P1-280 - Phytohemagglutinin chemosensitizes lung cancer cells to Liposomal Cisplatin by cell cycle arrest

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Phytohemagglutinin (PHA) has mitogenic and potent cell agglutinating activities. It binds to T-cell membranes and stimulates cell division and metabolic activity. PHA has the ability to stimulate close contacts between cell membranes. Lipoplatin (Liposomal cisplatin) is a nanoparticle of 110 nm average diameter composed of lipids and cisplatin. This new drug has successfully finished Phase I, Phase II and Phase III human clinical trials. It has shown superiority to cisplatin in combination with paclitaxel as a chemotherapy regimen in non-small cell lung cancer (NSCLC) adenocarcinomas. The aim of this study was to investigate whether PHA would be able to enhance the antitumor effects of Lipoplatin in MCF-7 and MDA-MB-231 cells. PHA potentiated the cytotoxic effects of Lipoplatin in human lung cancer cells. This finding was related to the ability of PHA to sensitize MCF-7 cells to Lipoplatin-induced apoptosis. The sensitization by PHA involved the enhancement of p53 levels, the decrease of procaspase 8 and the activation of caspases 7 and 9. Another proposed mechanism for the chemosensitization effect of MCF-7 cells to Lipoplatin by PHA was the cell cycle arrest in the S phase. The treatment with PHA or Lipoplatin increased the levels of p-Chk2. The increase became pronounced in the combined treatments of the compounds. The expression of cyclin A was decreased by treatment with PHA and by the combination of PHA with Lipoplatin. While the levels of cyclin dependent kinase 2 (CDK2) remained unchanged by treatments, its active form (Thr(160) -phosphorylated CDK2) was decreased by treatment with PHA and by the combination of PHA with Lipoplatin. The activity of CDK7, kinase that phosphorylates CDK2 at Thr(160), was inhibited by PHA and by the combination of PHA with Lipoplatin. These results indicate that PHA could be used as an adjuvant agent during lung cancer therapy with Lipoplatin.