PURPOSE: Activation of the mitogen activated extracellular signal protein kinase (MEK) and phosphatidylinositol-3 kinase (PI3K)/ Akt signaling pathways have been implicated in tumorigenesis, malignant cell proliferation and survival as well as in the resistant phenotype of a variety of human tumor cells to chemotherapy and irradiation. In hyperthermic cancer therapy, heat shock activates these anti-apoptotic/cellular proliferative signaling pathways, which is associated with heat-resistance. Additionally, accumulation of heat shock proteins (Hsps) also plays an anti-apoptotic role. To develop more effective strategies, it is significant to find effective heat sensitizers which can specifically inhibit the heat-induced activation of these prosurvival signalings and enhance heat-induced apoptosis.
METHODS: Using two human lung cancer cell lines, which were transfected with wild type p53 (H1299/wtp53) or mutated p53 gene (H1299/mp53), we investigated the effect of PD98059 (MEK inhibitor) and LY294002 (PI3K inhibitor), on heat sensitivity by colonogenic assay. In addition, the effects of these selective inhibitors on the several heat-induced key signaling factors, such as anti-apoptotic factors (survivin, Hsp27, Hsp70) and apoptotic factor (caspase-3), were analyzed with Western blot analysis. The efficacy of the induction of apoptosis were detected Hoechst33342 staining.
RESULTS: Both PD98059 and LY294002 sensitized two cell types of H1299/wtp53 and H1299/mp53 to heat. Furthermore, these two agents significantly suppressed heat-induced accumulation of survivin, Hsp27, Hsp70 and enhanced heat-induced activation of caspase-3 and apoptosis with an independent manner on p53 gene status.
CONCLUSION: It is suggested that combination of hyperthermia and MEK pathway inhibitor or PI3K/Akt pathway inhibitor provides effective hyperthermic strategies for the treatment of lung cancers regardless of p53 gene status.
CLINICAL IMPLICATIONS: Hyperthermic cancer therapy combined with MEK pathway inhibitors or PI3K/Akt pathway inhibitors has the potential to be a useful tool for refractory disease.
DISCLOSURE: Yoko Nagata, No Financial Disclosure Information; No Product/Research Disclosure Information