Journal article
Endogenous production and exogenous exposure to nitric oxide augment doxorubicin cytotoxicity for breast cancer cells but not cardiac myoblasts
Nitric oxide, Vol.10(3), pp.119-129
2004
DOI: 10.1016/j.niox.2004.03.006
PMID: 15158691
Abstract
We studied the effect of nitric oxide (
NO) on the anticancer activity of doxorubicin. When MCF-7 human breast cancer cells were exposed to an aqueous solution of
NO delivered as a bolus 30
min prior to doxorubicin, the cytotoxic effect as measured in a clonogenic assay was increased (doxorubicin alone, 40% survival, doxorubicin plus
NO, 5% survival). The
NO donor diethylamine nitric oxide, but not inactivated donor, also yielded an increase in doxorubicin cytotoxicity. The sequence was important since the simultaneous application of
NO with doxorubicin yielded only a small augmentation of effect, and the exposure of the cells to doxorubicin prior to the
NO obliterated the augmentation. Prior depletion of glutathione by incubation of the cells for 24
h with
d,
l-buthionine-
S,
R-sulfoximine (BSO) further increased the cytotoxicity so that BSO plus
NO plus doxorubicin killed all of the clones. MCF-7 cells transduced with inducible nitric oxide synthase gene (iNOS) through an adenoviral vector overexpressed iNOS and produced increased amounts of nitrite, an indicator of increased
NO production. These iNOS transduced cells were more susceptible to doxorubicin than vector control or wild-type cells. Cell cycle progression of iNOS transduced cells was not different from controls. Likewise, iNOS transduction resulted in no change in cellular glutathione levels. For comparison, we examined the effect of iNOS transduction on the sensitivity of MCF-7 to edelfosine, a membrane-localizing anticancer drug without direct DNA interaction. Insertion of the iNOS had no effect on killing of the MCF-7 cells by this ether lipid class drug. We also tested the effect of iNOS transduction on doxorubicin sensitivity of H9c2 rat heart-derived myoblasts. We found no augmentation of cytotoxicity by
NO, and this observation offers potential therapeutic tumor selectivity by using
NO with doxorubicin. Therefore, we conclude that
NO produced intracellularly by iNOS overexpression or delivered as a bolus sensitizes human breast cancer cells in culture to doxorubicin, but not to a cardiac cell line or to edelfosine. This augmentation is not due to a modulation of cell cycle distribution or measurable cellular glutathione resulting from the transduction.
Details
- Title: Subtitle
- Endogenous production and exogenous exposure to nitric oxide augment doxorubicin cytotoxicity for breast cancer cells but not cardiac myoblasts
- Creators
- Crystal B Evig - Department of Medicine, The University of Iowa Carver College of Medicine and The University of Iowa Holden Comprehensive Cancer Center, Iowa City, IA 52242, USAEric E Kelley - Department of Medicine, The University of Iowa Carver College of Medicine and The University of Iowa Holden Comprehensive Cancer Center, Iowa City, IA 52242, USAChristine J Weydert - Department of Radiation Oncology (Free Radical and Radiation Biology Graduate Program), The University of Iowa Carver College of Medicine and The University of Iowa Holden Comprehensive Cancer Center, Iowa City, IA 52242, USAYi Chu - Department of Medicine, The University of Iowa Carver College of Medicine and The University of Iowa Holden Comprehensive Cancer Center, Iowa City, IA 52242, USAGarry R Buettner - Department of Radiation Oncology (Free Radical and Radiation Biology Graduate Program), The University of Iowa Carver College of Medicine and The University of Iowa Holden Comprehensive Cancer Center, Iowa City, IA 52242, USAC. Patrick Burns - Department of Medicine, The University of Iowa Carver College of Medicine and The University of Iowa Holden Comprehensive Cancer Center, Iowa City, IA 52242, USA
- Resource Type
- Journal article
- Publication Details
- Nitric oxide, Vol.10(3), pp.119-129
- Publisher
- Elsevier Inc
- DOI
- 10.1016/j.niox.2004.03.006
- PMID
- 15158691
- ISSN
- 1089-8603
- eISSN
- 1089-8611
- Language
- English
- Date published
- 2004
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Radiation Oncology; Internal Medicine
- Record Identifier
- 9984047628602771
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