Epithelial ovarian cancer (EOC) is the leading cause of gynecological
cancer death in the United States.
Cisplatin is
a DNA damaging agent initially effective against EOC but limited by resistance. P53 plays a critical role in cellular response to DNA damage and has been implicated in EOC response to
platinum chemotherapy. In this study, we examined the role of p53 status in EOC response to a novel combination of
cisplatin,
sodium arsenite, and
hyperthermia. Human EOC cells were treated with
cisplatin ± 20μM
sodium arsenite at 37°C or 39°C for 1 h.
Sodium arsenite ±
hyperthermia sensitized wild-type p53-expressing (A2780, A2780/CP70, OVCA 420, OVCA 429, and OVCA 433) EOC cells to
cisplatin.
Hyperthermia sensitized p53-null SKOV-3 and p53-mutant (OVCA 432 and OVCAR-3) cells to
cisplatin. P53
small interfering RNA (
siRNA) transfection abrogated
sodium arsenite sensitization effect. XPC, a critical DNA damage recognition
protein in global genome repair pathway, was induced by
cisplatin only in wild-type p53-expressing cells. Cotreatment with
sodium arsenite ±
hyperthermia attenuated
cisplatin-induced XPC in wild-type p53-expressing cells. XPC
siRNA transfection sensitized wild-type p53-expressing cells to
cisplatin, suggesting that
sodium arsenite ±
hyperthermia attenuation of XPC is a mechanism by which wild-type p53-expressing cells are sensitized to
cisplatin.
Hyperthermia ±
sodium arsenite enhanced cellular and
DNA accumulation of
platinum in wild-type p53-expressing cells. Only
hyperthermia enhanced
platinum accumulation in p53-null cells. In conclusion,
sodium arsenite ±
hyperthermia sensitizes wild-type p53-expressing EOC cells to
cisplatin by suppressing DNA repair
protein XPC and increasing cellular and
DNA platinum accumulation.