Induction of apoptosis by arachidonic acid in chronic myeloid leukemia cells

Maria Teresa Rizzo, Ester Regazzi, Daniela Garau, Luke Akard, Michael Dugan, H. Scott Boswell, Vittorio Rizzoli, Carmelo Carlo-Stella

Research output: Contribution to journalArticle

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Abstract

The hallmark of chronic myeloid leukemia (CML) is the presence of the bcr-abl oncogene, which is associated with transforming ability and an intrinsic resistance to induction of apoptosis by genotoxic agents. Arachidonic acid (AA), a biologically active fatty acid, plays a crucial role as a mediator of signaling pathways involved in cell proliferation and survival. In this study, we investigated the potential role of AA as a proapoptotic agent in CML. Pretreatment of human CML isolated progenitor cells with AA (100 μM for 18 h) induced 71-75% inhibition of in vitro colony formation of granulocyte-macrophage colony-forming units, multilineage colony-forming units, and erythroid burst-forming units. This inhibition was significantly greater than the effect on normal progenitor cells (1939% growth inhibition of erythroid burst-forming units, multilineage colony- forming units, and granulocyte-macrophage colony-forming units). AA also inhibited growth of the bcr-abl-transformed cell line H7.bcr-abl A54. In contrast, a minimal effect of AA on inhibition of cell growth was observed in the parental nontransformed NSF/N1.H7 cell line. The antiproliferative effect of AA was associated with apoptosis. γ-Linolenic acid, a precursor of AA, also inhibited cell growth, whereas other unsaturated and saturated fatty acids had no effect. Pharmacological inhibition of cyclooxygenase, lipooxygenase, and cytochrome P450 monooxygenase enzymes prior to exposure to AA did not rescue cells from the inhibitory effect of AA. Moreover, 5,8,11,14-eicosatetraynoic acid, a nonmetabolizable arachidonate analogue, also inhibited cell growth, suggesting that the effect of AA did not require further metabolism. Treatment with antioxidants prior to stimulation with AA was also ineffective in preventing its antiproliferative effect. Thus, AA inhibited proliferation of CML cells by inducing apoptotic cell death. The signaling mechanisms of AA-induced inhibition of cell growth appeared to be independent of its conversion into eicosanoids or free radical generation.

Original languageEnglish (US)
Pages (from-to)5047-5053
Number of pages7
JournalCancer Research
Volume59
Issue number19
StatePublished - Oct 1 1999

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Myeloid Cells
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Arachidonic Acid
Apoptosis
Stem Cells
Growth
Granulocyte-Macrophage Progenitor Cells
Erythroid Precursor Cells
Cytochrome P-450 Enzyme System
Fatty Acids
5,8,11,14-Eicosatetraynoic Acid
abl Genes
Transformed Cell Line
alpha-Linolenic Acid
Eicosanoids
Prostaglandin-Endoperoxide Synthases
Mixed Function Oxygenases
Unsaturated Fatty Acids
Free Radicals
Cell Survival

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Rizzo, M. T., Regazzi, E., Garau, D., Akard, L., Dugan, M., Boswell, H. S., ... Carlo-Stella, C. (1999). Induction of apoptosis by arachidonic acid in chronic myeloid leukemia cells. Cancer Research, 59(19), 5047-5053.

Induction of apoptosis by arachidonic acid in chronic myeloid leukemia cells. / Rizzo, Maria Teresa; Regazzi, Ester; Garau, Daniela; Akard, Luke; Dugan, Michael; Boswell, H. Scott; Rizzoli, Vittorio; Carlo-Stella, Carmelo.

In: Cancer Research, Vol. 59, No. 19, 01.10.1999, p. 5047-5053.

Research output: Contribution to journalArticle

Rizzo, MT, Regazzi, E, Garau, D, Akard, L, Dugan, M, Boswell, HS, Rizzoli, V & Carlo-Stella, C 1999, 'Induction of apoptosis by arachidonic acid in chronic myeloid leukemia cells', Cancer Research, vol. 59, no. 19, pp. 5047-5053.
Rizzo MT, Regazzi E, Garau D, Akard L, Dugan M, Boswell HS et al. Induction of apoptosis by arachidonic acid in chronic myeloid leukemia cells. Cancer Research. 1999 Oct 1;59(19):5047-5053.
Rizzo, Maria Teresa ; Regazzi, Ester ; Garau, Daniela ; Akard, Luke ; Dugan, Michael ; Boswell, H. Scott ; Rizzoli, Vittorio ; Carlo-Stella, Carmelo. / Induction of apoptosis by arachidonic acid in chronic myeloid leukemia cells. In: Cancer Research. 1999 ; Vol. 59, No. 19. pp. 5047-5053.
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