PRIMA-1 increases cisplatin sensitivity in chemoresistant ovarian cancer cells with p53 mutation: a requirement for Akt down-regulation.
BACKGROUND
Since ovarian cancer is associated with high frequency of p53 mutation, the availability of p53 reactivation and induction of massive apoptosis (PRIMA-1) offers a possible new therapeutic strategy for overcoming this devastating disease. Although Akt activation is believed to be a determinant in chemoresistance in ovarian cancer, whether Akt plays a role in regulating the effectiveness of PRIMA-1 in sensitizing chemoresistant ovarian cancer cells with p53 mutation to cisplatin (CDDP), remains to be determined.


METHODS
In the present studies, we examined the influence of Akt down-regulation following dominant-negative (DN-Akt) expression on the ability of PRIMA-1 (0-10 μM) to facilitate CDDP (0-10 μM)-induced apoptosis in p53-mutated chemoresistant ovarian cancer cells (A2780cp).


RESULTS
Apoptosis rate was significantly higher at the combined treatment of low PRIMA-1 concentrations (0.156 - 0.938 μM) plus CDDP (10 μM) in the DN-Akt groups than control (p<0.001). Apoptosis in cells treated with PRIMA-1 (0.156 μM) and CDDP treatment (10 μM) was significantly suppressed by p53-siRNA. PRIMA-1 increased phospho-p53 (Ser15) content in Akt down-regulated cells treated with CDDP.


CONCLUSIONS
These results demonstrate that PRIMA-1 can sensitize chemoresistant ovarian cancer cells with p53 mutation to CDDP when Akt is down-regulated, and the action of PRIMA-1 is associated with p53 activation. Our findings raise the possibility that PRIMA-1 may be useful candidate for adjuvant therapy with CDDP in chemoresistant ovarian cancer with p53 mutation when Akt is down-regulated.
Department of Obstetrics & Gynecology and Cellular & Molecular Medicine, University of Ottawa; Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa K1H 8L6, Canada ; Department of Gynecology, Hokkaido University Graduate School of Medicine and School of Medicine, Sapporo, Japan.
Noriko
N
Kobayashi
Department of Obstetrics & Gynecology and Cellular & Molecular Medicine, University of Ottawa; Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa K1H 8L6, Canada ; Cellular and Molecular Medicine Research Center, Department of Physiology and Pharmacology, Birjand University of Medical Sciences, Birjand, Iran.
Mohammadreza
M
Abedini
Department of Gynecology, Hokkaido University Graduate School of Medicine and School of Medicine, Sapporo, Japan.
Noriaki
N
Sakuragi
Department of Obstetrics & Gynecology and Cellular & Molecular Medicine, University of Ottawa; Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa K1H 8L6, Canada ; World Class University (WCU) Biomodulation Major, Department of Agricultural Biotechnology, College of Agriculture and Life Sciences, Seoul National University, Seoul, Republic of Korea.
Benjamin K
BK
Tsang
Akt; Chemoresistance; Cisplatin; Ovarian cancer; PRIMA-1; p53