Rosiglitazone suppresses angiogenesis in multiple myeloma via downregulation of hypoxia-inducible factor-1α and insulin-like growth factor-1 mRNA expression

Abstract

Rosiglitazone (RGZ) is a thiazolidinedione ligand of peroxisome proliferator-activated receptor-γ. Our previous studies have confirmed that RGZ possesses antitumoral properties. Bone marrow angiogenesis exhibits an important role in multiple myeloma (MM), and angiogenesis often correlates with the prognosis and disease burden of MM. However, to the best of our knowledge, inhibition of angiopoiesis by RGZ in MM has not yet been reported. The present study aimed to investigate whether RGZ prevents angiogenesis and the possible underlying mechanism of this effect in MM. RPMI‑8226 cells, primary myeloma cells from patients with MM or mononuclear cells from healthy patients were treated with different concentrations of RGZ, and various biological responses were detected using MTT, reverse transcription-polymerase chain reaction and western blot assays. The expression levels of hypoxia-inducible transcription factor‑1α (HIF1α) and insulin-like growth factor‑1 (IGF1) were significantly increased in the RPMI-8226 cells and the primary myeloma cells from the patients with MM compared with those in the mononuclear cells from the healthy patients. The results also showed that RGZ was able to inhibit proliferation and reduce viability of RPMI-8226 cells in a concentration-and time-dependent manner. RGZ was able to concentration‑dependently inhibit the expression of HIF1α and IGF1 mRNA in RPMI-8226 and primary myeloma cells from patients with MM. RGZ also inhibited the expression of pAKT and downregulated the expression levels of phosphorylated extracellular signal-regulated kinase (ERK) in RPMI-8226 cells. The results suggested that RGZ inhibits the angiopoiesis of tumors by interfering with the phosphatidylinositol 3-kinase/AKT and ERK signaling pathways.

Silybin suppresses cell proliferation and induces apoptosis of multiple myeloma cells via the PI3K/Akt/mTOR signaling pathway

“…Following phosphorylative activation of p70S6K, protein synthesis is enhanced. Therefore, PI3K/Akt/mTOR is considered to be the main signal-regulating pathway of protein synthesis and is involved in the regulation of cell proliferation, differentiation and migration (11). Of note, in the present study, inhibition of PI3K enhanced the potency of silybin to reduce cell proliferation and induce apoptosis, and reduced the protein levels of p-mTOR in U266 cells.…”

“…MM is a neoplastic condition featuring malignant plasma cells, whose main clinical manifestations include hypergammaglobulinemia, renal insufficiency, bone damage and pancytopenia (11). In spite of MM currently being considered to be incurable, significant progress has recently been made in clinical treatments, including the application of thalidomide, proteasome inhibitors and bone marrow transplantation, which, however, has not significantly increased the survival of MM patients (12,13).…”

PPAR-γ Modulators as Current and Potential Cancer Treatments

“…Basic fibroblast growth factor (bFGF) and VEGF, two mitogenic cytokines, are highly responsible for endothelial cell growth and differentiation, hence angiogenesis. In a non-tumor model, ROSI has been reported to inhibit the activities of those two factors; in myeloma cell line, ROSI inhibits insulin-like growth factor 1 (IGF-1) or HIF-1α, which could boost VEGF’s pro-angiogenesis effects, via PI3K/AKT and ERK signaling in a PPAR-γ-dependent fashion ( 105 , 106 ).…”

Signaling Interplay between Bone Marrow Adipose Tissue and Multiple Myeloma cells

“…Recent data have also found that the PPARγ agonist pioglitazone (PIO) enhances the cytotoxic effect of the histone deacetylase inhibitor (HDACi) and valproic acid (VPA) on MM cells, in vitro and in vivo , suggesting that agonizing PPARγ while inhibiting HDACs could decrease MM growth ( 83 ). Similarly, the PPARγ agonist rosiglitazone (RGZ) suppressed the expression of angiogenic factors in MM cells (HIF-1α and IGF-1) and inhibited proliferation and reduced viability of RPMI-8226 cells in a concentration- and time-dependent manner ( 84 ). RGZ also inhibited the expression of pAKT and downregulated the expression levels of phosphorylated extracellular signal-regulated kinase (pERK) in MM cells ( 84 ).…”

“…Similarly, the PPARγ agonist rosiglitazone (RGZ) suppressed the expression of angiogenic factors in MM cells (HIF-1α and IGF-1) and inhibited proliferation and reduced viability of RPMI-8226 cells in a concentration- and time-dependent manner ( 84 ). RGZ also inhibited the expression of pAKT and downregulated the expression levels of phosphorylated extracellular signal-regulated kinase (pERK) in MM cells ( 84 ). However, PPARγ has a strong osteoclastogenic effect that would likely worsen osteolysis for MM patients, highlighting a downside of using RGZ in MM.…”