2018 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, 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 – 2020-03-31
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| Keywords | sarcoma / metabolism / mitochondria / glycolysis / phytochmicals / c-myc / mesenchymal stem cells |
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| Outline of Annual Research Achievements |
We found that pterostilbene (PTE), a natural compound of phytochemical, inhibits cell growth and augments the efficacy of doxorubicin through stem cell phenotype suppression in osteosarcoma (OS) cells in vitro. It has been reported that cancer stem cells metabolize predominantly oxidative metabolism (OXPHOS) rather than glycolysis. This metabolic characteristic could be potential new therapeutic target. In this context, we further investigated the anti-sarcoma efficacy in combination with c-Myc inhibitors like Honokiol, or JQ-1, both of which result in glycolysis inhibition. These current results lead the novel treatment targeting dual metabolic inhibition against osteosarcoma as well as a very unique characteristic of the interaction between OS cells and mesenchymal stem cells through mitochondria transfer as described below.
1.PTE treatment reduced viabilities of human and rat OS cells in dose dependent manner, and decreased the ability of spheroid formation as well as stem cell marker expression, and decreased oxygen consumption rates and increased 4-Hydroxynonenal and intracellular lactate as well as ROS production. The activity of F0 - F1 ATP synthase was predominantly reduced, and the synthesis amount of ATP was also decreased in spheroid cultured condition.
2.c-myc inhibitors of JQ1 and Honokiol decreased c-Myc expression and reduced cell viability of OS cells in combination with PTE.
3.Mesenchymal stem cells co-cultured with osteosarcoma cells transfer their mitochondria to OS cells under the stress of cytotoxic agents like doxorubicin and cisplatinum.
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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 inhibitors of JQ1 and Honokiol. The possible mechanisms of anti-sarcoma efficacy by PTE involve mitochondrial metabolism modulation and co-treatment with c-Myc inhibitor augmented the anti-sarcoma efficacy via glycolytic metabolic flux to OXSPHOS, so called dual inhibition. We also found that very unique interaction between OS cells and mesenchymal stem cells through mitochondria transfer form mesenchymal stem cells and OS cells. We have made several conference presentations at both domestic and international conferences such as Japanese Cancer Association, Japanese Orthopedic Association and American Association for Cancer Research and now preparing the manuscript to submit.
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| Strategy for Future Research Activity |
Targeting mitochondria could be the possible candidate for novel therapeutic modality through the metabolic modulation. In addition, the interaction between sarcoma cells and tumor stromal cells like mesenchymal stem cells could be a potential target for sarcoma treatment. We have found that mesenchymal stem cells co-cultured with osteosarcoma cells transfer their mitochondria to osteosarcoma (OS) cells under the stress of cytotoxic agents and we speculate that this phenomenon might contribute to the disease progression of OS through the compensation of mitochondrial function in OS cells by mesenchymal stem cells.
Future plan of our work is to investigate the mechanisms of interaction between tumor cells and tumor stromal cells like mesenchymal stem cells, which represented by mitochondrial transfer from tumor stromal cells to tumor cells, which may contribute to the modulation of mitochondrial metabolism in tumor cells. We will target this interaction to develop the novel therapeutic means against sarcomas as well as various types of cancer.
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| Causes of Carryover |
We are aiming to publish our data collected from the current project in the past years. The reason for the usage of incurring amounts in the next fiscal year is that we need the budget for publishing fee, conference fee to complete our project.
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Research Products
(9 results)
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[Journal Article] Miscorrelation of Functional Outcome and Sociooccupational Status of Childhood, Adolescent, and Young Adult Generation With Bone and Soft Tissue Sarcoma Patients.2019
Author(s)
Fujii H, Honoki K, Ishihara T, Shinomiya T, Tsukamoto S, Kido A, Kondoh Y, Kishi S, Shima M, Tanaka Y
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Journal Title
J Pediatr Hematol Oncol.
Volume: 41
Pages: 112-117
DOI
Peer Reviewed
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[Journal Article] Frequent mutations of genes encoding vacuolar H+ -ATPase components in granular cell tumors.2019
Author(s)
Sekimizu M, Yoshida A, Mitani S, Asano N, Hirata M, Kubo T, Yamazaki F, Sakamoto H, Kato M, Makise N, Mori T, Yamazaki N, Sekine S, Oda I, Watanabe SI, Hiraga H, Yonemoto T, Kawamoto T, Naka N, Funauchi Y, Nishida Y, Honoki K, Kawano H, Tsuchiya H, Kunisada T, Matsuda K, Inagaki K, Kawai A, Ichikawa H.
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Journal Title
Genes Chromosomes Cancer
Volume: 58
Pages: 373-380
DOI
Peer Reviewed
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