The generality of methylglyoxal bis(guanylhydrazone)-induced mitochondrial damage and the dependence of this effect on cell proliferation

F. Mikles-Robertson, Burt G.F. Feuerstein, C. Dave, C. W. Porter

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Abstract

Methylglyoxal bis(guanylhydrazone) (MGBG) is a clinically useful antileukemic agent which has been found to produce selective ultrastructural damage to the mitochondria of L1210 cells. In this report, the generality of this phenomenon has been tested in several human and murine cell types including P288 mouse leukemia, L-cell mouse fibroblast, C3H/19T 1/2 mouse embryo fibroblast, and NALM-1 human chronic myelocytic leukemia cells. In all cases, MGBG produced ultrastructural damage nearly identical to that seen in L1210 cells. Mitochondria were markedly distended, and their inner structure was distorted or lost. In the NALM-1 cells, conspicuous electron-dense granules were present in the mitochondrial matrix. Interestingly, the onset of mitochondrial damage in these cell lines correlated with the general time of the particular cell lines, suggesting a relationship between proliferative activity and drug-induced damage. This relationship between mitochondrial damage and cell proliferation was tested in two separate cell systems. In cultures of human lymphocytes stimulated with phytohemagglutinin, only those cells undergoing blastogenesis were found to be affected by MGBG. Similarly, MGBG treatment of confluent and subconfluent cultures of C3H/10T 1/2 mouse embryo fibroblasts affected only the dividing subconfluent cells. In this particular cell type, the mitochondrial damage was observed in unfixed cells at the light microscopic level, establishing that the damage was not related to preparative tehniques for electron microscopy. Results from both cell systems confirm that the drug-induced damage, or its expression, is dependent on cell-proliferative activity. The possibility exists that the mitochondrial damage may be responsible for the antiproliferative activity of the drug including host toxicities or may be related to the known ability of the drug to interfere with the biosynthesis of polyamines.

Original languageEnglish (US)
Pages (from-to)1919-1926
Number of pages8
JournalCancer Research
Volume39
Issue number6 I
StatePublished - 1979
Externally publishedYes

Fingerprint

Mitoguazone
Cell Proliferation
Fibroblasts
Pharmaceutical Preparations
Mitochondria
Embryonic Structures
Cell Line
Inbred C3H Mouse
Polyamines
Phytohemagglutinins
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Lymphocyte Activation

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

The generality of methylglyoxal bis(guanylhydrazone)-induced mitochondrial damage and the dependence of this effect on cell proliferation. / Mikles-Robertson, F.; Feuerstein, Burt G.F.; Dave, C.; Porter, C. W.

In: Cancer Research, Vol. 39, No. 6 I, 1979, p. 1919-1926.

Research output: Contribution to journalArticle

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abstract = "Methylglyoxal bis(guanylhydrazone) (MGBG) is a clinically useful antileukemic agent which has been found to produce selective ultrastructural damage to the mitochondria of L1210 cells. In this report, the generality of this phenomenon has been tested in several human and murine cell types including P288 mouse leukemia, L-cell mouse fibroblast, C3H/19T 1/2 mouse embryo fibroblast, and NALM-1 human chronic myelocytic leukemia cells. In all cases, MGBG produced ultrastructural damage nearly identical to that seen in L1210 cells. Mitochondria were markedly distended, and their inner structure was distorted or lost. In the NALM-1 cells, conspicuous electron-dense granules were present in the mitochondrial matrix. Interestingly, the onset of mitochondrial damage in these cell lines correlated with the general time of the particular cell lines, suggesting a relationship between proliferative activity and drug-induced damage. This relationship between mitochondrial damage and cell proliferation was tested in two separate cell systems. In cultures of human lymphocytes stimulated with phytohemagglutinin, only those cells undergoing blastogenesis were found to be affected by MGBG. Similarly, MGBG treatment of confluent and subconfluent cultures of C3H/10T 1/2 mouse embryo fibroblasts affected only the dividing subconfluent cells. In this particular cell type, the mitochondrial damage was observed in unfixed cells at the light microscopic level, establishing that the damage was not related to preparative tehniques for electron microscopy. Results from both cell systems confirm that the drug-induced damage, or its expression, is dependent on cell-proliferative activity. The possibility exists that the mitochondrial damage may be responsible for the antiproliferative activity of the drug including host toxicities or may be related to the known ability of the drug to interfere with the biosynthesis of polyamines.",
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