Fractionated radiation‐induced nitric oxide promotes expansion of glioma stem‐like cells

Abstract

Glioblastoma remains an incurable brain disease due to the prevalence of its recurrence. Considerable evidence suggests that glioma stem-like cells are responsible for glioma relapse after treatment, which commonly involves ionizing radiation. Here, we found that fractionated ionizing radiation (2 Gy ⁄ day for 3 days) induced glioma stem-like cell expansion and resistance to anticancer treatment such as cisplatin (50 lM) or taxol (500 nM), or by ionizing radiation (10 Gy) in both glioma cell lines (U87, U373) and patient-derived glioma cells. Of note, concomitant increase of nitric oxide production occurred with the radiation-induced increase of the glioma stem-like cell population through upregulation of inducible nitric oxide synthase (iNOS). In line with this observation, downregulation of iNOS effectively reduced the glioma stem-like cell population and decreased resistance to anticancer treatment. Collectively, our results suggest that targeting iNOS in combination with ionizing radiation might increase the efficacy of radiotherapy for glioma treatment. (Cancer Sci 2013;

Nitric oxide antagonism to glioblastoma photodynamic therapy and mitigation thereof by BET bromodomain inhibitor JQ1

“…For example, ionizing radiation has been reported to elicit such responses and overexpressed iNOS/NO has been implicated (76), but the underlying regulation of iNOS expression were not investigated. Of related interest is a recent study demonstrating that JQ1 can function as a radiosensitizer, i.e.…”

“…In addition to exploiting iNOS/NO for proliferative signaling, glioblastoma cells are known to rely on NO for migratory and invasive potency (26,(42)(43)(44). We compared the effects of 1400W and JQ1 on surviving U87 cell invasiveness after a typical ALA/light challenge.…”

Radiation treatment and cancer stem cells

“…glioblastoma cells preferentially activate the signaling components that are involved in DNA damage checkpoint and thereby repair IR-induced DNA damage more efficiently than CD133-glioblastoma cells. However, previously, Kim et al observed an increase of cancer stem cell population to a greater extent by fractionated radiation than a single high dose of radiation (Kim et al 2013a). Since a higher single dose of radiation is predicted to be more powerful for selection of cancer stem cells than fractionated radiation, it is hard to explain this phenomena with the selection hypothesis.…”

“…The percentage of CD133-expressing cells as analyzed by FACS also correlated with the rate of tumor formation when implanted in mice. Likewise, Kim et al reported that treatment of glioblastoma cells with radiation stimulates expansion of glioma stem cells through nitric oxide (NO) production mediated by inducible NO synthase (iNOS) (Kim et al 2013a). They demonstrated that treatment with either single radiation (6 Gy) or fractionated radiation (2 Gy x3) resulted in the increase of CD133?…”

Malignant Tumours of the Central Nervous System in Kazakhstan - Incidence Trends from 2004-2011

“…However, only associate with an increased risk of radiation is not possible, as these specialists have had contact with other possibly carcinogenic factors, such as, for example, arsenic, chemotherapy, etc. Negative results were obtained by observing a cohort of radiologists in China and employees of nuclear facilities of US and UK (Kim et al, 2013). Based on a number of epidemiological studies can be concluded that occupational exposure to ionizing radiation does not increase the risk of brain tumors.…”