ku-55933 and Adenocarcinoma

Low dose irradiation (LDIR) induces hormesis and adaptive response in organism and mammalian cell lines. Notably, LDIR generates distinct biological effects in cancer cells from normal cells, e.g., it may affect the growth of cancer cells via the activation of certain cell signaling pathway, which does not exist in normal cells. Therefore, LDIR is considered as a promising assistant method of clinical cancer therapy. In this study, we chose human colorectal adenocarcinoma cell line HT-29 as the experimental model, and investigated the differential biological effects between 250 mGy single dose LDIR and 250 mGy intermittent LDIR pretreatments in high dose irradiation (HDIR) radiotherapy and 5-fluorouracil (5-FU) based chemotherapy. Through the cell growth assays, we observed that 250 mGy intermittent LDIR pretreatment significantly increased the killing effect of both radiotherapy and chemotherapy. Western blotting results showed that intermittent LDIR pretreatment apparently activated the ATM/p53 (ataxia telangiectasia mutated, ATM) pathway in radiotherapy; it also activated ERK and p38MAPK pathways in chemotherapy. When we used chemical inhibitors to block the ATM/p53 or p38MAPK pathways, the intermittent LDIR induced cell growth inhibitions were reversed. However, blockage of ERK pathway could not affect the cell growth inhibiton in chemotherapy. Taken together, our findings evaluated the intermittent LDIR as a potential valuable method that can enhance the effectiveness of radiotherapy and chemotherapy, especially in the radio- or chemo-resistant tumor types.

Topics: Adenocarcinoma; Antimetabolites, Antineoplastic; Ataxia Telangiectasia Mutated Proteins; Benzothiazoles; Cell Proliferation; Chemoradiotherapy; Colorectal Neoplasms; Extracellular Signal-Regulated MAP Kinases; Flavonoids; Fluorouracil; HT29 Cells; Humans; Imidazoles; MAP Kinase Signaling System; Morpholines; p38 Mitogen-Activated Protein Kinases; Pyridines; Pyrones; Radiation Dosage; Toluene; Tumor Suppressor Protein p53

Ataxia-telangiectasia mutated (ATM) kinase is a component of a signalling mechanism that determines the process of decision-making in response to DNA damage and involves the participation of multiple proteins. ATM is activated by DNA double-strand breaks (DSBs) through the Mre11-Rad50-Nbs1 (MRN) DNA repair complex, and orchestrates signalling cascades that initiate the DNA damage response. Cells lacking ATM are hypersensitive to insults, particularly genotoxic stress, induced through radiation or radiomimetic drugs. Here, we investigate the degree of ATM activation during time-dependent treatment with genotoxic agents and the effects of ATM on phospho-induction and localization of its downstream substrates. Additionally, we have demonstrated a new cell-cycle-independent mechanism of ATM gene regulation following ATM kinase inhibition with KU5593. Inhibition of ATM activity causes induction of ATM protein followed by oscillation and this mechanism is governed at the transcriptional level. Furthermore, this autoregulatory induction of ATM is also accompanied by a transient upregulation of p53, pATR and E2F1 levels. Since ATM inhibition is believed to sensitize cancer cells to genotoxic agents, this novel insight into the mechanism of ATM regulation might be useful for designing more precise strategies for modulation of ATM activity in cancer therapy.

Topics: Adenocarcinoma; Ataxia Telangiectasia Mutated Proteins; Breast Neoplasms; Cell Cycle Proteins; Cell Line; Cell Line, Tumor; Cells, Cultured; DNA Damage; DNA-Binding Proteins; E2F1 Transcription Factor; Enzyme Inhibitors; Epithelial Cells; Humans; Keratinocytes; Morpholines; Protein Serine-Threonine Kinases; Pyrones; Transcriptional Activation; Tumor Suppressor Protein p53; Tumor Suppressor Proteins; Up-Regulation