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Overview

Inducible nitric oxide synthase (iNOS or NOS2) is expressed in malignant glioma. Previously we noted that C6 glioma cells overexpressing NOS2 displayed chemoresistance against 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and other chloroethylnitrosourea derivatives with carbamoylating action. Herein we report experimental evidence supporting the contention that this NOS2 effect is mediated, at least in part, by S-nitrosoglutathione (GSNO), a potent antioxidant derived from interaction of NO and glutathione. Out of three NO donors tested, only GSNO was effective in protecting glioma cells against BCNU cytotoxicity. Furthermore, the protective effect of GSNO, similar to that of NOS2, was confined to carbamoylating, but not alkylating action. Experimental manipulations that were expected to increase or decrease cellular GSNO stores, as confirmed by immunocytochemical staining using a GSNO-specific antibody and HPLC analysis of GSNO contents in culture medium, led respectively to enhanced or reduced chemoresistance against carbamoylating cytotoxicity. Finally, neocuproine, a selective cuprous ion chelator known to neutralize GSNO actions, abolished NOS2-mediated chemoresistance against carbamoylating agents. Our results reveal a novel action of NOS2/GSNO that may potentially contribute to the development of chemoresistance against BCNU, which remains a mainstay in chemotherapy for glioblastoma multiforme.

01 Jan 2004·Inflammation ResearchQ3 · MEDICINE

Spatial distribution and temporal onset of NF-kB activation and inducible nitric oxide synthase within pancreatic islets in the pre-diabetic stage of genetic, diabetic-prone BB rats: Attenuation by drug intervention decreases inflammatory cell infiltration and incidence of diabetes

Q3 · MEDICINE

Article

Author: J. D. Henderson ; C. M. Pieper ; C.-S. Lai ; Y.-R. Zhu ; A. M. Roza

OBJECTIVE AND DESIGNTo document in vivo immunolocalization and activation of nuclear factor-kappaB (NF-kappaB) and inducible nitric oxide synthase (iNOS) expression in prediabetic stages of diabetes mellitus.MATERIAL OR SUBJECTSGenetic, diabetic-prone or diabetic-resistant BB rats (total = 189).TREATMENTVarious doses of an oral dithiocarbamate derivative, NOX-700, or cyclosporine (2.5 mg/kg) starting at 30 or 60 days of age.METHODSImmunohistochemistry, electrophoretic mobility shift assays, plasma glucose.RESULTSNF-kappaB and iNOS was increased in pancreas of hyperglycemic, diabetic-prone rats but not normoglycemic, diabetic-resistant rats. Immunostaining for NF-kappaB and iNOS was largely confined to islets and occurred in diabetic-prone rats prior to overt hyperglycemia. NOX-700 decreased cell infiltration, delayed the onset of disease and decreased the incidence of hyperglycemia to levels achieved by immunosuppressant therapy. NOX-700 also decreased the intensity of immunoreactive NF-kappaB and iNOS within pancreatic islets.CONCLUSIONSThese studies support a role of NF-kB and iNOS in diabetogenesis in vivo.

01 Oct 2002·Critical Reviews of Oxidative Stress and Aging

Nitric Oxide-Blocking Therapeutics

Author: Orida, Norman K. ; Lai, Ching-San (Monte)

100 Deals associated with Medinox, Inc.

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100 Translational Medicine associated with Medinox, Inc.

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Pipeline

Pipeline Snapshot as of 22 Nov 2024

The statistics for drugs in the Pipeline is the current organization and its subsidiaries are counted as organizations,Early Phase 1 is incorporated into Phase 1, Phase 1/2 is incorporated into phase 2, and phase 2/3 is incorporated into phase 3

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Current Projects

Drug(Targets)	Indications	Global Highest Phase

NOX-200	Diabetes Mellitus, Type 1 More	Discontinued
NOX-1520 ( Hemoglobins )	Anemia, Sickle Cell More	Pending
NOX-100	Hypotension More	Pending
NOX-700	Diabetes Mellitus, Type 2 More	Pending