| Project/Area Number |
11671853
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Functional basic dentistry
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| Research Institution | Meikai University |
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Principal Investigator |
SAKAGAMI Hiroshi Meikai University School of Dentistry, Professor, 歯学部, 教授 (50138484)
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| Co-Investigator(Kenkyū-buntansha) |
KASHIMATA Masanori Meikai University School of Dentistry Professor, 歯学部, 教授 (30152630)
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| Project Period (FY) |
1999 – 2001
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| Project Status |
Completed (Fiscal Year 2001)
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| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2001: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 2000: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 1999: ¥1,400,000 (Direct Cost: ¥1,400,000)
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| Keywords | Antioxidant / Human squamous cell carcinoma / Cell death / Apoptosis / HlF-1α / MnSOD / Bax / NO / HIF-1 / ビタミンC / ボリフュノール / 口腔癌細胞 / VEGF / M30モノクローナル抗体 / DNA断片化 / ポリフェノール |
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| Research Abstract |
We screened various natural polyphenols and antioxidants to isolate tumor-specific antitumor agents. Lignins showed very weak cytotoxic activity, but synergistically stimulated the cytotoxic action of vitamin C and K. Macrocyclic ellagitannins and isoflavones showed some tumor specificity. Steroidal saponins showed the most potent cytotoxic activity by non-oxidizing action. Various plant extracts showed tumor specificity and reversed the multidrug resistance against the antitumor drugs. CaCl_2 significantly reduced the cytotoxic activity of antioxidants by modifing the diol structures by oxidation. When human oral squamous carcinoma cell lines HSC-2 were exposed to hypoxia, the binding of HIF-1α to HRE was stimulated. This was inhibited effectively by NAC and GSH ethylester, but only marginally by sodium ascoibate. We next investigated the activation of HE7- 1 by reporter assay with HSC-2 variants which stably express VEGF HRE tandem repeat linked to luciferase gene in the promoter region. We found that sodium ascorbate did not significantly activate the HIF at 6h under nonnoxia condition. On the other hand, sodium ascorbate (0.25-5 mM) dose dependently induced the rapid increase in the mRNA expression of HIF-1α and decrease the MnSOD activity/mRNA expression in HL-60 cells. This might explain how the cells respond to the hypoxia (induced by ascorbate) and express the proteins necessary for the oxygen supply. There remains to identify these protein species and why cells are destined to death even if HIF-1α was induced. EGCG and isoflavones also induced the apoptotic cell death in mouse macrophage-like cells Raw 264.7, and changed the expression of bax, proapoptotic protein, in bimodal fashions. There remains, to investigate the mechanism by which antioxidant action is switched to prooxiant action, and vice versa.
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