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

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.

[1]  J. Sicklick,et al.  NCCN Guidelines Insights: Soft Tissue Sarcoma, Version 1.2021. , 2020, Journal of the National Comprehensive Cancer Network : JNCCN.

[2]  E. Wagner,et al.  Wnt signaling and Loxl2 promote aggressive osteosarcoma , 2020, Cell Research.

[3]  P. Shang,et al.  Iron Promotes Dihydroartemisinin Cytotoxicity via ROS Production and Blockade of Autophagic Flux via Lysosomal Damage in Osteosarcoma , 2020, Frontiers in Pharmacology.

[4]  Xiaoyu Xia,et al.  Protective effect of dihydroartemisinin in inhibiting senescence of myeloid-derived suppressor cells from lupus mice via Nrf2/HO-1 pathway. , 2019, Free radical biology & medicine.

[5]  Long Wu,et al.  Dihydroartemisinin Inhibits Proliferation and Induces Apoptosis of Human Hepatocellular Carcinoma Cell by Upregulating Tumor Necrosis Factor via JNK/NF-κB Pathways , 2019, Evidence-based complementary and alternative medicine : eCAM.

[6]  Q. Ma,et al.  Dihydroartemisinin inhibits HepG2.2.15 proliferation by inducing cellular senescence and autophagy , 2019, BMB reports.

[7]  X. Deng,et al.  The interaction of LOXL2 with GATA6 induces VEGFA expression and angiogenesis in cholangiocarcinoma , 2019, International journal of oncology.

[8]  Qi Li,et al.  Dihydroartemisinin Regulates the Th/Treg Balance by Inducing Activated CD4+ T cell Apoptosis via Heme Oxygenase-1 Induction in Mouse Models of Inflammatory Bowel Disease , 2019, Molecules.

[9]  R. Weichselbaum,et al.  Immunostimulatory nanomedicines synergize with checkpoint blockade immunotherapy to eradicate colorectal tumors , 2019, Nature Communications.

[10]  Haiyan Zhang,et al.  Dihydroartemisinin induces apoptosis and inhibits proliferation, migration, and invasion in epithelial ovarian cancer via inhibition of the hedgehog signaling pathway , 2018, Cancer medicine.

[11]  Yihai Cao,et al.  Cancer Lipid Metabolism Confers Antiangiogenic Drug Resistance. , 2018, Cell metabolism.

[12]  J. An,et al.  Antimalarial Drugs as Immune Modulators: New Mechanisms for Old Drugs. , 2017, Annual review of medicine.

[13]  M. Golzio,et al.  Adipocyte Exosomes Promote Melanoma Aggressiveness through Fatty Acid Oxidation: A Novel Mechanism Linking Obesity and Cancer. , 2016, Cancer research.

[14]  P. Trackman.  Enzymatic and non-enzymatic functions of the lysyl oxidase family in bone. , 2016, Matrix biology : journal of the International Society for Matrix Biology.

[15]  D. Heymann,et al.  L-MTP-PE and zoledronic acid combination in osteosarcoma: preclinical evidence of positive therapeutic combination for clinical transfer. , 2016, American journal of cancer research.

[16]  S. Beloribi-Djefaflia,et al.  Lipid metabolic reprogramming in cancer cells , 2016, Oncogenesis.

[17]  A. Harris,et al.  Fatty acid uptake and lipid storage induced by HIF-1α contribute to cell growth and survival after hypoxia-reoxygenation. , 2014, Cell reports.

[18]  D. Adam,et al.  Lysyl oxidase-like-2 promotes tumour angiogenesis and is a potential therapeutic target in angiogenic tumours. , 2013, Carcinogenesis.

[19]  A. Harris,et al.  How cancer metabolism is tuned for proliferation and vulnerable to disruption , 2012, Nature.

[20]  D. Ingber,et al.  Forty-Year Journey of Angiogenesis Translational Research , 2011, Science Translational Medicine.

[21]  S. Germain,et al.  Lysyl oxidase-like protein-2 regulates sprouting angiogenesis and type IV collagen assembly in the endothelial basement membrane. , 2011, Blood.

[22]  D. Hanahan,et al.  Hallmarks of Cancer: The Next Generation , 2011, Cell.

[23]  Xianglin Shi,et al.  Interruption of the MEK/ERK signaling cascade promotes dihydroartemisinin-induced apoptosis in vitro and in vivo , 2011, Apoptosis.

[24]  R. Kong,et al.  Dihydroartemisinin inactivates NF-kappaB and potentiates the anti-tumor effect of gemcitabine on pancreatic cancer both in vitro and in vivo. , 2010, Cancer letters.

[25]  K. Eckardt,et al.  The Lysyl Oxidases LOX and LOXL2 Are Necessary and Sufficient to Repress E-cadherin in Hypoxia , 2009, The Journal of Biological Chemistry.

[26]  Qian Liu,et al.  Secreted LOXL2 is a novel therapeutic target that promotes gastric cancer metastasis via the Src/FAK pathway. , 2009, Carcinogenesis.

[27]  Yihai Cao,et al.  Improvement of antiangiogenic cancer therapy by understanding the mechanisms of angiogenic factor interplay and drug resistance. , 2009, Seminars in cancer biology.

[28]  Ji-hui Du,et al.  Artesunate induces oncosis-like cell death in vitro and has antitumor activity against pancreatic cancer xenografts in vivo , 2009, Cancer Chemotherapy and Pharmacology.

[29]  Hui Wang,et al.  Experimental Therapy of Hepatoma with Artemisinin and Its Derivatives: In vitro and In vivo Activity, Chemosensitization, and Mechanisms of Action , 2008, Clinical Cancer Research.

[30]  Narendra Singh,et al.  Anticancer properties of artemisinin derivatives and their targeted delivery by transferrin conjugation. , 2008, International journal of pharmaceutics.

[31]  S. Fong,et al.  Lysyl oxidase‐like 2 expression is increased in colon and esophageal tumors and associated with less differentiated colon tumors , 2007, Genes, chromosomes & cancer.

[32]  Rakesh K Jain,et al.  Antiangiogenic therapy for cancer: current and emerging concepts. , 2005, Oncology.

[33]  M. Neeman,et al.  Lysyl oxidase-related protein-1 promotes tumor fibrosis and tumor progression in vivo. , 2003, Cancer research.

[34]  G. Melillo,et al.  Role of the VEGF/VEGFR axis in cancer biology and therapy. , 2012, Advances in cancer research.

[35]  T. Chou,et al.  Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. , 1984, Advances in enzyme regulation.