FOXM1 is implicated in genotoxic drug resistance but its role and mechanism of action remain unclear. Here, we establish that γH2AX foci, indicative of DNA double strand breaks, accumulate in a time-dependent manner in the drug sensitive MCF-7 cells but not in the resistant counterparts in response to epirubicin. We find that FOXM1 expression is associated with epirubicin sensitivity and double strand break (DSB) repair. Ectopic expression of FOXM1 can increase cell viability and abrogate DSBs sustained by MCF-7 cells following epirubicin, owing to an enhancement in repair efficiency. Conversely, alkaline comet and γH2AX foci formation assays show that Foxm1-null cells are hypersensitive to DNA damage, epirubicin and γ-irradiation. Furthermore, we find that FOXM1 is required for DNA repair by homologous recombination (HR) but not non-homologous end joining (NHEJ), using HeLa cell lines habouring an integrated direct repeat green fluorescent protein (DR-GFP) reporter for DSB repair. We also identify BRIP1 as a direct transcription target of FOXM1 by promoter analysis and chromatin-immunoprecipitation assay. In agreement, depletion of FOXM1 expression by siRNA down-regulates BRIP1 expression at the protein and mRNA levels in MCF-7 and the epirubicin resistant MCF-7 EpiR cells. Remarkably, the requirement for FOXM1 for DSB repair can be circumvented by reintroduction of BRIP1, suggesting that BRIP1 is an important target of FOXM1 in DSB repair. Indeed, like FOXM1, BRIP1 is needed for HR. These data suggest that FOXM1 regulates BRIP1 expression to modulate epirubicin-induced DNA damage repair and drug resistance.

Resistance to 5-Fluoruracil (5-FU) has been linked to elevated expression of the main target, thymidylate synthase (TYMS), which catalyses the de novo pathway for production of deoxythymidine monophosphate. The potent oncogenic forkhead box transcription factor, FOXM1 is is regulated by E2F1 which also controls TYMS. This study reveals a significant role of FOXM1 in 5-FU resistance. Overexpression and knock-down studies of FOXM1 in colon cancer cells suggest the importance of FOXM1 in TYMS regulation. ChIP and global ChIP-seq data also confirms that FOXM1 can also potentially regulate other 5-FU targets, such as TYMS, thymidine kinase 1 (TK-1) and thymidine phosphorylase (TYMP). In human colorectal cancer tissue specimens, a strong correlation of FOXM1 and TYMS staining was observed. Elevated FOXM1 and TYMS expression was also observed in acquired 5-FU resistant colon cancer cells (HCT116 5-FU Res). A synergistic effect was observed following treatment of CRC cells with an inhibitor of FOXM1, thiostrepton, in combination with 5-FU. The combination treatment decreased colony formation and migration, and induced cell cycle arrest, DNA damage, and apoptosis in CRC cell lines. In summary, this research demonstrated that FOXM1 plays a pivotal role in 5-FU resistance at least partially through the regulation of TYMS.

Objective: To evaluate the outcome of using radiotherapy (RT) alone to treat patients with early-stage Hodgkin’s disease (HD). Method: The records of 28 patients with HD treated with RT alone at Kuwait Cancer Control Center between 1980 and 1998 were reviewed. Results: Twenty-three patients had stage I HD and 5 stage II. Two patients had B symptoms, 12 (42.9%) patients lymphocyte-predominant histology, 9 (32.1%) nodular sclerosis and 7 (25%) mixed cellularity. Overall survival and relapse-free survival at 10 years were 100 and 83%, respectively. Conclusion: Our data indicate that the use of RT alone for treatment of early stages of HD appears to be effective.

Environmental monitoring is a recent world-wide approach to save the future in line. The present study focuses on toxicity of heavy metals and pesticides on the freshwater aquarium fish (Poecilia reticulata and Poecilia sphenops). The study intense on drawing the acute and chronic safe levels of metals and pesticide exposed to 96 h and 28 day respectively. On exposure, the fish were observed to be under stress and showed excitability. It was observed that both species were highly sensitive to arsenic and cypermethrin, meanwhile resistant to cadmium and chlorpyrifos. The acute safe levels for As irrespective of species was comparatively lesser than that of Cd exposed fish and the range of safe values for pesticides exposure were between 0.018 and 0.059 ppb. As the water quality is influencedby many environmental factors, the present study helps the aquarist in monitoring the safe level of toxicants in the medium. This in turn increases the economic growth of the aquarist.