Azacitidine enhances sensitivity of platinum-resistant ovarian cancer cells to carboplatin through induction of apoptosis.
OBJECTIVE
The objective of the study was to investigate whether azacitidine sensitizes platinum-resistant ovarian cancer cells to carboplatin and the possible mechanisms involved.


METHODS
We tested the in vitro antitumor activity of azacitidine both alone and combined with carboplatin in the ovarian cancer cell line 2008/C13 and Hey by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide assays and investigated the potential mechanisms by flow cytometry, terminal transferase deoxyuridine 5-triphosphate nick-end labeling assay, Western blot, reverse transcriptase-polymerase chain reaction (PCR), and promoter methylation-specific PCR.


RESULTS
Sequential treatment (ie, 24-hour azacitidine pretreatment followed by 48-hour cotreatment with azacitidine and carboplatin) significantly inhibited growth in 2008/C13 and Hey cells. More apoptotic cells were induced in 2008/C13 cells by sequential treatment than by a single drug. Increased cleaved caspase-3 and -8 were seen in 2008/C13 cells after sequential treatment with azacitidine and carboplatin. DR4 was demethylated, and DR4 messenger ribonucleic acid expression was increased in 2008/C13 cells after the 24-hour azacitidine treatment.


CONCLUSIONS
Azacitidine enhanced the sensitivity of platinum-resistant ovarian cancer cells to carboplatin associated with caspase-3- and -8-dependent apoptosis pathway and reexpression of DR4.
Li
Yanfang
Y
Department of Gynecologic Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Hu
Wei
W
Shen
De-Yu
DY
Kavanagh
John J
JJ
Fu
Siqing
S
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001374:Azacitidine / Q000494:pharmacology*; D016190:Carboplatin / Q000494:pharmacology*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D006801:Humans; D010051:Ovarian Neoplasms
D000970:Antineoplastic Agents; D016190:Carboplatin; D001374:Azacitidine