Kyle McCall

Introduction. Osteosarcoma is a cancer of bone-forming mesenchymal cells^1,3. It is the most common malignant bone tumor with approximately 900 cases diagnosed annually in the United States.^1,2 The cure rate for osteosarcoma has stagnated over the past 30 years and new therapy options are needed.^2,4 Vascular endothelial growth factor receptor-2 (VEGFR2) is a tyrosine kinase that influences angiogenesis. VEGFR2 expression has been detected in osteosarcoma and is associated with poor overall survival.^4,5,6 Anti-angiogenesis therapy has demonstrated promising anti-tumor effects in other cancers; therefore, inhibition of the VEGFR2 pathway is a potential therapeutic target in the treatment of osteosarcoma.⁶ Apatinib is a highly selective inhibitor of VEGFR2 currently being investigated as a potential treatment option.⁴   Methods. The mRNA and protein levels of VEGFR2 were examined in five osteosarcoma cell lines, including the KHOS and MG63 cell lines.⁴ The KHOS and MG63 cell lines were cultured in five concentrations of Apatinib for 24, 48, and 72 hours to determine the effect of Apatinib on osteosarcoma cell growth.⁴ To further evaluate the role of Apatinib in osteosarcoma cells, cells stained with Annexin V-FITC and propidium iodide were analyzed via flow cytometry to detect apoptosis.⁴ To determine the ability of Apatinib to induce autophagy in osteosarcoma cells, transmission electron microscopy (TEM) and Western blot were used to assess Apatinib-treated cell samples for autophagic vacuoles and LC3-II protein expression, respectively.⁴ Lastly, xenograft-derived osteosarcoma tumors were implanted to immunodeficient mice. The mice were then treated with Apatinib to assess its effects in vivo.⁴  Results. The KHOS and MG63 osteosarcoma cell lines showed the highest VEGFR2 expression out of the five cell lines tested.⁴ The growth of KHOS and MG63 cells was suppressed by Apatinib in both a time- and dose-dependent manner.⁴ Following treatment with Apatinib, Western blot analysis showed a significant increase in cleaved Poly(ADP-ribose) polymerase (PARP), a key indicator of apoptosis.⁴ TEM analysis of Apatinib-treated cells revealed the presence of more autophagosomes compared with the control group.⁴ Additionally, Apatinib-treated cells were found to have higher levels of LC3-II expression—a biomarker of autophagy—than the control cells.⁴ Apatinib significantly inhibited tumor volume in vivo.⁴  Conclusions. Apatinib, a highly selective VEGFR2 inhibitor, has a promising antitumoral effect. These studies show the ability of Apatinib to inhibit the growth of osteosarcoma cells in vitro and in vivo through cell cycle arrest, apoptosis, and autophagy.⁴ In summary, Apatinib has promising anti-osteosarcoma effects and warrants further investigation to determine the potential of Apatinib as a treatment for osteosarcoma.

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4. Liu K, Ren T, Huang Y, et al. Apatinib promotes autophagy and apoptosis through VEGFR2/STAT3/BCL-2 signaling in osteosarcoma. Cell Death Dis. 2017;8(8):e3015. Published 2017 Aug 24. doi:10.1038/cddis.2017.422
5. Zheng B, Zhou C, Qu G, et al. VEGFR2 Promotes Metastasis and PD-L2 Expression of Human Osteosarcoma Cells by Activating the STAT3 and RhoA-ROCK-LIMK2 Pathways. Front Oncol. 2020;10:543562. Published 2020 Sep 9. doi:10.3389/fonc.2020.543562
6. Zheng B, Ren T, Huang Y, Guo W. Apatinib inhibits migration and invasion as well as PD-L1 expression in osteosarcoma by targeting STAT3. Biochem Biophys Res Commun. 2018;495(2):1695-1701. doi:10.1016/j.bbrc.2017.12.032