Abstract
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 (MeWo(Eto01), MeWo(Eto1), (and) MeWoCis01, MeWo(Cis1)). 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 (MeWo(Eto01)) demonstrated reduced but detectable apoptotic activities, highly etoposide-resistant cells (MeWo(Eto1)) 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 (MeWo(Cis1)), 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.
Original language | English |
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Pages (from-to) | 923-32 |
Number of pages | 10 |
Journal | Journal of Investigative Dermatology |
Volume | 118 |
Issue number | 6 |
DOIs | |
Publication status | Published - Jun 2002 |
Keywords
- Antineoplastic Agents
- Antineoplastic Agents, Phytogenic
- Caspases
- Cisplatin
- Coumarins
- Cytochrome c Group
- DNA Fragmentation
- Drug Resistance, Neoplasm
- Enzyme Activation
- Etoposide
- Gene Expression Regulation, Enzymologic
- Gene Expression Regulation, Neoplastic
- Humans
- Melanoma
- Peptide Fragments
- Poly(ADP-ribose) Polymerases
- RNA, Messenger
- Tumor Cells, Cultured