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Research ArticleCELLULAR AND MOLECULAR

Induction of Apoptosis by 1,4-Benzothiazine Analogs in Mouse Thymocytes

C. Marchetti, S. Ulisse, S. Bruscoli, F. P. Russo, G. Migliorati, F. Schiaffella, M. G. Cifone, C. Riccardi and R. Fringuelli
Journal of Pharmacology and Experimental Therapeutics March 2002, 300 (3) 1053-1062; DOI: https://doi.org/10.1124/jpet.300.3.1053
C. Marchetti
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S. Ulisse
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S. Bruscoli
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F. P. Russo
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G. Migliorati
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F. Schiaffella
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M. G. Cifone
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C. Riccardi
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R. Fringuelli
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Abstract

1,4-Benzothiazine (1,4-B) derivatives exert numerous effects in vivo and in vitro, including neurotoxicity and antitumor cytotoxicity. To analyze the mechanisms responsible for 1,4-B-induced cytotoxicity, we performed experiments to evaluate the possible apoptotic effect. For that purpose, we used mouse thymocytes, a cell population well sensitive to induction of apoptosis that has been used to assay apoptosis in many experimental systems. Results indicate that a number of 1,4-B analogs are able to induce both thymocyte apoptosis in vitro and thymus cell loss in vivo. Moreover, analysis of the structure-activity relationship indicate that the sulfur (S) oxidation state, the presence of the carbonyl group, and the nature and position of the side chain modulate the apoptotic efficacy. Moreover, results of in vitro experiments show that the 1,4-B-induced apoptosis associates with different biochemical events including phosphatidylcholine-specific phospholipase C activation, acidic sphingomyelinase activation and ceramide generation, loss of mitochondrial membrane potential (ΔΨm) and cytochromec release, and caspase-8, -9, and -3 activation. These results indicate that 1,4-B analogs induce apoptosis through a complex of biochemical events.

Footnotes

  • This work was supported by Consiglio Nazionale delle Ricerche target project on Biotechnology, Rome, Italy.

  • Abbreviations:
    1,4-B
    1,4-benzothiazine
    SAR
    structure-activity relationship
    PC-PLC
    phosphatidylcholine specific-phospholipase C
    PI-PLC
    phosphatidylinositol-specific phospholipase C
    DAG
    diacylglycerol
    aSMase
    acidic sphingomyelinase
    ΔΨm
    mitochondrial membrane potential transition (or loss of mitochondrial membrane potential)
    JC-1
    5,5′,6,6′-tetraethylbenzimidazolylcarbocyanine iodide
    DEX
    dexamethasone
    PBS
    phosphate-buffered saline
    PMSF
    phenylmethylsulfonyl fluoride
    SM
    sphingomyelin
    TLC
    thin layer chromatography
    PI
    propidium iodide
    PCD
    programmed cell death
    pNA
    p-nitroanilide
    TSO
    4-methyl-3,4-dihydro-2H-1,4-benzothiazin-3-one
    • Received August 29, 2001.
    • Accepted November 12, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 300 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 300, Issue 3
1 Mar 2002
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Research ArticleCELLULAR AND MOLECULAR

Induction of Apoptosis by 1,4-Benzothiazine Analogs in Mouse Thymocytes

C. Marchetti, S. Ulisse, S. Bruscoli, F. P. Russo, G. Migliorati, F. Schiaffella, M. G. Cifone, C. Riccardi and R. Fringuelli
Journal of Pharmacology and Experimental Therapeutics March 1, 2002, 300 (3) 1053-1062; DOI: https://doi.org/10.1124/jpet.300.3.1053

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Research ArticleCELLULAR AND MOLECULAR

Induction of Apoptosis by 1,4-Benzothiazine Analogs in Mouse Thymocytes

C. Marchetti, S. Ulisse, S. Bruscoli, F. P. Russo, G. Migliorati, F. Schiaffella, M. G. Cifone, C. Riccardi and R. Fringuelli
Journal of Pharmacology and Experimental Therapeutics March 1, 2002, 300 (3) 1053-1062; DOI: https://doi.org/10.1124/jpet.300.3.1053
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