| Project/Area Number |
17590273
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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 |
Pathological medical chemistry
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| Research Institution | Sapporo Medical University |
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Principal Investigator |
ADACHI Masaaki SAPPORO MEDICAL UNIVERSITY, FIRST DEPARTMENT OF INTERNAL MEDICINE, ASSOCIATE PROF., 医学部, 助教授 (70240926)
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| Co-Investigator(Kenkyū-buntansha) |
HAYASHI Toshiaki SAPPORO MEDICAL UNIVERSITY, FIRST DEPARTMENT OF INTERNAL MEDICINE, INSTRUCTOR, 医学部, 助手 (30381271)
IMAI Kohzoh SAPPORO MEDICAL UNIVERSITY, PRESIDENT, 学長 (60117603)
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| Project Period (FY) |
2005 – 2006
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| Project Status |
Completed (Fiscal Year 2006)
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| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2006: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 2005: ¥1,800,000 (Direct Cost: ¥1,800,000)
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| Keywords | Histone acetylation / apoptosis / mitochondria / ROS / DNA damage / chromatin / JNK |
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| Research Abstract |
To establish a new anticancer therapy, we investigate whether modification of histone structure may enhance radiosensitivity. Histone acetylation is dynamically regulated by histone deacetylase (HDAC) and histone acetylation enzymes. Alternation of the chromatin structure extensively affects transcription activity, and susceptibility to many proapoptotic stimuli. We first investigated effect of several HDAC inhibitors on ionizing radiation (IR)-induced cell death in cancer cell lines. Next, we evaluated their effects on IR-induced DNA damage, namely double strand DNA break (DSB), which can be evaluated by histone H2AX phosphorylation. We also investigated if BH3-only protein Bmf induction is crucial for HDAC inhibitor-mediated radioenhancement. From these studies, we obtained following results.
1.HDAC inhibitors induce Bmf expression strongly and enhance radiosensitivity.
2.HDAC inhibitor-mediated radioenhancement is caused by a substantial increase of DSB.
3.Bmf induction is crucial for the HDAC inhibitor-mediated apoptosis and radioenhancement activity.
4.2-ME also enhances radiosensitivity by JNK activation and subsequent increase of DSB.
These data indicate that histone modification is useful for development of new anticancer therapies.
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