Induction of apoptosis by anti-cancer drugs with disparate modes of action: kinetics of cell death and changes in c-myc expression.
Incubation of CCRF CEM C7A human lymphoblastic leukaemia cells with etoposide (VP16) or N-methylformamide (NMF) induced apoptotic cell death. The kinetics of onset of apoptosis was determined and compared with that for dexamethasone-treated cells. The drugs induced 50% apoptosis at different rates: etoposide by approximately 18 h, NMF by 40 h and dexamethasone (DEX) by 52 h. In each case, the onset of apoptosis above 10% was preceded by a delay period. This was 8 h for etoposide, between 8 and 12 h for NMF and 36 h for dexamethasone. When cells were incubated for 36 h with dexamethasone and the drug washed out, addition of NMF induced apoptosis without any delay, suggesting that certain common biochemical events are required to prime the cells for apoptosis. However, cells treated for 8 h with NMF did not undergo immediate apoptosis on the addition of DEX. Analysis of the cellular content of the c-myc protein showed this to be undetectable by 2, 6 and 12 h after treatment with etoposide, NMF and DEX respectively. The rapid onset of NMF-induced cell death after a 36 h DEX pretreatment occurred 24 h after the loss of expression of c-Myc protein, suggesting that the expression of c-myc is not required for drug-induced cell death. In contrast to DEX-induced apoptosis, concomitant incubation of cells with NMF or etoposide and 200 nM of the protein synthesis inhibitor cycloheximide did not inhibit apoptotic cell death. The idea that drugs with different modes of action initiate conserved responses which engage a programmed cell death is discussed.
Wood
A C
AC
Cancer Research Campaign Molecular and Cellular Pharmacology Group, School of Biological Sciences, University of Manchester, UK.
Elvin
P
P
Hickman
J A
JA
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology*; D002453:Cell Cycle / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D003513:Cycloheximide / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology; D005047:Etoposide / Q000494:pharmacology; D005559:Formamides / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D016259:Genes, myc; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D005559:Formamides; D005047:Etoposide; D003907:Dexamethasone; D003513:Cycloheximide; C002950:methylformamide