Correlates of imexon sensitivity in human multiple myeloma cell lines

Betty K. Samulitis, Terry H Landowski, Robert T Dorr

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Imexon (NSC-714597) is an aziridine-containing imminopyrolidone in Phase I clinical trials. The current studies compared biological indices of cytotoxicity in 7 human multiple myeloma (MM) cell lines to develop a correlative model for imexon sensitivity. In the MM cell lines there was a wide range of sensitivity to imexon measured by standard cytotoxicity assays (MTT) and by viability/apoptosis/necrosis (Annexin-V-FITC/PI) measurements. The following sensitivity pattern was observed in order of decreasing sensitivity: IM-9 > 8226/S > MM.1S, ARH-77, H929 > 8226/I > U266. The same descending rank order was seen for loss of mitochondrial membrane potential (MMP), generation of reactive oxygen species (ROS) and, at high drug concentrations, thiol depletion. Cell cycle analysis showed imexon sensitive cells accumulate at the G2/M interphase. Although there was a positive correlation between increasing CuZnSOD levels and imexon resistance, no relationship was found for catalase, Bcl-2, mitochondrial thioredoxin or MnSOD levels. These findings suggest consistent phenotypes for imexon sensitivity and resistance in human MM cell lines exposed to drug for 48 h, with a combination of apoptosis and necrosis. Resistance is correlated with CuZnSOD expression, reduced drug accumulation, lack of ROS generation and maintenance of MMP. Oxidation of cellular thiols occurs only at high (supra-cytotoxic) drug levels and is, therefore, weakly correlated with cytotoxicity. This unique mechanism involving oxidation and the previously reported absence of myelosuppression suggests that imexon may be rationally combined with existing cytotoxic agents to improve therapeutic activity in MM.

Original languageEnglish (US)
Pages (from-to)97-109
Number of pages13
JournalLeukemia and Lymphoma
Volume47
Issue number1
DOIs
StatePublished - Jan 2006

Fingerprint

Multiple Myeloma
Cell Line
Mitochondrial Membrane Potential
Sulfhydryl Compounds
Pharmaceutical Preparations
Reactive Oxygen Species
Necrosis
Apoptosis
Clinical Trials, Phase I
Thioredoxins
Fluorescein-5-isothiocyanate
Annexin A5
Interphase
Cytotoxins
4-imino-1,3-diazabicyclo(3.1.0)hexan-2-one
Catalase
Cell Cycle
Maintenance
Phenotype

Keywords

  • Apoptosis
  • Imexon
  • Multiple myeloma
  • Oxidative stress

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

Cite this

Correlates of imexon sensitivity in human multiple myeloma cell lines. / Samulitis, Betty K.; Landowski, Terry H; Dorr, Robert T.

In: Leukemia and Lymphoma, Vol. 47, No. 1, 01.2006, p. 97-109.

Research output: Contribution to journalArticle

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