Nutlin sensitizes lung carcinoma cells to interferon-alpha treatment in MDM2-dependent but p53-independent manner

• Published in: Biochemical and biophysical research communications Vol. 495; no. 1; pp. 1233 - 1239
• Main Authors: Shuvalov, Oleg, Kizenko, Alena, Shakirova, Aigul, Fedorova, Olga, Petukhov, Alexey, Aksenov, Nikolai, Vasileva, Elena, Daks, Alexandra, Barlev, Nickolai
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-01-2018
• Subjects: 60 APPLIED LIFE SCIENCES; ABLATION; Anticancer therapy; Antineoplastic Agents - administration & dosage; Apoptosis - drug effects; CARCINOMAS; CELL CYCLE; Cell Line, Tumor; Dose-Response Relationship, Drug; Drug Synergism; Humans; Imidazoles - administration & dosage; INTERFERON; Interferon-alpha (IFNα); Interferon-alpha - administration & dosage; Lung Neoplasms - drug therapy; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; LUNGS; MDM2; Nutlin; p53; Piperazines - administration & dosage; Proto-Oncogene Proteins c-mdm2 - antagonists & inhibitors; Proto-Oncogene Proteins c-mdm2 - metabolism; THERAPY; TOXICITY; Treatment Outcome; TUMOR CELLS; Tumor Suppressor Protein p53 - metabolism; IFNα; Nutlin; Interferon-alpha (IFNα); MDM2; СI; CXM; DRI; Anticancer therapy; p53
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2017.11.118

As an anticancer therapeutic, Interferon-alpha (IFNα) is used to treat a number of malignancies. However, the application of IFNα is restricted mostly due to its high toxicity. Therefore, novel combination therapeutic regimens are required to decrease the toxicity of IFNα and enhance its efficacy. Here we show that the treatment of p53-deficient human non-small lung carcinoma H1299 cells with IFNα in combination with an inhibitor of MDM2, Nutlin-3a, synergistically affects the proliferation of cancer cells. Importantly, Nutlin-3a was able to reduce the effective dose of IFNα about 3.4 times. Strikingly, this phenomenon is p53-independent, because H1299 cells lack p53, but is highly dependent on MDM2 because its ablation makes tumor cells completely insensitive to IFNα alone or in combination with Nutlin-3a. On the contrary, overexpression of MDM2 makes H1299 cells more susceptible to both IFNα and IFNα/Nutlin-3a treatments. Mechanistically, treatment with combination of IFNα and Nutlin-3a attenuates cyclin D1/CDK4 on the protein level and hence blocks cell cycle progression. This mechanism may be responsible, at least in part, for the anti-proliferative effects on H1299 cells observed.
Our data suggest that the expression of MDM2 confers sensitivity of cancer cells to IFNα/Nutlin-3a treatment. Moreover, our data also confirm positive effect of Nutlin even on p53-deficient neoplasms.
•Nutlin-3a/IFNα acts synergistically to down-regulate proliferation of p53-null carcinoma cells in the MDM2-dependent manner.•The expression of MDM2 confers sensitivity of cancer cells to IFNα/Nutlin-3a treatment.•The combination of IFNα and Nutlin-3a diminishes the expression of cyclin D1/CDK4 attenuating cell cycle progression.