Enhanced lung cancer cell killing by the combination of selenium and ionizing radiation

Abstract

Selenium has been associated with anticancer activity by affecting multiple cellular processes. We reasoned that the simultaneous modulation of multiple radioresponse regulators by selenium should increase radiosensitivity if selenium is combined with radiation in cancer therapy. Therefore, we explored the possibility of whether we could obtain an enhancement of radiosensitivity by the combination of selenium and ionizing radiation. We used two human lung cancer cell lines, NCI-H460 and H1299, as well as a human diploid lung fibroblast, WI-38, as the normal cell counterpart. The combined treatment of the cancer cell lines with Selenomethionine and ionizing radiation resulted in increased cell killing as assessed by clonogenic survival assay whereas it had little effect on the normal diploid WI-38 cells. The increased radiosensitivity in the cancer cells was correlated with the attenuation of the key proteins involved in either cell survival signaling [Akt, EGFR (epidermal growth factor receptor), ErbB2 and Raf1] or DNA damage response (Mre11, Rad50, Nbs1, Ku80, 53BP1 and DNAPK). The attenuation of the proteins by the selenium compound was possibly caused by the effect on transcription and on protein stability since selenium treatment decreased both the RNA transcript and the protein stability of EGFR and DNAPK. By contrast, Seleno-L-methionine had no effect on the protein profile of a normal diploid fibroblast which is consistent with an intact radiosensitivity. These data provide possible clinical applications, as selenium selectively enhanced the radiosensitivity of the tumor cells whereas that of the normal cells was unaffected. Moreover, the selective decrease of cell proliferation signaling in tumor cells but not in normal cells should facilitate the repopulation of normal cells required for healing during radiation therapy. On the whole, the results suggest that the cancer preventive activity of selenium can be combined with ionizing radiation to improve the control of lung cancer.

Sodium selenite induces apoptosis by generation of superoxide via the mitochondrial-dependent pathway in human prostate cancer cells

“…These observations suggest that high levels of MnSOD may protect normal cells against superoxide generated apoptosis by Se. Studies also showed that selenite enhanced cancer cell killing by radiation, suggesting a synergism of prooxidant effects of Se and radiation in cancer cells [38,39]. These data support the notion that prooxidant effects of superoxide and other ROS are responsible for apoptosis induced by certain Se compounds.…”

Ku80 Is Differentially Expressed in Human Lung Carcinomas and Upregulated in Response to Irradiation in Mice

“…Nuclear Ku70/ Ku80 proteins were upregulated during gastric cancer cell hyperplasia in a COX-2-dependent manner, and inhibition of Ku80 using COX-2 inhibitors suppressed cell proliferation (Lim et al, 2002). Suppression of Ku80 was also shown to inhibit cell proliferation and induce apoptosis in human colon cancer cells (Li et al, 2002), and downregulation of Ku80 along with other proteins involved in the DNA damage response enhanced the radiosensitivity of lung cancer cells exposed to selenium and ionizing radiation (Shin et al, 2007). Introduction of antisense Ku70 into a human squamous cell lung carcinoma cell lines was also previously shown to increase the radiosensitivity as well as chemosensitivity of these cells (Omori et al, 2002).…”

Sodium Selenite Radiosensitizes Hormone-Refractory Prostate Cancer Xenograft Tumors but Not Intestinal Crypt Cells In Vivo

“…These characteristics help to explain both the cytotoxic activity of sodium selenite (SSE) alone and its radiosensitizing effect. Sodium selenite has been reported to radiosensitize both hormone-dependent (LAPC-4) and hormone-independent (DU-145) prostate cancer cells (6) and lung cancer cells (9) in vitro. In the experiments described in this report, we studied the in vivo effect of SSE in combination with local tumor irradiation of hormone-independent prostate cancer xenograft tumors.…”