Hydrogen sulfide (H 2 S) is the last gaseous transmitter identified in mammals, and previous studies have reported disparate conclusions regarding the implication of H 2 S in cancer progression. In the present study, we hypothesized that sodium hydrosulfide (NaHS), a fast H 2 S-releasing donor, might interfere with the mitochondrial respiratory chain of tumor cells, increase tumor oxygenation, and potentiate the response to irradiation. Using electron paramagnetic resonance (EPR) oximetry, we found a rapid increase in tumor pO 2 after NaHS administration (0.1 mmol/kg) in two human tumor models (breast MDA-MB-231 and cervix SiHa), an effect that was due to a decreased oxygen consumption and an increased tumor perfusion. Tumors irradiated 15 minutes after a single NaHS administration were more sensitive to irradiation compared with those that received irradiation alone (increase in growth delay by 50%). This radiosensitization was due to the oxygen effect, as the increased growth delay was abolished when temporarily clamped tumors were irradiated. In contrast, daily NaHS injection (0.1 mmol/kg/ day for 14 days) did not provide any effect on tumor growth in vivo. To understand these paradoxical data, we analyzed the impact of external factors on the cellular response to NaHS. We found that extracellular pH had a dramatic effect on the cell response to NaHS, as the proliferation rate (measured in vitro by BrdU incorporation) was increased at pH ¼ 7.4, but decreased at pH ¼ 6.5. Overall, our study highlights the complex role of environmental components in the response of cancer cells to H 2 S and suggests a new approach for the use of H 2 S donors in combination with radiotherapy. Mol Cancer Ther; 15(1); 154-61. Ó2015 AACR.
<p>MDA-MB-231 cancer cells were incubated with vehicle (NaCl 0.9 %), 50 µM NaHS alone or pre-treated with 3 mM N-acetyl cysteine (NAC, a ROS scavenger) before NaHS exposure in the presence of different pHe values during 4 hours. Proliferation rates were compared using BrdU incorporation measurements. No change was observed when cells were treated with NAC, suggesting that ROS were not implicated in the pro or anti-proliferative effects induced by NaHS.</p>
<p>Viability of MDA-MB-231 and SiHa cancer cells was measured in vitro using trypan blue exclusion after OCR measurements. (A-B) Cancer cells treated with 50 µM NaHS or vehicle (NaCl 0.9 %) in the presence of different pHe values. (C-D) Cancer cells treated with increasing NaHS concentration or vehicle in the presence of pHe = 6.5. No significant cell death was found in any of the experimental conditions.</p>
<p>Viability of MDA-MB-231 was measured in vitro using trypan blue exclusion after BrdU incorporation measurements. Cancer cells were treated with 50 µM NaHS or vehicle (NaCl 0.9 %) in the presence of pHe = 6.5. No significant cell death was found in any of the experimental conditions.</p>
<p>MDA-MB-231 cancer cells were incubated with vehicle (NaCl 0.9 %), 50 µM NaHS alone or pre-treated with 3 mM N-acetyl cysteine (NAC, a ROS scavenger) before NaHS exposure in the presence of different pHe values during 4 hours. Proliferation rates were compared using BrdU incorporation measurements. No change was observed when cells were treated with NAC, suggesting that ROS were not implicated in the pro or anti-proliferative effects induced by NaHS.</p>
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