• Journal of Radiation Protection and Research
• /
• v.28 no.3
• /
• pp.233-237
• /
• 2003

It has been known that ATM plays a central role in response of cells to ionizing radiation by enhancing DNA repair. We have investigated the feasibility of increasing radiosensitivity of tumor cells with the use of ATM inhibitors such as caffeine, pentoxifylline and wortmannin. Human colorectal cancer RKO.C cells and RKO-ATM cells (RKO cells overexpressing ATM) were used in the present study. The clonogenic cell survival in vitro indicated that RKO-ATM cells were markdely radioresistant than RKO.C cells. Treatment with 3 mM of caffeine significantly increased the radiosensitivity of cells, particulary the RKO-ATM cells, so that the radiosensitivity of RKO.C cells and RKO-ATM cells were almost similar. The radiation induced G2/M arrest in RKO-ATM cells was noticeably longer than that in RKO.C cells and caffeine treatment significantly reduced the length of the radiation induced G2/M arrest in both RKO.C and RKO-ATM cells. Pentoxifylline and wortmannin were also less effective than caffeine to radiosensitize RKO.C or RKO-ATM cells. However, wortmannin was more effective than caffeine against human lung adenocarcinoma A549 cells indicating the efficacy of ATM inhibitor to increase radiosensitivity is cell line dependent. For in vivo study, RKO.C cells were injected s.c. into the hind-leg of BALB/C-nuslc nude mice, and allowed to grow to 130mm3 tumor. The mice were i.p. injected with caffeine solution or saline and the tumors irradiated with 10 Gy of X-rays. The radiation induced growth delay was markedly increased by 1-2 mg/g of caffeine. It was concluded that caffeine increases radiosensitivity of tumor cells by inhibiting ATM kinase function, thereby inhibiting DNA repair, that occurs during the G2/M arrest after radiation.

• Journal of Life Science
• /
• v.19 no.8
• /
• pp.1073-1080
• /
• 2009

A number of studies have demonstrated that the regular use of nonsteroidal anti-inflammatory drugs (NSAIDs) can reduce the risks of colorectal, oesophageal and lung cancers. NSAIDs have been shown to exert their anti-cancer effects through inducing apoptosis in cancer cells. The susceptibility of tumor cells to anti-tumor drug-induced apoptosis appears to depend on the balance between pro-apoptotic and anti-apoptotic programs such as nuclear factor kB (NF-kB), phosphatidylinositol 3-kinase (PI3K)-Akt/protein kinase B (PKB) and MEK1/2-ERK1/2 pathways. We examined the effects of pro-survival PI3K and ERK1/2 signal pathways on cell cycle arrest and apoptosis in response to NSAIDs including sulindac sulfide and NS398. We show that simultaneous inhibition of the Akt/PKB and ERK1/2 signal cascades could synergistically enhance the potential pro-apoptotic activities of sulindac sulfide and NS398. Similar enhancement was observed in cells treated with sulindac sulfide or NS398 and 100 ${\mu}$M genistein, an inhibitor of receptor tyrosine kinases (RTKs) that are upstream of PI3K and MEK1/2 signaling. We further demonstrate that NAG-1 is induced and plays a critical role(s) in apoptosis by NSAIDs-based combined treatment. In sum, our results show that combinatorialtreatment of sulindac sulfide or NS398 and genistein results in a highlysynergistic induction of apoptotic cell death to increase the chemopreventive effects of the NSAIDs, sulindac sulfide and NS398.