| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2006: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 2005: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 2004: ¥1,500,000 (Direct Cost: ¥1,500,000)
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| Research Abstract |
Lung cancer is a major cause of cancer death. However, the limitation of conventional chemotherapy requires the introduction of new agents. Cell growth signal, cellular immortality, and escape from apoptosis are critical for the proliferation of lung cancer cells. Epidermal growth factor (EGF) receptor gene mutations, telomerase, and survivin are overexpressed in cancer cells, and involved in these processes. The development of agents for these cancer-specific processes is promising. In the current study, we examined whether the histone deacetylase (HDAC) inhibitor FR901228, and the EGF receptor tyrosine kinase (EGFR-TK) inhibitor gefitinib may target these proteins.
In small-cell lung cancer, FR901228 induced caspase-dependent apoptosis through the mitochondrial pathway, and inhibited the expression of BCL-2, BCL-xL, and survivin. Additionally, FR901228 suppressed telomerase activity. In contrast, in non-small-cell lung cancer, the antiproliferative effect of gefitinib is associated with the inhibition of telomerase activity and E2F-1 expression. Gefitinib blocked the function of the drug-efflux pumps, BCRP and P-glycoprotein that were overexpressed in drug-resistant cancer cells. Furthermore, the expression of AKT was observed in bronchioloalveolar carcinoma, and gefitinib suppressed mucin production from lung cancer cells as well as the antiproliferative effects through signal-transduction pathways. These findings suggest that the HDAC inhibitor and EGFR-TK inhibitor simultaneously suppress cell growth signaling, cell immortality, and escape from apoptosis.
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