Chemosensitization by STI571 targeting the PDGF/PDGFR-signaling pathway in the tumor progression and angiogenesis of gastric and breast carcinoma

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Purpose : Autocrine and paracrine growth mediated by the PDGF/PDGFR-signaling pathway plays an important role in the progression of solid tumors. We assessed the effect of STI571 on the tumor growth of gastric and breast carcinoma in combination with 5-fluorouracil (5-FU), paclitaxel (TXL) or docetaxel (TXT) targeting the PDGF/PDGFR-signaling pathway. Experimental Design : In MKN-45 gastric and MDA-MB-231 breast carcinoma cells, the cytotoxic effect was evaluated by MTT assay and the in vivo antitumor effect was evaluated by the nude mice xenograft. Both STI571 and one anticancer drug were administered intraperitoneally. Gene expression was assessed by Western blot analysis and immunohistochemical staining. Apoptotic cell death was evaluated by the TUNEL assay and tumor angiogenesis was evaluated by microvessel density (MVD). Results: Treatment with STI571 alone was not effective in vitro, assessed by an IC_<50> value of 24.3 and 9.2 micro M, respectively. Combination treatment with STI571 and 5-FU or TXL somewhat enhanced the cytotoxic effect when the concentration of STI571 was increased to 10 micro M in MKN-45 cells. In contrast, combination treatment with STI571 and 5-FU or TXL significantly enhanced the antitumor effect of the anticancer drug in vivo. The enhanced antitumor effect was associated with increased apoptotic cell death and inhibition of tumor angiogenesis. Treatment with STI571 downregulated the expression of PDGF-BB and PDGFR-beta in tumor cells and decreased the production of pPDGFR-beta and pAkt. Furthermore, treatment with STI571 inhibited the expression of PDGFR-beta in stromal cells. Similar results for MDA-MB-231 in vivo cells were observed. Conclusions : STI571 is an effective chemosensitizer of anticancer drugs such as 5-FU, TXL, and TXT for gastric and breast carcinoma, targeting the PDGF/PDGFR-signaling pathway of tumor and stromal cells in progression and angiogenesis.