Mdm2 antagonists induce apoptosis and synergize with cisplatin overcoming chemoresistance in TP53 wild‐type ovarian cancer cells

• Published in: International journal of cancer Vol. 132; no. 7; pp. 1525 - 1536
• Main Authors: Mir, Roser, Tortosa, Avelina, Martinez‐Soler, Fina, Vidal, August, Condom, Enric, Pérez‐Perarnau, Alba, Ruiz‐Larroya, Tatiana, Gil, Joan, Giménez‐Bonafé, Pepita
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.04.2013; Wiley-Blackwell; Wiley Subscription Services, Inc
• Subjects: Adenocarcinoma, Mucinous - drug therapy; Adenocarcinoma, Mucinous - metabolism; Adenocarcinoma, Mucinous - pathology; Antineoplastic agents; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Biological and medical sciences; Blotting, Western; Cancer; Cell Cycle - drug effects; Cell Proliferation - drug effects; chemoresistance; Chemotherapy; Cisplatin - pharmacology; Cystadenocarcinoma, Serous - drug therapy; Cystadenocarcinoma, Serous - metabolism; Cystadenocarcinoma, Serous - pathology; Drug resistance; Drug Resistance, Neoplasm - drug effects; Drug Synergism; Endometrial Neoplasms - drug therapy; Endometrial Neoplasms - metabolism; Endometrial Neoplasms - pathology; Female; Flow Cytometry; General aspects; Humans; Imidazoles - pharmacology; Inhibitor of Apoptosis Proteins - antagonists & inhibitors; Inhibitor of Apoptosis Proteins - genetics; Inhibitor of Apoptosis Proteins - metabolism; Mdm2; Medical research; Medical sciences; Neoplasm Grading; Nut3a; Ovarian cancer; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - metabolism; Ovarian Neoplasms - pathology; Pharmacology. Drug treatments; Piperazines - pharmacology; Proto-Oncogene Proteins c-mdm2 - antagonists & inhibitors; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; RNA, Small Interfering - genetics; Survivin; Tumor Cells, Cultured; Tumor Suppressor Protein p53 - antagonists & inhibitors; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Tumors; Antineoplastic agent; Nutlin; Ovary cancer; mdm2 Gene; Cancerology; TP53 Gene; Genetics; Drug interaction; Antagonist; Protooncogene; Platinum II Complexes; Tumor suppressor gene; Human; Treatment resistance; ovarian cancer; Malignant tumor; Survivin; Wild type; Cisplatin; Female genital diseases; Ovarian diseases; Alkylating agent; chemoresistance; Treatment; Apoptosis inhibitory protein; Cell death; C-Onc gene; Mdm2; Reversibility; Nut3a; Cancer; Apoptosis
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.27832

Ovarian cancer (OVCa) is the leading cause of death from gynecological malignancies. Although treatment for advanced OVCa has improved with the introduction of taxane–platinum chemotherapy, the majority of patients will develop resistance to the treatment, leading to poor prognosis. One of the causes of chemoresistance is the reduced ability to undergo apoptosis. Cisplatin is a genotoxic drug that leads cells to apoptosis through the activation of the p53 pathway. Defective signaling in this pathway compromises p53 function, and thus cisplatin does not induce apoptosis. A new group of nongenotoxic small molecules called Nutlins have been developed to inhibit p53‐Mdm2 binding, inducing apoptosis in chemoresistant tumors through the activation of the p53 pathway. The wild‐type p53 cisplatin‐resistant ovarian cancer cell‐line A2780cis was used to test the effect of Nutlin‐3a (Nut3a) on apoptosis response. The results showed that Nut3a synergized with cisplatin, inducing cell‐cycle arrest in G2/M and potentiating apoptotic cell death. Increased apoptosis was also induced in wild‐type TP53 primary OVCa cultures by double cisplatin–Nut3a treatment. In conclusion, Nut3a appears to sensitize chemoresistant OVCa cells to cisplatin, inducing apoptosis. As increased response was generalized in primary tumors, this cisplatin–Nut3a combination could be useful for the treatment of patients harboring wild‐type TP53 who do not respond to standard chemotherapy. What's new? Ovarian cancer is the leading cause of death from gynecological malignancies, with the majority of patients developing resistance to the treatment, leading to poor prognosis. While the chemotherapeutic drug cisplatin initially leads tumor cells to apoptosis through activation of the p53 pathway, over time defective signaling compromises p53 function, resulting in reduced apoptosis. The study shows that non‐genotoxic Nut3a can sensitize chemoresistant ovarian cancer cells to cisplatin by potentiating apoptosis. The results also suggest that cisplatin and Nut3a could be used in combination for the treatment of patients harboring wild type TP53 who do not respond to standard chemotherapy.