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Sphinganine potentiation of cellular differentiation induced by various anti-leukemia drugs in human leukemia cell line HL-60

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Abstract

A slight induction of cellular differentiation (myelocytes and granulocytes) of HL-60 cells occurred after treatment with anti-tumor agents etoposide (VP-16), mitoxantrone (MXT), mitomycin C (MMC), actinomycin D (Act-D) or novobiocin (NOVO). Addition of sphinganine (SP), an inhibitor of protein kinase C (PKC) enhanced (2–3fold) the VP-16, MXT, MMC or Act-D-induced differentiation but not the NOVO-induced differentiation. No induction of differentiation was observed with 5-fluorouracil (5-FU) in the absence or presence of SP. The addition of SP in the fresh medium after the removal of VP-16, MXT, or MMC (0.5 h treatment) enhanced the induction of differentiation. In contrast, SP post-treatment did not have any effect on enhancing the differentiation which was induced by Act-D short exposure (0.5 h).

In an attempt to characterize the biochemical requirements for potentiation of VP-16-induced differentiation, we examined the effects of calcium depletion using calcium chelator ethylene glycol-bis(β-aminoethyl ether) N,N,N′,N′-tetraacetic acid (EGTA) or calcium channel blocker verapamil. Potentiation of VP-16-induced differentiation by SP was not observed in EGTA- or verapamiltreated cells. Calcium supplementation to the cells during the treatment with EGTA restored the SP-potentiation of VP-16-induced differentiation. Our results also showed that the induction of differentiation was accompanied by a decrease in PKC activity (70% of the control). PKC activity decreased to a greater extent (50% of control) in SP potentiation of differentiation induction.

Our results suggested that calcium-dependent biological action of antitumor agents and the inhibition of PKC activity are required for SP-potentiation of differentiation induction.

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Authors and Affiliations

  1. Cancer Biochemistry Laboratory, Department of Pharmacology, Chang Gung Medical College, 259 Wen-Hwa 1st Road, Kwei-San, TaoYuan, Taiwan, 333, Republic of China

    Benjamin Yat-Ming Yung

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This work was supported by Chang Gung Research Grant CMRP 352 and National Science Council (R.O.C.) Grants NSC 81-0412-B-182-41 and NSC 82-0412-B-182-006

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Yat-Ming Yung, B. Sphinganine potentiation of cellular differentiation induced by various anti-leukemia drugs in human leukemia cell line HL-60. Naunyn-Schmiedeberg's Arch Pharmacol 350, 575–581 (1994). https://doi.org/10.1007/BF00173029

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  • DOI: https://doi.org/10.1007/BF00173029

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