2017 Fiscal Year Research-status Report
Translational applications of broad spectrum natural compounds and phytochemicals or their derivatives to the novel treatment strategy against sarcomas
| Project/Area Number |
15K10455
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| Research Institution | Nara Medical University |
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Principal Investigator |
朴木 寛弥 奈良県立医科大学, 医学部, 准教授 (40336863)
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| Co-Investigator(Kenkyū-buntansha) |
藤井 宏真 奈良県立医科大学, 医学部, 学内講師 (00625791)
辻内 俊文 近畿大学, 理工学部, 教授 (10254492)
藤間 保晶 奈良県立医科大学, 医学部, 研究員 (60448777)
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| Project Period (FY) |
2015-04-01 – 2019-03-31
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| Keywords | osteosarcoma / mitochondria metabolism / phytechemicals / pterostilbene / honokiol / c-myc inhibitor / glycolysis |
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| Outline of Annual Research Achievements |
We investigated the anti-sarcoma efficacy of pterostilbene (PTE) in combination with c-Myc inhibition by Honokiol, another natural compound of phytochemical, and JQ-1, a bromodomain inhibitor. In the current investigation, we have found a very unique characteristic of the mechanism of action of PTE which could have inhibitory effect of mitochondrial energy producing enzyme, F0-F1 ATP synthase, and sensitize the cytotoxic action by c-Myc inhibition as described below.
1. PTE treatment reduced viabilities of SaOS2, U2OS and MG63 osteosarcoma cells in dose dependent manner, and decreased the ability of spheroid formation as well as stem cell marker expression.
2. PTE treatments decreased oxygen consumption rates and increased 4-Hydroxynonenal and intracellular lactate in osteosarcoma cells.
3. The activity of F0-F1 ATP synthase was predominantly reduced, and the synthesis amount of ATP was also decreased in spheroid cultured condition.
4. JQ1 and Honokiol reduced cell viability of osteosarcoma cells and decreased c-Myc expression in those cells, and PTE is strongly potentiated its anti-cancer activity in combination with JQ1 or Honokiol.
The current results suggest that PTE inhibits the mitochondrial metabolism of ATP synthesis in osteosarcoma stem cells via F0-F1 ATP synthase inhibition, and JQ1 and Honokiol strongly potentiated the anti-cancer activity of PTE.
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| Current Status of Research Progress |
Current Status of Research Progress
2: Research has progressed on the whole more than it was originally planned.
Reason
Primary goal of this project is seeking the novel treatment against sarcomas and various other cancers using agents from natural resources such as phytochemicals including polyphenols and flavonoids to not only enhances the anti-tumor efficacy but also hopefully reduce the side effects and treatment costs. We have found so far that pterostilbene (3',5'-dimethoxyresveratrol; PTE) showed the anti-tumor efficacy against osteosarcoma (OS) cells through the suppression of stem cell phenotype and could augment the efficacy of cytotoxic agents such as doxorubicin as well as c-Myc inhibitor of JQ1 and Honokiol.
The possible mechanisms of anti-sarcoma efficacy by PTE are could be multi-factorial, but involve mitochondrial metabolism modulation and co-treatment with c-Myc inhibitor augmented the anti-sarcoma efficacy via glycolytic metabolic flux to OXSPHOS. Taken together, these results could illuminate future directions of our research by following these footsteps and will be able to propose the novel treatment strategies targeting cancer stem cells or tumor initiating cells for various cancers and sarcomas.
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| Strategy for Future Research Activity |
Mechanisms of mitochondrial metabolism modulation by PTE will be confirmed. Previously, we reported the suppression of stem cell phenotype could be one of the efficacy against osteosarcoma cells and that lead to enhance the efficacy of cytotoxic chemotherapeutic agents such as doxorubicin, and this time other agents from natural products such as Honokiol. We are planning to perform in vivo studies using rat osteosarcoma model with co-treatment of PTE and Honokiol. We will present above results in the major conferences of Japan Cancer Association and American Association of Cancer Research, and will publish in the journals in coming years.
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| Causes of Carryover |
We have planed the further investigation of metabolic flux analysis and gene expression analysis using multiple cDNA Plate Arrays with cells treated by PTE and honokiol comparing non-treated cells.
We will conduct the experiments with cDNA Plate Array and the results of the analysis will apply for further detailed genetic alteration analysis. In addition, in vivo experiments using rat osteosarcoma model should be planned for the coming fiscal year.
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