Drug Resistance Towards Etoposide and Cisplatin in Human Melanoma Cells is Associated with Drug-Dependent Apoptosis Deficiency

Anticancer drugs kill susceptible cells through induction of apoptosis. Alterations of apoptotic pathways in drug-resistant tumor cells leading to apoptosis deficiency might represent a potent mechanism conferring drug resistance. We have assessed the effect of etoposide and cisplatin on the apoptot...

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Bibliographic Details
Published in:	Journal of investigative dermatology Vol. 118; no. 6; pp. 923 - 932
Main Authors:	Helmbach, Heike, Kern, Monika A., Rossmann, Evelyn, Renz, Kristina, Kissel, Christine, Gschwendt, Brigitte, Schadendorf, Dirk
Format:	Journal Article
Language:	English
Published:	Danvers, MA Elsevier Inc 01-06-2002 Nature Publishing Elsevier Limited
Subjects:	Antineoplastic Agents - pharmacology Antineoplastic Agents, Phytogenic - pharmacology Biological and medical sciences caspase Caspases - genetics Caspases - immunology Caspases - metabolism Cisplatin - pharmacology Coumarins - metabolism Coumarins - pharmacology Cytochrome c Group - metabolism cytochrome caspase antibodies Dermatology DNA Fragmentation - drug effects Drug Resistance, Neoplasm Enzyme Activation - drug effects Etoposide - pharmacology Gene Expression Regulation, Enzymologic Gene Expression Regulation, Neoplastic Humans Medical sciences Melanoma mitochondric Peptide Fragments - metabolism Peptide Fragments - pharmacology Poly(ADP-ribose) Polymerases - metabolism RNA, Messenger - analysis Tumor Cells, Cultured - cytology Tumor Cells, Cultured - drug effects Tumor Cells, Cultured - metabolism Tumors of the skin and soft tissue. Premalignant lesions mitochondric cytochrome caspase antibodies caspase Antineoplastic agent Cell culture DNA topoisomerase (ATP-hydrolysing) Skin disease Treatment resistance Enzyme Deficiency Etoposide Enzyme inhibitor Malignant tumor Experimental study Cisplatin Podophyllotoxine derivatives Alkylating agent Chemotherapy Isomerases Treatment Malignant melanoma Complication Skin Antimitotic Apoptosis Platinum II Complexes
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Summary:	Anticancer drugs kill susceptible cells through induction of apoptosis. Alterations of apoptotic pathways in drug-resistant tumor cells leading to apoptosis deficiency might represent a potent mechanism conferring drug resistance. We have assessed the effect of etoposide and cisplatin on the apoptotic pathways of the drug-sensitive human melanoma cell line MeWo as well as its etoposide- and cisplatin-resistant sublines (MeWoEto01, MeWoEto1, and MeWoCis01, MeWoCis1). Etoposide and cisplatin induced apoptosis in drug-sensitive MeWo cells as indicated by dose-dependent (i) cytochrome c release, (ii) caspase activation, (iii) DNA fragmentation, and (iv) cleavage of poly(ADP-ribose)polymerase. In contrast, whereas low etoposide-resistant cells (MeWoEto01) demonstrated reduced but detectable apoptotic activities, highly etoposide-resistant cells (MeWoEto1) did not exhibit any of the apoptotic events observed in etoposide-induced cell death downstream of a strongly reduced cytochrome c release. Highly cisplatin-resistant cells (MeWoCis1), however, demonstrated a reduced caspase 9 activity and cytochrome c release but the extent of effector caspase activation as well as DNA fragmentation was comparable to that of sensitive MeWo cells at equitoxic concentrations. In addition, poly(ADP-ribose)polymerase cleavage was strongly reduced in highly cisplatin-resistant sublines. Taken together, sensitive and drug-resistant MeWo cells utilized different apoptotic pathways upon drug exposure in a drug-dependent fashion and apoptosis deficiency was strongly associated with the drug-resistant phenotype.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0022-202X 1523-1747
DOI:	10.1046/j.1523-1747.2002.01786.x