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Enhancement of Paclitaxel and Carboplatin Therapies by CCL2 Blockade in Ovarian Cancers

Ovarian cancer is strongly associated with a pro- inflammatory leukocyte infiltrate, and high levels of chemokines such as CCL2. CNTO 888, a neutralizing anti-human CCL2 antibody, can inhibit the pro-tumor inflammatory infiltrate and tumor growth. In the present study, we tested the hypothesis that CCL2 neutralization can inhibit tumor growth of ovarian cancer cell line pairs formed by a parental cell line and a non-multi- drug resistant (MDR) paclitaxel-resistant line. Furthermore, we investigated whether mouse stromal CCL2 plays a role in tumor growth promotion. Elevated CCL2 expression was determined by quantitative PCR in three non-MDR paclitaxel resistant (TP) ovarian cancer cell lines ES-2/TP, MES-OV/TP and OVCAR-3/TP, and compared to their related parental cells. Increased CCL2 protein expression levels in vitro and in vivo were confirmed in the drug resistant variants. In order to determine the role of CCL2 on tumor growth upon drug treatment, we established parental and non- MDR paclitaxel resistant cell lines expressing a GFP-luciferase fusion gene. These cells were implanted intraperitoneally (i.p.) and subcutaneously (s.c.) in nude mice. Mice were treated with the anti-human CCL2 antibody (CNTO 888) and the anti-mouse MCP-1 antibody (C1142), orthologous of human CCL2, with and without chemotherapy (paclitaxel or carboplatin). Tumor growth was evaluated by both bioluminescence and caliper measurements. Our results show a significant additive effect of CCL2 blockade on the efficacy of paclitaxel and carboplatin. The mechanism of this therapeutic effect was largely due to inhibition of mouse stromal CCL2. Our findings show that inhibition of CCL2 can enhance paclitaxel and carboplatin treatments of ovarian cancer.

CCL2 ; CCR2 ; EMT ; paclitaxel ; carboplatin ; resistance

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