Radiosensitization of hypoxic tumor cells in vitro by nitric oxide

Griffin, Robert J.; Makepeace, Carol M.; Hur, Won-Joo; Song, Chang W.

doi:10.1016/s0360-3016(96)00329-x

Cited by 49 publications

(30 citation statements)

References 17 publications

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“…Table 2 lists the top ten and bottom ten genes that were most up-regulated or downregulated for each of the four breast cancer call line pairs. settings [32][33][34][35][36][37][38][39]. It has also been shown that the cytotoxic impact of radiation is significantly increased through upregulated NOS in tumor cells [34].…”

Section: Resultsmentioning

confidence: 99%

Part I. Molecular and cellular characterization of high nitric oxide-adapted human breast adenocarcinoma cell lines

et al. 2012

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There is a lack of understanding of the casual mechanisms behind the observation that some breast adenocarcinomas have identical morphology and comparatively different cellular growth behavior. This is exemplified by a differential response to radiation, chemotherapy, and other biological intervention therapies. Elevated concentrations of the free radical nitric oxide (NO), coupled with the upregulated enzyme nitric oxide synthase (NOS) which produces NO, are activities which impact tumor growth. Previously, we adapted four human breast cancer cell lines: BT-20, Hs578T, T-47D, and MCF-7 to elevated concentrations of nitric oxide (or high NO [HNO]). This was accomplished by exposing the cell lines to increasing levels of an NO donor over time. Significantly, the HNO cell lines grew faster than did each respective ("PARENT") cell line even in the absence of NO donor-supplemented media. This was evident despite each "parent" being morphologically equivalent to the HNO adapted cell line. Herein, we characterize the HNO cells and their biological attributes against those of the parent cells. Pairs of HNO/parent cell lines were then analyzed using a number of key cellular activity criteria including: cell cycle distribution, DNA ploidy, response to DNA damage, UV radiation response, X-ray radiation response, and the expression of significant cellular enzymes. Other key enzyme activities studied were NOS, p53, and glutathione S-transferase-pi (GST-pi) expression. HNO cells were typified by a far more aggressive pattern of growth and resistance to various treatments than the corresponding parent cells. This was evidenced by a higher S-phase percentage, variable radioresistance, and up-regulated GST-pi and p53. Taken collectively, this data provides evidence that cancer cells subjected to HNO concentrations become resistant to free radicals such as NO via up-regulated cellular defense mechanisms, including p53 and GST-pi. The

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Section: Resultsmentioning

confidence: 99%

Part I. Molecular and cellular characterization of high nitric oxide-adapted human breast adenocarcinoma cell lines

et al. 2012

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“…This balance between vasodilatory and cytotoxic effects is likely to be very variable as sensitivity to the cytotoxic/antiproliferative effects of NO ¼ have been shown to differ by a factor of 10 between tumour cell lines. 11 The mechanisms responsible for cell death resulting from NO ¼ production are complex, but involve the formation of peroxynitrite, 22 nitrosating agents such as N 2 O 3 23 or nitroxyl; 24 the concentrations required are probably in the 3-10 mm range as shown for the production of DNA single strand breaks. 22 In the present study the cytotoxic effects of NO ¼ were evident in both the in vitro and in vivo systems.…”

Section: Discussionmentioning

confidence: 99%

“…Very similar results were reported for DEA/NO (SER = 3.0 at 2 mm) and for another NO ¼ donor, spermine/nitric oxide complex (SER = 2.8 at 2 mm) in SCK tumour cells in vitro. 11 Kurimoto et al 10 examined the radiosensitizing effect of the NO ¼ -generating agents S-nitroso-N-acetyl-penicillamine (SNAP) and sodium nitroprusside (SNP) in glioma cells, observing SERs of 1.4 and 1.9 respectively at concentrations of 100 m. Furthermore, a rise in NO ¼ levels as a secondary consequence of IFN-␥ exposure in EMT-6 tumour cells resulted in hypoxic cell radiosensitization. 9 Spontaneous and bioreductive NO ¼ donors, such as SNP and SNAP, elicit systemic vasodilation and hypotension; they cannot therefore be administered in sufficient doses to achieve tumour radiosensitization in the clinic.…”

Section: Demonstrated That No ¼ Was Almost As Effective As Oxy-tivelymentioning

confidence: 99%

Tumour cell radiosensitization using constitutive (CMV) and radiation inducible (WAF1) promoters to drive the iNOS gene: a novel suicide gene therapy

et al. 2002

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“…This activity is far less than the observation of Mitchell et al (1996), who used V79 lung fibroblasts in a model of metabolic hypoxia and reported enhancement ratios of 2.5Ð2.6 for 0.1Ð1 mM SNAP. With the same approach, many other NO donors (DEA/NO, SPER/NO, GSNO, SNP) were investigated, and in some but not all cell lines enhancement ratios close to that of oxygen (2.6Ð3.0) were observed (Mitchell et al, 1993(Mitchell et al, , 1996Griffin et al, 1996;Verovski et al, 1996).…”

Section: Discussionmentioning

confidence: 99%

“…Mitchell et al (1993Mitchell et al ( , 1996 demonstrated that 2-(N,N,-diethylamino)-diazenolate-2-oxide-Na + (DEA/NO), SNAP and S-nitroso-L-glutathione (GSNO) at a concentration of 1 mM, radiosensitized Chinese hamster V79 lung fibroblasts to a similar extent as oxygen. Griffin et al (1996) reported comparable activity for DEA/NO and (Z)-1-{N- [3-aminopropyl]-N-[4-(3-aminopropylammonio)butyl-amino}-diazen-1-ium-1,2-diolate (SPER/NO) with enhancement ratios of 2.8Ð3.0 in SCK mammary carcinoma cells exposed to 1Ð2 mM radiosensitizer. Our laboratory investigated the radiosensitizing activity of SNP in a panel of eight human pancreatic tumour cell lines and found an overall enhancement ratio of 1.9 at 0.1 mM (Verovski et al, 1996).…”

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confidence: 99%

Radiosensitization of hypoxic tumour cells by S-nitroso-N-acetylpenicillamine implicates a bioreductive mechanism of nitric oxide generation

Janssens¹,

Verovski²,

Berge³

et al. 1999

Br J Cancer

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Nitric oxide (NO) donors have recently been evaluated as radiosensitizers of hypoxic cells in a model of metabolisminduced hypoxia at high cell densities. Mitchell et al (1993Mitchell et al ( , 1996 demonstrated that 2-(N,N,-diethylamino)-diazenolate-2-oxide-Na + (DEA/NO), SNAP and S-nitroso-L-glutathione (GSNO) at a concentration of 1 mM, radiosensitized Chinese hamster V79 lung fibroblasts to a similar extent as oxygen. Griffin et al (1996) reported comparable activity for DEA/NO and (Z)-1-{N- [3-aminopropyl]-N-[4-(3-aminopropylammonio)butyl-amino}-diazen-1-ium-1,2-diolate (SPER/NO) with enhancement ratios of 2.8Ð3.0 in SCK mammary carcinoma cells exposed to 1Ð2 mM radiosensitizer. Our laboratory investigated the radiosensitizing activity of SNP in a panel of eight human pancreatic tumour cell lines and found an overall enhancement ratio of 1.9 at 0.1 mM (Verovski et al, 1996). At 0.3Ð1 mM, SNP caused almost complete radiosensitization in hypoxic PSN1/ADR cells that was accompanied by restoration of radiation-induced DNA breakage up to the level in aerated cells.These data collectively confirm the high radiosensitizing efficiency of NO donors at 1Ð2 mM and suggest a role of NO in the fixation of DNA damage caused by radiation. Whether DNA is the main target for NO, as was postulated by Howard-Flanders (1957), or whether other mechanisms contribute to the enhanced DNA damage remains unclear. As NO can interact with ironÐsulphur containing enzymes, this may result in the inhibition of cellular respiration and sparing of the natural sensitizer oxygen (Mitchell et al, 1996). This sensitizing effect mediated by residual oxygen can be minimized under hypoxic conditions induced by nitrogen gassing, a general approach to study radiosensitizers. Moreover, the latter model of hypoxia allows the use of a broad range of cell densities, which is a necessary step to establish whether the rate of NO release is enhanced by the presence of cells. The NO donors DEA/NO and SPER/NO are known to liberate NO by a purely spontaneous mechanism (Maragos et al, 1991). Some NO donors, such as SNAP and GSNO, have generally been assumed to release NO in a spontaneous manner although the slow decomposition rate of S-nitrosothiols appeared to underestimate their biological effects (Kowaluk and Fung, 1990). In fact, the chemistry of Snitrosothiols containing NO as a nitrosonium cation (Stamler et al, 1992), supports the idea of reductive catalysis of NO release, which may occur on the cellular membrane (Bates et al, 1991;Kowaluk et al, 1990;Rochelle et al, 1994). In the report of Mitchell et al (1996), the possibility of bioreductive generation of NO from SNAP has not been explored, but NO output in a cellfree system was apparently too low to account for radiosensitization. The same conclusion was drawn for another nitrosonium-like NO donor, SNP, whose bioreductive activation was found to be responsible for radiosensitization (Verovski et al, 1996).The objective of the present study was to examine whether bioreductive release of NO from SNAP...

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Radiosensitization of hypoxic tumor cells in vitro by nitric oxide

Cited by 49 publications

References 17 publications

Part I. Molecular and cellular characterization of high nitric oxide-adapted human breast adenocarcinoma cell lines

Part I. Molecular and cellular characterization of high nitric oxide-adapted human breast adenocarcinoma cell lines

Tumour cell radiosensitization using constitutive (CMV) and radiation inducible (WAF1) promoters to drive the iNOS gene: a novel suicide gene therapy

Radiosensitization of hypoxic tumour cells by S-nitroso-N-acetylpenicillamine implicates a bioreductive mechanism of nitric oxide generation

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