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Background. High levels of activated p38 MAPK are detected in poorly differentiated gastric cancers, associates with a poor clinical outcome and are thought to promote the local invasion and metastastic dissemination. Aims. In this study we have evaluated the effects of a new p38 MAPK inhibitor, ML3403, on metastatic dissemination of gastric cancer cells and sensitization to chemotherapy. Methods. peritoneal metastasis was induced, by intra-peritoneal (I.P.) implantation of 1 X 107 of gastric cancer cells (MKN74 and MKN45) in 8-week-old NOD-SCID mice. In the first set of experiments we have compared the peritoneal metastasis of MKN45 and MKN74, that express different levels of activated p38 MAPK. In a second set of experiments we have investigated whether ML3403 (13 mg/kg I.P. for 7 days) protects against peritoneal dissemination. In addition, to invetsigate the role of p38 inhibition in cancer cells, MKN45 cells were incubated with ML3403 (10 µM) for 16 hours before inoculation. Finally, mice inoculated with vcvancer cells and treated with ML 3403 (6.5 mg/kg, I.P. daily) were randomized to receive cisplatin (9.08 mg/kg; I.P. single dose) or 5-Fluorouracil (300 mg/kg, orally for 4 days) alone or in combination with ML3403. Assessment of peritoneal diffusion was made 10 days later. Results. In the present study we have found that two gastric cell lines - the moderately differentiated MKN74 cell line and the poorly differentiated MKN45 cell line - present different levels of activated p38 MAPK and that high levels of expression of this kinase associates to an increased capacity to induce cancer dissemination in a rodent model of peritoneal carcinomatosis. One important observation we made was that administration of ML3403 caused a robust reduction of peritoneal diffusion of MNK45 cells. Moreover pre-implant exposure to ML3403, caused a robust attenuation of the metastatic potential of MNK45 cells. By gene array analysis we found that such a protective effect correlates with a robust downregulation in the expression of CXC chemokine Receptor-4 (CXCR4), Fms-related tyrosine kinase 4 (FLT4), the non-receptor spleen tyrosine kinase (SYK) and the collagen α2(IV)in neoplasic foci. Finally the inhibition of p38 MAPK in vivo increased the sensitivity of tumor cells to cisplatin and associated with a robust downregulation in the expression of the multidrugs resistance (MDR)-1, a well defined marker of resistance to chemotherapy. Finally, P38 inhibition increases longterm survival (5 weeks). Conclusions. p38 MAPK inhibition is beneficial in preventing the peritoneal dissemination of poorly differentiated gastric cancer cells by modulating attachment and diffusion of tumor cells in the peritoneum. In addition p38 inhibition increases susceptibility to chemotherapy.