Proteasome inhibitors induce growth inhibition and apoptosis in myeloma cell lines and in human bone marrow myeloma cells irrespective of chromosome 13 deletion.

Abstract

PURPOSE:

In this study, we investigated the effects of cell-permeable proteasome inhibitors MG-132, MG-262, PSI, and lactacystin on multiple myeloma cell lines OPM-2, U266, RPMI 8226-S, freshly isolated plasma cells with or without deletion of chromosome 13 from patients with multiple myeloma and plasma cell leukemia, and CD34+ human hematopoietic stem cells. The effects of proteasome inhibitors on cell cycle progression, cell growth, and apoptosis were determined.

METHODS:

MTT-assay was used to examine the cytotoxicity, and annexin-V staining to quantify apoptosis. Cell cycle analyses were performed using 7-ADD and Ki-67 staining by flow cytometry.

RESULTS:

PSI was the most potent proteasome inhibitor among those tested with a half maximal cytotoxicity (IC(50)) of 5.7 nM, followed by MG-262, MG-132, and lactacystin. Growth inhibition occurred irrespective of chromosome 13 status. Cell cycle arrest occurred in a dose- and time-dependent manner. Low, subapoptotic dosages led to a partial loss of Ki-67 antigen, whereas apoptotic dosages led to reduced Ki-67 levels. Apoptosis was partially dependent on activation of caspase-3, since Ac-DEVD-cho, a caspase-3 inhibitor, could reduce apoptosis significantly. The cytotoxicity of the four proteasome inhibitors tested was significantly lower in human hematopoietic stem cells than in myeloma cells.

CONCLUSIONS:

Our results show that proteasome inhibitors induce time- and dose-dependent cell cycle alterations, growth inhibition, and apoptosis in human myeloma cells irrespective of chromosome 13 deletion.

• Authors: Ivana Zavrski, Cord Naujokat, Kathrin Niemöller, Christian Jakob, Ulrike Heider, Corinna Langelotz, Claudia Fleissner, Jan Eucker, Kurt Possinger, Orhan Sezer
• Journal: Journal of cancer research and clinical oncology (J Cancer Res Clin Oncol) Vol. 129 Issue 7 Pg. 383-91 (Jul 2003) ISSN: 0171-5216 [Print] Germany
• PMID: 12851815 (Publication Type: Journal Article)

Chemical References

• Antigens, CD34
• Multienzyme Complexes
• CASP3 protein, human
• CASP7 protein, human
• Caspase 3
• Caspase 7
• Caspases
• Cysteine Endopeptidases
• Proteasome Endopeptidase Complex

Topics

• Antigens, CD34 (metabolism)
• Apoptosis (drug effects)
• Caspase 3
• Caspase 7
• Caspases (metabolism)
• Cell Cycle (drug effects)
• Cell Division (drug effects)
• Chromosome Deletion
• Chromosomes, Human, Pair 13 (physiology)
• Cysteine Endopeptidases
• Hematopoietic Stem Cells (drug effects, metabolism)
• Humans
• Multienzyme Complexes (antagonists & inhibitors)
• Multiple Myeloma (enzymology, genetics, pathology)
• Proteasome Endopeptidase Complex
• Tumor Cells, Cultured