title: Dihydromyricetin activates AMP-activated protein kinase and P38(MAPK) exerting antitumor potential in osteosarcoma.
abstract: Numerous patients with osteosarcoma either are not sensitive to chemotherapy or develop drug resistance to current chemotherapy regimens. Therefore, it is necessary to develop several potentially useful therapeutic agents. Dihydromyricetin is the major flavonoid component derived from Ampelopsis grossedentata, which has a long history of use in food and medicine. The present study examined the antitumor activity both in vitro and in vivo without noticeable side effects and the underlying mechanism of action of dihydromyricetin in osteosarcoma cells. We found that dihydromyricetin induced increased p21 expression and G2-M cell-cycle arrest, caused DNA damage, activated ATM-CHK2-H2AX signaling pathways, and induced apoptosis in osteosarcoma cells as well as decreasing the sphere formation capability by downregulating Sox2 expression. Mechanistic analysis showed that the antitumor potential of dihydromyricetin may be due to the activation of AMPKα and p38(MAPK), as the activating AMPKα led to the inactivation of GSK3β in osteosarcoma cells. Moreover, GSK3β deletion or GSK3β inhibition by LiCl treatment resulted in increased p21 expression and reduced Sox2 expression in osteosarcoma cells. Taken together, our results strongly indicate that the antitumor potential of dihydromyricetin is correlated with P38(MAPK) and the AMPKα-GSK3β-Sox2 signaling pathway. Finally, immunohistochemical analysis indicated that some patients had a lower p-AMPK expression after chemotherapy, which supports that the combination of dihydromyricetin and chemotherapy drug will be beneficial for patients with osteosarcoma. In conclusion, our results are the first to suggest that dihydromyricetin may be a therapeutic candidate for the treatment of osteosarcoma.
authors.affiliation: Department of Musculoskeletal Oncology, The First Affiliated Hospital of Sun Yat-Sen University;
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: Department of Musculoskeletal Oncology, The First Affiliated Hospital of Sun Yat-Sen University;
authors.forename: Jun-qiang
authors.initials: JQ
authors.lastname: Yin
authors.affiliation: State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou; and.
authors.forename: Man-si
authors.initials: MS
authors.lastname: Wu
authors.affiliation: Department of Musculoskeletal Oncology, The First Affiliated Hospital of Sun Yat-Sen University;
authors.forename: Guohui
authors.initials: G
authors.lastname: Song
authors.affiliation: Department of Musculoskeletal Oncology, The First Affiliated Hospital of Sun Yat-Sen University;
authors.forename: Xian-biao
authors.initials: XB
authors.lastname: Xie
authors.affiliation: Department of Musculoskeletal Oncology, The First Affiliated Hospital of Sun Yat-Sen University;
authors.forename: Changye
authors.initials: C
authors.lastname: Zou
authors.affiliation: Department of Musculoskeletal Oncology, The First Affiliated Hospital of Sun Yat-Sen University;
authors.forename: Qinglian
authors.initials: Q
authors.lastname: Tang
authors.affiliation: State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou; and.
authors.forename: Yuanzhong
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Department of Musculoskeletal Oncology, The First Affiliated Hospital of Sun Yat-Sen University;
authors.forename: Jinchang
authors.initials: J
authors.lastname: Lu
authors.affiliation: Department of Musculoskeletal Oncology, The First Affiliated Hospital of Sun Yat-Sen University;
authors.forename: Yongqian
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Musculoskeletal Oncology, The First Affiliated Hospital of Sun Yat-Sen University;
authors.forename: Jin
authors.initials: J
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou; and.
authors.forename: Tiebang
authors.initials: T
authors.lastname: Kang
authors.affiliation: The Institute of Biology, Guizhou Academy of Sciences, Guiyang, China shenjingnan@126.com ytjq0629_cn@sina.com.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Jia
authors.affiliation: Department of Musculoskeletal Oncology, The First Affiliated Hospital of Sun Yat-Sen University; shenjingnan@126.com ytjq0629_cn@sina.com.
authors.forename: Jingnan
authors.initials: J
authors.lastname: Shen
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D001859:Bone Neoplasms / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D044948:Flavonols / Q000494:pharmacology*; D005455:Fluorescent Antibody Technique; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D051379:Mice; D008819:Mice, Nude; D012516:Osteosarcoma / Q000378:metabolism / Q000473:pathology*; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D044948:Flavonols; D048051:p38 Mitogen-Activated Protein Kinases; D055372:AMP-Activated Protein Kinases; C472036:dihydromyricetin