holothurin-a and Prostatic-Neoplasms

Topics: Cell Line, Tumor; Cell Movement; Core Binding Factor Alpha 2 Subunit; Epithelial-Mesenchymal Transition; Humans; Male; Neoplasm Invasiveness; Neoplasm Metastasis; p38 Mitogen-Activated Protein Kinases; Prostatic Neoplasms; Proto-Oncogene Proteins c-akt; Signal Transduction

Topics: Cell Line, Tumor; Furylfuramide; Humans; Male; Molecular Docking Simulation; Prostatic Neoplasms; Receptors, Androgen

A series of new 11-keto-β-boswellic acid were partially-synthesized by modifying the hydroxyl and carboxylic acid functional groups of ring A. The structures of the new analogs were confirmed by detailed spectral data analysis. Compounds

Topics: Apoptosis; Boswellia; Breast Neoplasms; Cell Line, Tumor; Chromatin; Female; Humans; Inhibitory Concentration 50; Male; Plant Extracts; Prostatic Neoplasms; Signal Transduction; Solubility; Triterpenes

Topics: Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Drug Design; Humans; Male; Molecular Docking Simulation; NIMA-Interacting Peptidylprolyl Isomerase; Prostatic Neoplasms; Structure-Activity Relationship; Triterpenes

Topics: Antineoplastic Agents; Apoptosis; Catalytic Domain; Cell Line, Tumor; Chemistry Techniques, Synthetic; Drug Design; Humans; Male; Molecular Docking Simulation; NIMA-Interacting Peptidylprolyl Isomerase; Prostatic Neoplasms; Triterpenes

The mammalian target of rapamycin (mTOR) is a key regulator of cell growth and its uncontrolled activation is a hallmark of cancer. Moreover, mTOR activation has been implicated in the resistance of cancer cells to many anticancer drugs, rendering this pathway a promising pharmacotherapeutic target. Here we explored the capability of a semisynthetic compound to intercept mTOR signaling. We synthesized and chemically characterized a novel, semisynthetic triterpenoid derivative, 3-cinnamoyl-11-keto-β-boswellic acid (C-KβBA). Its pharmacodynamic effects on mTOR and several other signaling pathways were assessed in a number of prostate and breast cancer cell lines as well as in normal prostate epithelial cells. C-KβBA exhibits specific antiproliferative and proapoptotic effects in cancer cell lines in vitro as well as in PC-3 prostate cancer xenografts in vivo. Mechanistically, the compound significantly inhibits the cap-dependent transition machinery, decreases expression of eukaryotic translation initiation factor 4E and cyclin D1, and induces G(1) cell-cycle arrest. In contrast to conventional mTOR inhibitors, C-KβBA downregulates the phosphorylation of p70 ribosomal S6 kinase, the major downstream target of mTOR complex 1, without concomitant activation of mTOR complex 2/Akt and extracellular signal-regulated kinase pathways, and independently of protein phosphatase 2A, liver kinase B1/AMP-activated protein kinase/tuberous sclerosis complex, and F12-protein binding. At the molecular level, the compound binds to the FKBP12-rapamycin-binding domain of mTOR with high affinity, thereby competing with the endogenous mTOR activator phosphatidic acid. C-KβBA represents a new type of proapoptotic mTOR inhibitor that, due to its special mechanistic profile, might overcome the therapeutic drawbacks of conventional mTOR inhibitors.

Topics: Apoptosis; Breast Neoplasms; Cell Cycle Checkpoints; Cell Proliferation; Down-Regulation; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Epithelial Cells; Female; G1 Phase; Humans; Male; Phosphorylation; Prostatic Neoplasms; Protein Interaction Domains and Motifs; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Triterpenes

The role of angiogenesis in tumor growth and metastasis is well established. Identification of a small molecule that blocks tumor angiogenesis and is safe and affordable has been a challenge in drug development. In this study, we showed that acetyl-11-keto-beta-boswellic acid (AKBA), an active component from an Ayurvedic medicinal plant (Boswellia serrata), could strongly inhibit tumor angiogenesis. AKBA suppressed tumor growth in the human prostate tumor xenograft mice treated daily (10 mg/kg AKBA) after solid tumors reached approximately 100 mm(3) (n = 5). The inhibitory effect of AKBA on tumor growth was well correlated with suppression of angiogenesis. When examined for the molecular mechanism, we found that AKBA significantly inhibited blood vessel formation in the Matrigel plug assay in mice and effectively suppressed vascular endothelial growth factor (VEGF)-induced microvessel sprouting in rat aortic ring assay ex vivo. Furthermore, AKBA inhibited VEGF-induced cell proliferation, chemotactic motility, and the formation of capillary-like structures from primary cultured human umbilical vascular endothelial cells in a dose-dependent manner. Western blot analysis and in vitro kinase assay revealed that AKBA suppressed VEGF-induced phosphorylation of VEGF receptor 2 (VEGFR2) kinase (KDR/Flk-1) with IC(50) of 1.68 micromol/L. Specifically, AKBA suppressed the downstream protein kinases of VEGFR2, including Src family kinase, focal adhesion kinase, extracellular signal-related kinase, AKT, mammalian target of rapamycin, and ribosomal protein S6 kinase. Our findings suggest that AKBA potently inhibits human prostate tumor growth through inhibition of angiogenesis induced by VEGFR2 signaling pathways.

Topics: Angiogenesis Inhibitors; Animals; Apoptosis; Blotting, Western; Cell Line; Cell Line, Tumor; Cell Movement; Cell Survival; Dose-Response Relationship, Drug; Humans; In Vitro Techniques; Male; Medicine, Ayurvedic; Mice; Mice, Inbred BALB C; Neovascularization, Pathologic; Neovascularization, Physiologic; Prostatic Neoplasms; Rats; Rats, Sprague-Dawley; Signal Transduction; Triterpenes; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2