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Apoptosis Induced by Anthracycline Antibiotics in P388 Parent and Multidrug-resistant Cells¹

Departments of Head, Neck, and Thoracic Medical Oncology [Y. H. L. R. P.] and Clinical Investigations [W. P.], The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030

The effect of the topoisomerase II inhibitor doxorubicin and its noncross-resistant analogue annamycin on DNA degradation and programmed cell death was examined in murine leukemia P388 cells. P388 parental cells exposed to various concentrations of doxorubicin and annamycin for 24 h displayed dose-dependent DNA cleavage: at 1 µM, both doxorubicin and annamycin were effective in inducing DNA breakdown, but at 10 µM, the effect was markedly decreased or totally absent. In multidrug-resistant P388/Dox cells, doxorubicin did not cause DNA cleavage, while 10 µM annamycin had a significant effect. By agarose gel analysis, drug-induced DNA fragmentation showed the characteristic pattern of internucleosomal ladder. Morphologically, P388 cells treated with 1 µM doxorubicin or annamycin for 24 h showed a reduction in cell volume and condensation of nuclear structures. Similar changes were observed in P388/Dox cells exposed to 10 µM annamycin for 24 h but not in cells exposed to 10 µM doxorubicin. Time course studies demonstrated that DNA fragmentation was detected 12 h after incubation with 1 µM doxorubicin or annamycin, while loss of membrane integrity appeared at 24 h, thus indicating that DNA degradation was a preceding event. DNA fragmentaton caused by doxorubicin and annamycin was inhibited by the RNA synthesis inhibitor actinomycin D, the protein synthesis inhibitor cycloheximide, and the endonuclease inhibitor aurintricarboxylic acid. Drug-induced cell death was partially prevented by cycloheximide and aurintricarboxylic acid, thus suggesting that the apoptotic process caused by these drugs requires gene expression, synthesis of new proteins, and activation of endogenous nucleases. In contrast, DNA cleavage was not affected by incubating cells with 1 mM ethylene glycol-bis(2-aminoethyl ether)-N,N,N',N'-tetraacetic acid, thus indicating that intracellular calcium depletion does not affect anthracycline-induced apoptosis. The results obtained demonstrate that the cell killing effect of anthracyclines is mediated, at least in part, by the induction of apoptosis.

¹ Supported in part by NIH Grant CA50270 and Argus Pharmaceutical, Inc.

² To whom requests for reprints should be addressed, at Department of Head, Neck, and Thoracic Medical Oncology, Box 80, 1515 Holcombe Boulevard, Houston, TX 77030.

Received 10/ 7/92. Accepted 1/18/93.

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