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Research ArticleCHEMOTHERAPY, ANTIBIOTICS, AND GENE THERAPY

Intrinsic Cytotoxicity and Chemomodulatory Actions of Novel Phenethylisothiocyanate Sphingoid Base Derivatives in HL-60 Human Promyelocytic Leukemia Cells

Charlene R. Johnson, Jiong Chun, Robert Bittman and W. David Jarvis
Journal of Pharmacology and Experimental Therapeutics May 2004, 309 (2) 452-461; DOI: https://doi.org/10.1124/jpet.103.060665
Charlene R. Johnson
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Jiong Chun
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Robert Bittman
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W. David Jarvis
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Abstract

The protein kinase C (PKC) isoenzyme superfamily represents a popular target in pharmacological interventions designed to elicit apoptosis directly in tumor cells or to potentiate the lethal effects of antineoplastic agents. Numerous observations support the clinical utility of PKC inhibition by experimental sphingolipid derivatives such as safingol. The present studies document the cytotoxicity and chemomodulatory capacity of phenethylisothiocyanate derivatives of sphinganine and sphingosine (PEITC-Sa and PEITC-So) in the human myeloid leukemia cell line HL-60. The biological actions of these novel derivatives were compared directly with those of the parent compounds sphinganine and sphingosine. Exposure to natural and modified sphingoid bases promoted extensive apoptotic cell death. The PEITC-sphingoid base derivatives exhibited higher cytotoxicity than their natural counterparts and were also distinctly superior to the clinically relevant sphingoid base analog safingol. In each instance, lethality was shown to correlate with inhibition of conventional and novel PKC isoforms and downstream loss of extracellular signal-regulated kinase (ERK)1/ERK2. The involvement of these signaling systems in potentiating the lethal actions of 1-(β-d-arabinofuranosyl)cytosine (araC) was also examined with regard to the differential actions of PEITC-Sa and PEITC-So to that of the parent compounds as well as safingol. Exposure to araC alone rapidly increased PKC activity. In the presence of PEITC-Sa or PEITC-So, the therapeutic efficacy of araC increased markedly; moreover, potentiation was directly related to the loss of araC-stimulated PKC activity. These findings demonstrate that PEITC-substituted sphingoid base analogs exert potent antineoplastic effects in human leukemia cells. We suggest that these synthetic lipids represent potentially useful agents in the development of conventional PKC/novel PKC-directed chemotherapeutic strategies.

Footnotes

  • ABBREVIATIONS: cPKC, conventional protein kinase C; nPKC, novel protein kinase C; araC, 1-(β-d-arabinofuranosyl)cytosine (cytarabine); MAPK, mitogen-activated protein kinase; ERK, extracellular signal-regulated kinase; PEITC-Sa, phenethylisothiocyanate-substituted sphinganine; PEITC-So, phenethylisothiocyanate-substituted sphingosine; PBS, phosphate-buffered saline; MDR, multidrug resistance; MEK, mitogen-activated protein kinase kinase; U0124, 1,4-diamino-2,3-dicyano-1,4-bis-[phenylthio]butadiene; U0125, 1,4-diamino-2,3-dicyano-1,4-bis-[methylthio]butadiene; U0126, 1,4-diamino-2,3-dicyano-1,4-bis-[aminophenylthio]butadiene.

  • This work was supported primarily through research grants CA-082404 from National Cancer Institute (to W.D.J.) and HL-16660 from National Heart, Lung, and Blood Institute (to R.B.).

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

  • DOI: 10.1124/jpet.103.060665.

    • Received September 30, 2003.
    • Accepted December 31, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 309 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 309, Issue 2
1 May 2004
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Research ArticleCHEMOTHERAPY, ANTIBIOTICS, AND GENE THERAPY

Intrinsic Cytotoxicity and Chemomodulatory Actions of Novel Phenethylisothiocyanate Sphingoid Base Derivatives in HL-60 Human Promyelocytic Leukemia Cells

Charlene R. Johnson, Jiong Chun, Robert Bittman and W. David Jarvis
Journal of Pharmacology and Experimental Therapeutics May 1, 2004, 309 (2) 452-461; DOI: https://doi.org/10.1124/jpet.103.060665

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Research ArticleCHEMOTHERAPY, ANTIBIOTICS, AND GENE THERAPY

Intrinsic Cytotoxicity and Chemomodulatory Actions of Novel Phenethylisothiocyanate Sphingoid Base Derivatives in HL-60 Human Promyelocytic Leukemia Cells

Charlene R. Johnson, Jiong Chun, Robert Bittman and W. David Jarvis
Journal of Pharmacology and Experimental Therapeutics May 1, 2004, 309 (2) 452-461; DOI: https://doi.org/10.1124/jpet.103.060665
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