoplasm Invasiveness; Neoplasm Metastasis; Neovascularization, Pathologic; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Signal Transduction; Skin Neoplasms; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2; Xanthones

Gambogic acid (GA) is considered a potent anti-tumor agent for its multiple effects on cancer cells in vitro and in vivo. Low concentrations of GA (0.3-1.2 µmol/L) can suppress invasion of human breast carcinoma cells without affecting cell viability. To get a whole profile of the inhibition on breast cancers, higher concentrations of GA and spontaneous metastatic animal models were employed. Treatment with GA (3 and 6 µmol/L) induced apoptosis in MDA-MB-231 cells and the accumulation of reactive oxygen species (ROS). Furthermore, GA induced PARP cleavage, activation of caspase-3, caspase-8, and caspase-9, as well as an increased ratio of Bax/Bcl-2. Moreover, the translocation of apoptotic inducing factor (AIF) and the release of cytochrome c (Cyt c) from mitochondria were observed, indicating that GA induced apoptosis through accumulation of ROS and mitochondrial apoptotic pathway. GA also inhibited cell survival via blocking Akt/mTOR signaling. In vivo, GA significantly inhibited the xenograft tumor growth and lung metastases in athymic BALB/c nude mice bearing MDA-MB-231 cells. Collectively, these data provide further support for the multiple effects of GA on human breast cancer cells, as well as for its potential application to inhibit tumor growth and prevent metastasis in human cancers.

Topics: Animals; Antineoplastic Agents; Apoptosis; Apoptosis Inducing Factor; bcl-2-Associated X Protein; Breast Neoplasms; Caspase 3; Caspase 8; Caspase 9; Cell Line, Tumor; Cell Survival; Cytochromes c; Female; Humans; Mice; Mice, Nude; Neoplasm Metastasis; Reactive Oxygen Species; Signal Transduction; Xanthones; Xenograft Model Antitumor Assays

Gambogic acid (GA), a xanthone derived from the resin of the Garcinia hanburyi, has been recently demonstrated to bind transferrin receptor and exhibit potential anticancer effects through a signaling mechanism that is not fully understood. Because of the critical role of NF-kappaB signaling pathway, we investigated the effects of GA on NF-kappaB-mediated cellular responses and NF-kappaB-regulated gene products in human leukemia cancer cells. Treatment of cells with GA enhanced apoptosis induced by tumor necrosis factor (TNF) and chemotherapeutic agents, inhibited the expression of gene products involved in antiapoptosis (IAP1 and IAP2, Bcl-2, Bcl-x(L), and TRAF1), proliferation (cyclin D1 and c-Myc), invasion (COX-2 and MMP-9), and angiogenesis (VEGF), all of which are known to be regulated by NF-kappaB. GA suppressed NF-kappaB activation induced by various inflammatory agents and carcinogens and this, accompanied by the inhibition of TAK1/TAB1-mediated IKK activation, inhibited IkappaBalpha phosphorylation and degradation, suppressed p65 phosphorylation and nuclear translocation, and finally abrogated NF-kappaB-dependent reporter gene expression. The NF-kappaB activation induced by TNFR1, TRADD, TRAF2, NIK, TAK1/TAB1, and IKKbeta was also inhibited. The effect of GA mediated through transferrin receptor as down-regulation of the receptor by RNA interference reversed its effects on NF-kappaB and apoptosis. Overall our results demonstrate that GA inhibits NF-kappaB signaling pathway and potentiates apoptosis through its interaction with the transferrin receptor.

Topics: Apoptosis; Cell Proliferation; Cells, Cultured; Drug Synergism; Gene Expression Regulation; Genes, Reporter; Humans; I-kappa B Proteins; Ligands; Models, Biological; Neoplasm Metastasis; NF-kappa B; NF-KappaB Inhibitor alpha; Phosphorylation; Receptors, Transferrin; Signal Transduction; Transfection; Tumor Necrosis Factor-alpha; Xanthones