Differential susceptibility to etoposide in clones derived from a human ovarian cancer cell line.
OBJECTIVE
To identify parameters/factors that may contribute to the differential sensitivity to etoposide in two clones isolated from the human ovarian carcinoma SKOV-3 cell line, which does not express p53 and is resistant to platinum-based regimens.


METHODS
Differential sensitivity of the cells to etoposide was monitored by microscopy to observe morphological changes, by flow cytometry analyses to detect cell cycle perturbations, and by molecular/biochemical assays to identify events involved in induction of apoptosis.


RESULTS
Etoposide treatment (1) induced apoptosis in one clone, ES, but not in another clone, ER, (2) had no effect on the expression of the antiapoptotic proteins Bcl-2 and Bcl-X(L) in both cell clones, whereas the proapoptotic proteins Bak and Bax were dramatically upregulated in ES, but not ER cells, and (3) induced more extensive processing of procaspase-8, procaspase-9, and the caspase-3-targeted substrates, topoisomerase I and PARP, in ES cells. Ectopic overexpression of Bcl-2 in ES cells failed to inhibit etoposide-induced apoptosis.


CONCLUSIONS
The differential susceptibility of ES and ER cells to etoposide-induced apoptosis is associated with differences in several events rather than with a specific single genetic regulator of the apoptotic machinery. We propose that the differential response of ovarian cancer patients to etoposide treatment is associated with the number of etoposide-sensitive cells in the tumor.
Balan
K V
KV
Department of Biology, University of Miami, Coral Gables, FL 33146, USA.
Sitaras
N M
NM
Dimas
K
K
Han
Z
Z
Wyche
J H
JH
Pantazis
P
P
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D000951:Antigens, Neoplasm / Q000378:metabolism; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002999:Clone Cells / Q000187:drug effects / Q000648:ultrastructure; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D005047:Etoposide / Q000627:therapeutic use*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015398:Signal Transduction
D000951:Antigens, Neoplasm; D000972:Antineoplastic Agents, Phytogenic; D004268:DNA-Binding Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D005047:Etoposide; D020169:Caspases; D004250:DNA Topoisomerases, Type II