Arsenic trioxide inhibits the proliferation of myeloma cell line through notch signaling pathway

Jiasheng Hu,Xiongpeng Zhu,Xiao Huang,Xiuli Hong,Quanyi Lu

doi:10.1186/1475-2867-13-25

Jiasheng Hu, Xiongpeng Zhu + Show 3 more

Open Access

https://doi.org/10.1186/1475-2867-13-25

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Abstract

Arsenic Trioxide (ATO) has shown remarkable efficacy for the treatment of multiple myeloma (MM). However, the mechanism by which ATO exerts its inhibitory effect on the proliferation of myeloma cells remains to be clarified. We study the inhibitory effect of ATO at various concentrations on the proliferation of the myeloma cell line RPMI 8226 and discussed the molecular mechanism of ATO on myeloma cell line. Our results proved that ATO had a significant dose-dependent and time-dependent inhibitory effect on the expressions of the Notch receptor (Notch1) and Notch ligand (Jag2). Data from the real-time PCR assay showed that the mRNA expression levels of the Jag2 gene and its downstream gene Hes1 were both significantly down-regulated after the myeloma cells were treated with ATO while the expression of the tumor suppressor gene PTEN was up-regulated. These results elucidated the molecular mechanism underlying the ATO mediated inhibition of myeloma cell proliferation. This is the first report on the anti-myeloma activity in myeloma cells through inhibition of the Notch signaling pathway.

Highlights

Multiple myeloma (MM) is a hematologic malignancy that results from clonal proliferation of plasma cells in the bone marrow
Arsenic Trioxide (ATO) inhibits Notch signaling levels in RPMI 8226 cells To investigate whether a decrease in notch signaling level could be achieved by ATO treatment in the myeloma cells, RPMI 8226 cells was treated with ATO at various concentrations, the results showed a gradual decrease in the expression of Notch1 and Jag2 proteins after 48 h of incubation
Our results indicated that down regulation of Notch signal may be one of molecular mechanism and ATO emerged as a promising class of anticancer drugs in myeloma

Summary

Introduction

Multiple myeloma (MM) is a hematologic malignancy that results from clonal proliferation of plasma cells in the bone marrow. Arsenic Trioxide (ATO) has been demonstrated the efficacy and safety treatment for acute promyelocytic leukemia (APL), Preclinical in vitro and in vivo studies showed that ATO has antimyeloma effects both as a single agent and in combination with other antimyeloma agents [6,7,8,9], in patients with relapsed MM refractory, ATO combination therapies with melphalan, thalidomide, and bortezomib have shown promising results [10,11]. Notch signaling influences multiple processes that govern normal morphogenesis, apoptosis, and cellular proliferation. This signaling is initiated by binding of a Notch ligand to the extracellular domain of the Notch receptor. Inhibition of Notch expression by antisense retrovirus or pharmacologic block of γ-secretase activity has a marked antineoplastic effect in Notch-expressing transformed cells in vitro and in xenograft models [19,20]

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