2016 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 | Pterostilbene / Osteosarcoma / Colon cancer / Cancer stem cells |
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| Outline of Annual Research Achievements |
We have found a very characteristic efficacy of pterostilbene (PTE) on human osteosarcoma (OS) cells and will propose its potential to a novel therapeutic intervention against OS at this point.
1.Treatment of PTE showed dose-dependent growth inhibitory effects on human OS cell lines and especially significant on MG63 cells at the highest inhibition rate of 65% at the concentration of 10μM for 48hrs treatment. In contrast, PTE did not show growth inhibition on normal mesenchymal stromal cells, one of the candidates for OS cell of origin.
2. Co-treatment of PTE with DXR indicated that PTE augmented the growth suppressive effects of DXR lifting the growth inhibition rate up to 5 to 15 % from DXR alone.
3. PTE treatments decreased sphere forming ability in both SaOS2 and U2OS cells in terms of sphere numbers and sphere sizes, and also decreased mRNA expression of stemness marker of Oct3 and CD44 in both cell lines.
Conclusions: PTE inhibits cellular growth and augments the efficacy of DXR against OS cells possibly through the suppression of stem cell characteristics. Current results suggest that PTE not only inhibits cellular growth of OS but also suppresses stem cell phenotype which was defined by sphere forming ability and mRNA expression of stemness marker. We also found the same effects on colon cancer cells as well. Thus, PTE could be a possible candidate for the novel therapeutic intervention against OS and colon cancers or others.
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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 as well as colon cancer cells through the suppression of stem cell phenotype and could augment the efficacy of cytotoxic agents such as doxorubicin. This is the novel findings of the effects of PTE on malignant tumor cells for the first time and we will present a part of these results in American Association for Cancer Research Special Conference on Advances in Sarcomas 2017 which is held in Philadelphia and Japanese Cancer Association meeting in 2017.
The mechanisms of the suppression of stem cell phenotype by PTE are still under the investigation; however, our preliminary studies showed that the suppression of PI3K/Akt/mTOR pathways could be one of the candidates for this PTE effect on OS cells. 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 stem cell phenotype suppression by pterostilbene (PTE) are still unknown, but it might be caused by either decrease or differentiation of stem cell subpopulation. The efficacy of PTE is cell-type dependent possibly due to the mechanisms of cell death or cell metabolism. Previous report suggested that anti-tumor activity of PTE against osteosarcoma (OS) cells targeted the JAK2/STAT3 signaling pathways. In our preliminary studies, PI3K/Akt/mTOR pathways might be involved in stem cell phenotype suppression by PTE in OS cells. Such that, we will conduct our research in the coming fiscal year focusing on the molecular pathways involved in growth inhibition and stem cell phenotype suppression caused by PTE against OS or other cancer cells using various pathway inhibitors and cell metabolism modulators.
Suppression of stem cell phenotype could lead to enhance the efficacy of cytotoxic chemotherapeutic agents such as doxorubicin as well as other agents from natural products such as polyphenols and flavonoids. Therefore, suppression or activation of pathways other than JAK2/STA3 or PI3K/Akt/mTOR, for instance, IGF1R or PTEN, would achieve more anti-tumor efficacy on OS or other cancer cells. Such that, we will investigate the efficacy of co-treatment of other phytochemicals including honokiol with PTE against OS cells first and may dig into other cancer cells as well in the future.
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| Causes of Carryover |
We have planed the gene expression analysis using multiple cDNA Plate Arrays with cells treated by pterostilebene and honokiol comparing non-treated cells. We have performed PI3K/Akt pathway analysis for pterostilebene last fiscal year for preliminary study. Due to the requirement of deep consideration for selection of the pathways for cDNA Array plates (i.e. pathway selection), we will this analysis in the next experiment's term for both peterostilebe and honokiol.
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| Expenditure Plan for Carryover Budget |
We will conduct the experiments with cDNA Plate Array and the results of the analysis will apply for further detailed genetic/pathway alteration analysis.
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Research Products
(12 results)
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[Journal Article] The clinical outcome of pazopanib treatment in Japanese patients with relapsed soft tissue sarcoma: A Japanese Musculoskeletal Oncology Group (JMOG) study.2016
Author(s)
Nakamura T, Matsumine A, Kawai A, Araki N, Goto T, Yonemoto T, Sugiura H, Nishida Y, Hiraga H, Honoki K, Yasuda T, Boku S, Sudo A, Ueda T.
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Journal Title
Cancer
Volume: 122
Pages: 1408-16
DOI
Peer Reviewed / Open Access
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