Dihydroartemisinin Potentiates VEGFR-TKIs Antitumorigenic Effect on Osteosarcoma by Regulating Loxl2/VEGFA Expression and Lipid Metabolism Pathway

Ding, Xiaomin; Zhang, YaWen; Liang, Jinrong; Li, Qian; Hu, Haiyan; Zhou, Yan; Zhang, Bing

doi:10.7150/jca.81623

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International Journal of Medical Sciences

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Journal of Genomics

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J Cancer 2023; 14(5):809-820. doi:10.7150/jca.81623 This issue Cite

Research Paper

Dihydroartemisinin Potentiates VEGFR-TKIs Antitumorigenic Effect on Osteosarcoma by Regulating Loxl2/VEGFA Expression and Lipid Metabolism Pathway

Xiaomin Ding^#1,2, YaWen Zhang^#2, Jinrong Liang², Qian Li², Haiyan Hu², Yan Zhou^2✉, Bing Zhang^1✉

1. Orthopaedic Department of the Affiliated Hospital of Jiangxi University of Traditional Chinese Medicine, Nanchang, 330006, China
2. Department of Oncology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China.
#Equal contribution

Citation:

Ding X, Zhang Y, Liang J, Li Q, Hu H, Zhou Y, Zhang B. Dihydroartemisinin Potentiates VEGFR-TKIs Antitumorigenic Effect on Osteosarcoma by Regulating Loxl2/VEGFA Expression and Lipid Metabolism Pathway. J Cancer 2023; 14(5):809-820. doi:10.7150/jca.81623. https://www.jcancer.org/v14p0809.htm

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Abstract

Anti-angiogenesis therapy has shown significant anti-tumor effects against a variety of cancers. But resistance to antiangiogenic drugs, intrinsic and evasive, is frequently found in patients during treatment. Here, we report that dihydroartemisinin (DHA), a derivative of the Chinese medicine artemisinin, enhances antiangiogenic drug-induced cytotoxicity in osteosarcoma (OS) cells. Proteomics analysis revealed that DHA treatment significantly affected the activity of the collagen-modifying enzyme lysyl oxidase-like 2 (LOXL2), a regulatory gene associated with poor prognosis of OS. Furthermore, we found that DHA reduced the expression of vascular endothelial growth factor (VEGFA) by downregulating LOXL2. This mechanism was confirmed by QRT-PCR, western blot, and ELISA assays. Correspondingly, vector-enforced expression of LOXL2 markedly reduced VEGFA secretion. Untargeted metabolomic analysis revealed that the lipid metabolism that confers antiangiogenic drug resistance, was also interfered with by DHA. Thus, DHA not only exerts antitumor effects in OS cells directly but also synergizes with the antiangiogenic drug by regulating vascular endothelial growth factor A (VEGFA) expression and lipid metabolism.

Keywords: Dihydroartemisinin, antiangiogenic drug, synergy, drug-resistance, LOXL2

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APA

Ding, X., Zhang, Y., Liang, J., Li, Q., Hu, H., Zhou, Y., Zhang, B. (2023). Dihydroartemisinin Potentiates VEGFR-TKIs Antitumorigenic Effect on Osteosarcoma by Regulating Loxl2/VEGFA Expression and Lipid Metabolism Pathway. Journal of Cancer, 14(5), 809-820. https://doi.org/10.7150/jca.81623.

ACS

Ding, X.; Zhang, Y.; Liang, J.; Li, Q.; Hu, H.; Zhou, Y.; Zhang, B. Dihydroartemisinin Potentiates VEGFR-TKIs Antitumorigenic Effect on Osteosarcoma by Regulating Loxl2/VEGFA Expression and Lipid Metabolism Pathway. J. Cancer 2023, 14 (5), 809-820. DOI: 10.7150/jca.81623.

NLM

CSE

Ding X, Zhang Y, Liang J, Li Q, Hu H, Zhou Y, Zhang B. 2023. Dihydroartemisinin Potentiates VEGFR-TKIs Antitumorigenic Effect on Osteosarcoma by Regulating Loxl2/VEGFA Expression and Lipid Metabolism Pathway. J Cancer. 14(5):809-820.

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