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Wegiel B.,Harvard University | Gallo D.,Harvard University | Csizmadia E.,Harvard University | Harris C.,Harvard University | And 12 more authors.
Cancer Research | Year: 2013

One classical feature of cancer cells is their metabolic acquisition of a highly glycolytic phenotype. Carbon monoxide (CO), one of the products of the cytoprotective molecule heme oxygenase-1 (HO-1) in cancer cells, has been implicated in carcinogenesis and therapeutic resistance. However, the functional contributions of CO and HO-1 to these processes are poorly defined. In human prostate cancers, we found that HO-1 was nuclear localized in malignant cells, with low enzymatic activity in moderately differentiated tumors correlating with relatively worse clinical outcomes. Exposure to CO sensitized prostate cancer cells but not normal cells to chemotherapy, with growth arrest and apoptosis induced in vivo in part throughmitotic catastrophe. CO targeted mitochondria activity in cancer cells as evidenced by higher oxygen consumption, free radical generation, and mitochondrial collapse. Collectively, our findings indicated that CO transiently induces an anti-Warburg effect by rapidly fueling cancer cell bioenergetics, ultimately resulting in metabolic exhaustion. ©2013 AACR.


Wegiel B.,Harvard University | Gallo D.J.,Alfama Inc. | Raman K.G.,University of Pittsburgh | Karlsson J.M.,University of Pittsburgh | And 7 more authors.
Circulation | Year: 2010

Background-:Carbon monoxide (CO) has emerged as a vascular homeostatic molecule that prevents balloon angioplasty-induced stenosis via antiproliferative effects on vascular smooth muscle cells. The effects of CO on reendothelialization have not been evaluated. Methods and Results-: Exposure to CO has diametrically opposite effects on endothelial cell (EC) and vascular smooth muscle cell proliferation in rodent models of carotid injury. In contrast to its effect of blocking vascular smooth muscle cell growth, CO administered as a gas or as a CO-releasing molecule enhances proliferation and motility of ECs in vitro by >50% versus air controls, and in vivo, it accelerates reendothelialization of the denuded artery by day 4 after injury versus day 6 in air-treated animals. CO enhanced EC proliferation via rapid activation of RhoA (Ras homolog gene family, member A), followed by downstream phosphorylation of Akt, endothelial nitric oxide (NO) synthase phosphorylation, and a 60% increase in NO generation by ECs. CO drives cell cycle progression through phosphorylation of retinoblastoma, which is dependent in part on endothelial NO synthase-generated NO. Similarly, endothelial repair in vivo requires NO-dependent mobilization of bone marrow-derived EC progenitors, and CO yielded a 4-fold increase in the number of mobilized green fluorescent protein-Tie2-positive endothelial progenitor cells versus controls, with a corresponding accelerated deposition of differentiated green fluorescent protein-Tie2-positive ECs at the site of injury. CO was ineffective in augmenting EC repair and the ensuing development of intimal hyperplasia in eNOS-/- mice. Conclusions-: Collectively, the present data demonstrate that CO accelerates EC proliferation and vessel repair in a manner dependent on NO generation and enhanced recruitment of bone marrow-derived endothelial progenitor cells. © 2010 American Heart Association, Inc.


Patent
Alfama Inc. | Date: 2012-04-19

Provided herein are novel carbon-monoxide releasing molecules (CO-RMs) of the Formula (I): and esters, amides, salts, solvates and hydrates thereof; wherein R


The present invention provides novel ruthenium compounds of Formula (I): or salts, isomers, hydrates, or solvates thereof, or combinations thereof; wherein E, R


Neves P.,University of Aveiro | Pereira C.C.L.,University of Aveiro | Pereira C.C.L.,Technological and Nuclear Institute of Portugal | Almeida Paz F.A.,University of Aveiro | And 7 more authors.
Journal of Organometallic Chemistry | Year: 2010

The complexes Cp′Mo(CO)2(η3-C 3H5) [Cp′ = η5-C5H 5 (1), η5-C5H4Me (2), η5-C5Me5 (3)] have been prepared, structurally characterised by X-ray diffraction (2, 3), and tested as catalyst precursors for the epoxidation of olefins at 55 °C. Complex 1 gave a turnover frequency (TOF) of 310 mol molMo -1 h-1 in the epoxidation of cis-cyclooctene with tert-butylhydroperoxide (TBHP, in decane) as oxidant, and 1,2-epoxycyclooctane was obtained quantitatively within 6 h. A similar result was obtained for complex 2, while the TOF for 3 was about one order of magnitude lower, suggesting a possible activity dependence on the ring substituents. For 1 the use of 1,2-dichloroethane as solvent increased the initial reaction rate to 361 mol molMo -1 h-1, with no decrease in epoxide selectivity. Under these conditions the reaction rates for other olefins increased in the order 1-octene < trans-2-octene < cyclododecene < (R)-(+)-limonene < cis-cyclooctene, and, with the exception of limonene, the corresponding epoxide was the only product. For 1 the selective epoxidation of cis-cyclooctene could also be achieved in aqueous solution, using TBHP or H2O2 as oxidants, which gave epoxide yields of 99% and 27% at 24 h, respectively. The possibility of facilitating catalyst recycling by using ionic liquids as solvents was investigated. © 2010 Elsevier B.V.

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