In vitro model of normal, immortalized ovarian surface epithelial and ovarian cancer cells for chemoprevention of ovarian cancer.
BACKGROUND
Epithelial ovarian cancer has the highest mortality rate among the gynecologic cancers. The synthetic retinoid, N-(4-hydroxyphenyl) retinamide (4-HPR), has been used in the chemoprevention of ovarian cancer. However, the effectiveness of its application for different populations has been questioned because of the genetic differences among normal, high risk, and women with cancer.


OBJECTIVE
To explore the similarities and the differences in 4-HPR effects on different ovarian epithelial cells which mimic different populations of women, normal ovarian surface epithelium to represent the normal population of women, immortalized ovarian surface epithelium to represent premalignant changes, and cells derived from ovarian cancer cells to represent malignant changes were used as in vitro models.


METHODS
Normal ovarian surface epithelial cells, immortalized ovarian surface epithelial cells, and ovarian cancer cells were incubated for different intervals with increasing concentrations of 4-HPR. Growth inhibition, the fraction of apoptotic cells, the expression of apoptosis-related genes, including p53, p16, p21, and caspase-3, and mitochondrial permeability transition were measured before and after 4-HPR treatment.


RESULTS
Treatment with 4-HPR produced growth inhibition and apoptosis in a dose-dependent manner for all 3 cell types. 4-HPR produced the strongest activation of the p53 pathway in normal ovarian epithelial (NOE) cells, while it caused the largest increase in MPT in the cancer cells, suggesting a different mechanism for growth inhibition and/or apoptosis in these cell lines. 4-HPR, at a concentration of 10 muM, had a maximal effect on caspase-3 activity at 72 h in normal cells and at 48 h in immortalized and cancer cells, although the effects were modest.


CONCLUSIONS
Normal ovarian surface epithelial cells, immortalized ovarian surface epithelial cells, and ovarian cancer cells showed a differential response to 4-HPR. Although the same endpoints of growth inhibition and apoptosis induction were present in response to 4-HPR, these endpoints may be regulated through different pathways.


CONCLUSIONS
Clinical trials with higher concentrations of 4-HPR should prove beneficial.
Brewer
Molly
M
Department of Gynecologic Oncology, University of Texas, The M. D. Anderson Cancer Center, Houston, TX 77030, USA. mbrewer@azcc.arizona.edu
Wharton
J Taylor
JT
Wang
Jian
J
McWatters
Amanda
A
Auersperg
Nelly
N
Gershenson
David
D
Bast
Robert
R
Zou
Changping
C
D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects / Q000473:pathology; D005260:Female; D017313:Fenretinide / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007425:Intracellular Membranes / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000517:prevention & control*; D010053:Ovary / Q000166:cytology / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics
D016588:Anticarcinogenic Agents; D000970:Antineoplastic Agents; D016159:Tumor Suppressor Protein p53; D017313:Fenretinide; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases