Small molecule targeting of the p38/Mk2 stress signaling pathways to improve cancer treatment.

PURPOSE: Although a long-term goal of cancer therapy always has been the development of agents that selectively destroy cancer cells, more recent trends have been to seek secondary agents that sensitize cancer cells to existing treatment regimens. In this regard, the present study explored the possibility of using small molecule inhibitors of p38MAPK/MK2 stress signaling pathways as potential agents to enhance the sensitivity of cancer cells with abrogated G1 checkpoint to the DNA damaging agent etoposide by specifically targeting the DNA damage-induced G2 cell cycle checkpoint. METHODS: We have applied CCK8 and FACS-based viability assays and cell cycle analysis to investigate the effect of small molecules SB203580 and MK2.III on the sensitivity of small cell lung cancer cells (SCLC) that lack the G1 checkpoint to the DNA damaging agent Etoposide when used in combination. We have also assessed the effectiveness of combination chemotherapy on tumor xenograft suppression with etoposide and MK2.III in immunosuppressed mice. In addition, additional CCK8 cell viability analysis of the MDA-MB-231 breast cancer cell line, and SW620, and SW480 colorectal cancer cell lines was performed. RESULTS: Results suggest that etoposide produces a profound effect on the cell cycle profile of cells in a manner that is consistent with the degree of cell viability that is seen using the viable cell assay. Results of the co-treatment experiments revealed that the p38/MK2 kinase inhibitors SB203580 and MK2.III both enhanced the DNA-damaging effects of etoposide on NCI-H69 cell viability in vitro. Results revealed that in vivo MK2.III was able to act as a chemosensitizer when used in combination with etoposide making NCI-H69 lung cancer cells sensitive to chemotherapeutic drug by 45% compared to single usage of the drug. We also report that MK2.III sensitizes metastatic cell lines SW-620 and MDA-MB-231 to etoposide but does not increase the sensitivity of non-metastasizing SW-480 colorectal cells to DNA damaging agent in vitro. CONCLUSION: Findings reported in this study provide evidence that specific inhibitors of MK2 may indeed improve overall cancer therapy; however, their effectiveness depends on cell types.

Establishment of a cynomolgus monkey (Macaca fascicularis) breeding colony in Malaysia: a feasibility study.

A breeding colony utilizing a harem mating system was established to study the feasibility of breeding cynomoglus monkeys, Macaca fascicularis, in Malaysia. Two groups consisting of 10 females and one male each were evaluated over a 3 period. Forty births were recorded; one was stillborn, 11 died while nursing, and 28 were weaned. The average time to wean offspring was 230 days with an average weight at weaning of 0.858 kg. The average time for conception to take place after weaning was 50 days. Of the 20 breeder females, six produced three offspring each, nine produced two offspring each, four produced one offspring each and one remained barren throughout the project. Three different weaning systems were evaluated. The best method was caging the mother-infant pair within or adjacent to the breeding room followed by a two-part cage system which allowed the infant to continue nursing and also obtain solid food inaccessible to the mother.