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1.
Hypoxia (Auckl) ; 4: 163-174, 2016.
Article in English | MEDLINE | ID: mdl-27995152

ABSTRACT

AIM: This study reports the influence of hypoxia on response of colorectal cancer cells to anticancer effects of sorafenib in combination with PI3K inhibitors GDC-0941 and BEZ-235. MATERIALS AND METHODS: All hypoxic exposures were carried out at 1% O2/5% CO2. Antiproliferation activity was evaluated by 48 hours propidium iodide and 14 days clonogenic assay. Protein levels were evaluated by fluorescence ELISA. Metabolites lactate and glucose were evaluated biochemically. RESULTS: In the 48-hour proliferation assay, sorafenib acted synergistically with GDC-0941 but not with BEZ-235. In long-term colony-forming assays, both GDC-0941 and BEZ-235 were shown to potentiate the antiproliferative activity of sorafenib. At the molecular level, the synergism is mediated through inhibition of pAKT, pS6, p4EBP1, pERK, cyclin D1, and Bcl-2. No change in hypoxia-inducible factor-1α (HIF-1α) levels was observed in cells treated with the combination of compounds under hypoxia. A significant reduction in glucose uptake and lactate release was observed in cells treated with the combination of compounds under normoxia and hypoxia. CONCLUSION: Combinations of sorafenib with PI3K inhibitors BEZ-235 and GDC-0941 are efficacious under hypoxia. Thus, these anticancer combinations have a potential to overcome the hypoxia-mediated resistance mechanisms to antiproliferative agents in cancer therapy.

2.
Nat Prod Res ; 30(12): 1455-8, 2016 Jun.
Article in English | MEDLINE | ID: mdl-26212208

ABSTRACT

The present work describes the anticancer activity of Ophiobolin A isolated from the endophytic fungus Bipolaris setariae. Ophiobolin A was isolated using preparative HPLC and its structure was confirmed by HRMS, (1)H NMR, (13)C NMR, COSY, DEPT, HSQC and HMBC. It inhibited solid and haematological cancer cell proliferation with IC50 of 0.4-4.3 µM. In comparison, IC50 against normal cells was 20.9 µM. It was found to inhibit the phosphorylation of S6 (IC50 = 1.9 ± 0.2 µM), ERK (IC50 = 0.28 ± 0.02 µM) and RB (IC50 = 1.42 ± 0.1 µM), the effector proteins of PI3K/mTOR, Ras/Raf/ERK and CDK/RB pathways, respectively. It induced apoptosis and inhibited cell cycle progression in MDA-MB-231 cancer cells with concomitant inhibition of signalling proteins. Thus, this study reveals that anticancer activity of Ophiobolin A is associated with simultaneous inhibition of multiple oncogenic signalling pathways namely PI3K/mTOR, Ras/Raf/ERK and CDK/RB.


Subject(s)
Antineoplastic Agents, Phytogenic/pharmacology , Sesterterpenes/pharmacology , Antineoplastic Agents, Phytogenic/isolation & purification , Apoptosis/drug effects , Ascomycota/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Chromatography, High Pressure Liquid , Drug Screening Assays, Antitumor , Endophytes/chemistry , Humans , Inhibitory Concentration 50 , Molecular Structure , Phosphatidylinositol 3-Kinases/metabolism , Phosphorylation/drug effects , Sesterterpenes/isolation & purification , Signal Transduction/drug effects , TOR Serine-Threonine Kinases/metabolism
3.
Mol Cancer Ther ; 14(5): 1095-106, 2015 May.
Article in English | MEDLINE | ID: mdl-25700704

ABSTRACT

The mTOR pathway is often upregulated in cancer and thus intensively pursued as a target to design novel anticancer therapies. Approved and emerging drugs targeting the mTOR pathway have positively affected the clinical landscape. Recently, activin receptor-like kinase 1 (ALK1), belonging to the TGFß receptor family, has been reported as an emerging target for antiangiogenic cancer therapy. Here, we describe a novel orally efficacious compound, P7170, that inhibits mTORC1/mTORC2/ALK1 activity with a potent cell growth inhibition. In cell-based assays, P7170 strongly inhibited (IC50 < 10 nmol/L) the phosphorylation of p70S6K (T389) and pAKT (S473). In many cancer cell lines, such as prostate, ovarian, colon, and renal, P7170 treatment resulted in marked cell growth inhibition. Furthermore, it induced G1-S cell-cycle arrest and autophagy. In vitro HUVEC tube formation, in vivo Matrigel plug, and rat aorta ring assays demonstrated that P7170 exhibited significant antiangiogenic activity. In addition, ALK1 knockdown studies in HUVEC confirmed that the antiangiogenic activity of P7170 was primarily due to ALK1 inhibition. Strong inhibition of ALK1 in addition to mTORC1/mTORC2 differentiates P7170 in its mechanism of action in comparison with existing inhibitors. In vivo mouse xenograft studies revealed P7170 to exhibit a significant dose-dependent tumor growth inhibition in a broad range of human tumor types when administered orally at 10 to 20 mg/kg doses. The distinctive pharmacological profile with favorable pharmacokinetic parameters and in vivo efficacy makes P7170 an attractive candidate for clinical development. It is currently being tested in phase I clinical studies.


Subject(s)
Angiogenesis Inhibitors/administration & dosage , Antineoplastic Agents/administration & dosage , Imidazoles/administration & dosage , Prostatic Neoplasms/drug therapy , Quinolines/administration & dosage , Activin Receptors, Type II/antagonists & inhibitors , Administration, Oral , Angiogenesis Inhibitors/pharmacology , Animals , Antineoplastic Agents/pharmacology , Aorta, Thoracic/cytology , Aorta, Thoracic/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Hep G2 Cells , Human Umbilical Vein Endothelial Cells , Humans , Imidazoles/pharmacology , Male , Mice , Prostatic Neoplasms/metabolism , Quinolines/pharmacology , Rats , TOR Serine-Threonine Kinases/antagonists & inhibitors , Xenograft Model Antitumor Assays
4.
Am J Physiol Gastrointest Liver Physiol ; 295(6): G1237-45, 2008 Dec.
Article in English | MEDLINE | ID: mdl-18927209

ABSTRACT

Ulcerative colitis is an autoimmune-inflammatory disease characterized by increased proliferation of colonic epithelial cells, dysregulation of signal transduction pathways, elevated mucosal T cell activation, increased production of proinflammatory cytokines, and enhanced leukocyte infiltration into colonic interstitium. Several compounds that possess antiproliferative properties and/or inhibit cytokine production exhibit a therapeutic effect in murine models of colitis. Mammalian target of rapamycin (mTOR), a protein kinase regulating cell proliferation, is implicated in colon carcinogenesis. In this study, we report that a novel haloacyl aminopyridine-based molecule (P2281) is a mTOR inhibitor and is efficacious in a murine model of human colitis. In vitro studies using Western blot analysis and cell-based ELISA assays showed that P2281 inhibits mTOR activity in colon cancer cells. In vitro and in vivo assays of proinflammatory cytokine production revealed that P2281 diminishes induced IFN-gamma production but not TNF-alpha production, indicating preferential inhibitory effects of P2281 on T cell function. In the dextran sulfate sodium (DSS) model of colitis, 1) macroscopic colon observations demonstrated that P2281 significantly inhibited DSS-induced weight loss, improved rectal bleeding index, decreased disease activity index, and reversed DSS-induced shortening of the colon; 2) histological analyses of colonic tissues revealed that P2281 distinctly attenuated DSS-induced edema, prominently diminished the leukocyte infiltration in the colonic mucosa, and resulted in protection against DSS-induced crypt damage; and 3) Western blot analysis showed that P2281 blocks DSS-induced activation of mTOR. Collectively, these results provide direct evidence that P2281, a novel mTOR inhibitor, suppresses DSS-induced colitis by inhibiting T cell function and is a potential therapeutic for colitis. Given that compounds with anticancer activity show promising anti-inflammatory efficacy, our findings reinforce the cross-therapeutic functionality of potential drugs.


Subject(s)
Aminopyridines/therapeutic use , Anilides/therapeutic use , Carrier Proteins/antagonists & inhibitors , Colitis/drug therapy , Phosphotransferases (Alcohol Group Acceptor)/antagonists & inhibitors , Animals , Cell Line, Tumor , Colitis/chemically induced , Dextran Sulfate , Disease Models, Animal , Humans , Interferon-gamma/antagonists & inhibitors , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , TOR Serine-Threonine Kinases , Tumor Necrosis Factor-alpha/antagonists & inhibitors
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