• AMG232 Inhibits Angiogenesis in Multiple Myeloma Cells via Downregulation of VEGF/VEGFR2 Expression and Suppressing Migration in HUVECs
  • Zahra Pooraskari,1,* Minoo Shahidi,2
    1. Student Research Committee, Department of Hematology and Blood Banking, Faculty of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran.
    2. Department of Hematology and Blood Banking, Faculty of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran.


  • Introduction: Angiogenesis markedly affects the progression and severity of multiple myeloma (MM), a malignant clonal tumor of plasma cells, representing approximately 18% of all hematologic malignancies. Despite advancements in treatments, MM remains incurable, and the identification of new targets, more specifically, the development of new anti-angiogenic drugs, is warranted. AMG232 is the most effective piperidinone inhibitor of the MDM2-p53 interaction and is currently in clinical studies for cancer prevention and the treatment of solid tumors and MM. Nonetheless, the capacity of AMG232 to modulate the angiogenesis of MM has not been shown. This in vitro study aims to assess the impact of AMG232 on cocultured HUVECs (Human umbilical vein endothelial cells) and AMO-1(Human myeloma cell line) cells via blocking the MDM2–p53 interaction. Inhibiting the malignant development of plasma cells may be a potential approach to treating MM angiogenesis.
  • Methods: HUVECs and AMO-1 cells were cocultured for about 24 hours. Following subjecting both cell types to varying dosages of AMG232, the MTT assay was used to evaluate cell viability. After 48 hours of treatment with 250nM of AMG232, VEGF and VEGFR2 mRNA levels were evaluated with quantitative real-time PCR from the HUVECs and AMO-1. A wound healing experiment was also undertaken to determine the impacts on cell migration. At 0, 24, and 48 h, wound closure was recorded by an inverted microscope. All data were presented as mean ± standard deviation (SD). The student t-test evaluated the comparison between two groups, while 2-way ANOVA was employed to examine several groups. A P-value of less than 0.05 was deemed statistically significant.
  • Results: AMG232 was evaluated for its effect on AMO-1 and HUVEC cells in cocultured conditions. Based on its IC50 dose, our investigation found that 250 nM is the effective dose for AMG232 therapy. AMG232 at concentrations of 250 nM significantly decreased VEGF and VEGFR2 mRNA expression in HUVECs and AMO-1 cells relative to the control group (P < 0.05). Furthermore, scratch wound healing assays demonstrated a suppression of HUVEC cell proliferation and migration, together with diminished wound closure rates at 24 and 48 hours in comparison to the controls (P < 0.01). Taken together, the results of this study demonstrate that AMG232 inhibits the accelerated angiogenesis of HUVECs.
  • Conclusion: Our research indicated that AMG232 successfully suppressed angiogenesis and adversely affected MM cells by downregulating essential angiogenic factors. The findings suggest that AMG232 possesses significant potential as an adjunct therapy for the treatment of multiple myeloma through the targeting of angiogenesis. Considering these encouraging findings, subsequent research should examine the combination of AMG232 with chemotherapeutic agents like lenalidomide, alongside other compounds aimed at p53-mutated neoplasms, to assess potential synergistic effects and strategies to mitigate resistance linked to extended MDM2 inhibitor treatment.
  • Keywords: AMG232, VEGF, VEGFR2, Multiple myeloma, Angiogenesis