The Effect Of Insulin And Retinoid Acid On Chemotherapeutic Drug Sensitivity In Human Esophageal And Lung Cancer Cells

BACKGROUND: Chemotherapy is the important treatment in tumor therapy. High-dose chemotherapy (HDC) has been proposed to be a potentially curative strategy. Drug resistance and toxicity is generally considered to be the major impediment to successful cancer chemotherapy. To enhance the drug sensitivity, we selected two pathways: the first, classic pathway, all-trans retinoic acid as a proliferation inhibitor, to be used for increasing the chemosensitivity; the second, non-classic pathway: insulin as a metabolic promoter, to be used for enhancement of the chemocytotoxicity. METHODS: 1. MTT colorimetry, to evaluate cell activity and metabolism status reflecting the cytotoxity of the anti-tumor agents; 2.Flow Cytometry: to detect the cell-cycle progresses. 3.RT-PCR: to show the cyclin D and retinoid acid receptor-β expression. RESULTS: We found that the ATRA and the insulin all can enhance the chemocytotoxity of cisplatin and etopside on human esophageal and human lung cancer cells using the MTT colorimetry. Cell cycle assay showed that the GLC and NEC cell can be blocked at G0/1 phase with cell apoptosis by the ATRA, the S phase arrested by 5-FU and S phase and G2/M phase blocked by cisplatin can be enhanced by ATRA. The S phase and G2/M phase block resulted from etopside and the G2/M block resulted from adriamycin can be enhanced by insulin. Etopside and 5-FU can enhance the G0/1 phase delay resulted form ATRA. The failure to complete cell-cycle progression can lead to cell growth inhibition and cell death. RT-PCR demonstrated that the expression of the Cyclin D mRNA can be induced by the insulin and can be inhibited by the ATRA. The effect of insulin is reversible; cisplatin and etopside can induce the expression of the ratinoid acid receptor-β, and can enhanced the effect of ATRA on tumor cells growth inhibition indirectly. This study emphasizes the critical role of schedule dependency to optimize the effectiveness of combination chemotherapy with the inducers. The optimal enhancement...