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Changes in gene expression profiles of multiple myeloma cells induced by arsenic trioxide (ATO): possible mechanisms to explain ATO resistance in vivo
Author(s) -
Zhou Ping,
Kalakonda Nagesh,
Comenzo Raymond L.
Publication year - 2005
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/j.1365-2141.2005.05369.x
Subject(s) - arsenic trioxide , reactive oxygen species , apoptosis , in vivo , chemistry , cell culture , metallothionein , acetylcysteine , gene expression , microbiology and biotechnology , gene , biochemistry , antioxidant , biology , genetics
Summary Multiple myeloma (MM) is an incurable plasma cell malignancy marked by eventual resistance to therapy. Although arsenic trioxide (ATO) can induce apoptosis in MM cell lines, the in vivo activity of ATO in MM has been disappointing. The existence of ATO resistance mechanisms in MM can be inferred. We sought to generate hypotheses for ATO resistance by studying the gene expression profiles of MM cells that survived in culture with 0·5 μ mol/l ATO. Among the 31 genes whose quantitative levels of expression (QLE) significantly increased in ATO were haem oxygenase 1 ( HO‐1 ) and metallothionein‐2A ( MT‐2A ). Among the 56 genes whose QLE were significantly decreased were genes that modulate cell cycling [ BTBD2 and IGFBP7 ( mac25 )] and sensitivity to reactive oxygen species (ROS) ( BACH2 ). HO‐1 exerts an anti‐apoptotic effect in ischaemic cells, and MT‐2A chelates ATO intracellularly. Inhibition of HO‐1 with tin protoporphyrin enhances ROS in MM cells in ATO, and addition of N ‐acetylcysteine increases MT‐2A . Protective antioxidant responses occur in MM cells exposed to ATO, and may occur in stromal cells as well, and act to quench ROS and provide diffusible anti‐apoptotic factors. They may also involve cysteine‐rich proteins that chelate ATO and modulate redox‐sensitive residues on proteins, such as nuclear factor κ B and p53. A better understanding of ATO resistance will enable ATO to be combined with other agents for MM.