Nitric oxide and BCNU chemoresistance in C6 glioma cells: Role of S-nitrosoglutathione

Ding I. Yang, Jiu Haw Yin, Tzyh Chwen Ju, Long Shiuh Chen, Chung Y. Hsu

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1317-1328
Number of pages12
JournalFree Radical Biology and Medicine
Volume36
Issue number10
DOIs
Publication statusPublished - May 15 2004

Fingerprint

S-Nitrosoglutathione
Carmustine
Glioma
Nitric Oxide
Cytotoxicity
Chemotherapy
Nitric Oxide Synthase Type II
Glioblastoma
Chelating Agents
Glutathione
Culture Media
Antioxidants
High Pressure Liquid Chromatography
Staining and Labeling
Derivatives
Drug Therapy
Antibodies

Keywords

  • 1,3-bis(2-chloroethyl)-1-nitrosourea
  • Alkylation
  • BCNU
  • BSO
  • Buthionine sulfoximine
  • Carbamoylation
  • CCNU
  • Free radicals
  • Inducible nitric oxide synthase
  • Malignant glioblastoma multiforme
  • N-Acetyl-L-cysteine
  • Nitric oxide
  • S-Nitrosoglutathione
  • S-Nitrosothiol

ASJC Scopus subject areas

  • Medicine(all)
  • Toxicology
  • Clinical Biochemistry

Cite this

Nitric oxide and BCNU chemoresistance in C6 glioma cells : Role of S-nitrosoglutathione. / Yang, Ding I.; Yin, Jiu Haw; Ju, Tzyh Chwen; Chen, Long Shiuh; Hsu, Chung Y.

In: Free Radical Biology and Medicine, Vol. 36, No. 10, 15.05.2004, p. 1317-1328.

Research output: Contribution to journalArticle

Yang, Ding I. ; Yin, Jiu Haw ; Ju, Tzyh Chwen ; Chen, Long Shiuh ; Hsu, Chung Y. / Nitric oxide and BCNU chemoresistance in C6 glioma cells : Role of S-nitrosoglutathione. In: Free Radical Biology and Medicine. 2004 ; Vol. 36, No. 10. pp. 1317-1328.
@article{2c7710b0784e494eb63504114dfbee02,
title = "Nitric oxide and BCNU chemoresistance in C6 glioma cells: Role of S-nitrosoglutathione",
abstract = "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.",
keywords = "1,3-bis(2-chloroethyl)-1-nitrosourea, Alkylation, BCNU, BSO, Buthionine sulfoximine, Carbamoylation, CCNU, Free radicals, Inducible nitric oxide synthase, Malignant glioblastoma multiforme, N-Acetyl-L-cysteine, Nitric oxide, S-Nitrosoglutathione, S-Nitrosothiol",
author = "Yang, {Ding I.} and Yin, {Jiu Haw} and Ju, {Tzyh Chwen} and Chen, {Long Shiuh} and Hsu, {Chung Y.}",
year = "2004",
month = "5",
day = "15",
doi = "10.1016/j.freeradbiomed.2004.02.010",
language = "English",
volume = "36",
pages = "1317--1328",
journal = "Free Radical Biology and Medicine",
issn = "0891-5849",
publisher = "Elsevier Inc.",
number = "10",

}

TY - JOUR

T1 - Nitric oxide and BCNU chemoresistance in C6 glioma cells

T2 - Role of S-nitrosoglutathione

AU - Yang, Ding I.

AU - Yin, Jiu Haw

AU - Ju, Tzyh Chwen

AU - Chen, Long Shiuh

AU - Hsu, Chung Y.

PY - 2004/5/15

Y1 - 2004/5/15

N2 - 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.

AB - 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.

KW - 1,3-bis(2-chloroethyl)-1-nitrosourea

KW - Alkylation

KW - BCNU

KW - BSO

KW - Buthionine sulfoximine

KW - Carbamoylation

KW - CCNU

KW - Free radicals

KW - Inducible nitric oxide synthase

KW - Malignant glioblastoma multiforme

KW - N-Acetyl-L-cysteine

KW - Nitric oxide

KW - S-Nitrosoglutathione

KW - S-Nitrosothiol

UR - http://www.scopus.com/inward/record.url?scp=1942532041&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=1942532041&partnerID=8YFLogxK

U2 - 10.1016/j.freeradbiomed.2004.02.010

DO - 10.1016/j.freeradbiomed.2004.02.010

M3 - Article

C2 - 15110396

AN - SCOPUS:1942532041

VL - 36

SP - 1317

EP - 1328

JO - Free Radical Biology and Medicine

JF - Free Radical Biology and Medicine

SN - 0891-5849

IS - 10

ER -