Changes in gene expression profiles of multiple myeloma cells induced by arsenic trioxide (ATO): Possible mechanisms to explain ATO resistance in vivo Journal Article
| Authors: | Zhou, P.; Kalakonda, N.; Comenzo, R. L. |
| Article Title: | Changes in gene expression profiles of multiple myeloma cells induced by arsenic trioxide (ATO): Possible mechanisms to explain ATO resistance in vivo |
| Abstract: | 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 μmol/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 κB and p53. A better understanding of ATO resistance will enable ATO to be combined with other agents for MM. © 2005 Blackwell Publishing Ltd. |
| Keywords: | controlled study; protein expression; human cell; antineoplastic agents; cell cycle; apoptosis; multiple myeloma; gene expression; drug resistance, neoplasm; cell line, tumor; arsenic trioxide; arsenicals; oxides; gene expression regulation, neoplastic; cell culture; reverse transcriptase polymerase chain reaction; quantitative analysis; immunoblotting; reactive oxygen species; heme oxygenase 1; reactive oxygen metabolite; dna fingerprinting; stroma cell; superoxides; oxidation reduction reaction; myeloma; myeloma cell; arsenic; metallothionein i |
| Journal Title: | British Journal of Haematology |
| Volume: | 128 |
| Issue: | 5 |
| ISSN: | 0007-1048 |
| Publisher: | John Wiley & Sons |
| Date Published: | 2005-03-01 |
| Start Page: | 636 |
| End Page: | 644 |
| Language: | English |
| DOI: | 10.1111/j.1365-2141.2005.05369.x |
| PUBMED: | 15725085 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 24" - "Export Date: 24 October 2012" - "CODEN: BJHEA" - "Source: Scopus" |
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