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CHEMOTHERAPY, ANTIBIOTICS, AND GENE THERAPY

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

Department of Integrative Biology and Pharmacology (C.R.J., W.D.J.) and the Institute for Molecular Medicine (W.D.J.), University of Texas Health Sciences Center, Houston, Texas; Research and Development Division (C.R.J., W.D.J.), Dominion Diagnostics, Inc., North Kingstown, Rhode Island; and Department of Chemistry and Biochemistry (J.C., R.B.), Queens College of the City University of New York, Flushing, New York

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-(-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.

Address correspondence to: Dr. W. David Jarvis, Dominion Diagnostics, Inc., Research and Development, 211 Circuit Dr., North Kingstown, RI 02852. E-mail: david.jarvis{at}dominiondiagnostics.com

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