| Budget Amount *help |
¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000)
Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2014: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
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| Outline of Final Research Achievements |
KEAP1 mutation found in malignant melanoma leads constitutive NRF2 activation and gene expression that confers cell proliferation and drug resistance to cisplatin and dacarbazine. NQO1 is a target gene of NRF2 and an enzyme catalyzing quinone reduction that convert HSP90 inhibitor 17-AAG to an active structure. 17-AAG efficiently eliminated not only melanoma cell lines with KEAP1 mutation but also cell lines with high NQO1 expression. Because cisplatin or dacarbazine produces reactive oxygen species that activate NRF2, toxicities of cisplatin and 17-AAG, or dacarbazine and 17-AAG combinations to cell lines with low NQO1 expression were analyzed. Cisplatin and 17-AAG combination showed synergistic effect in four out of five cell lines with low NQO1 expression but not in cell line with KEAP1 mutation. These data indicate that 17-AAG can be a potential chemotherapy for melanoma that acquires NRF2-mediated drug resistance.
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