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Nutlin-3a as a novel anticancer agent for adrenocortical carcinoma with CTNNB1 mutation

Wen Hui1,2, Shenghua Liu1,2, Jie Zheng1,2

  • 1Department of Urology, Huashan Hospital, Shanghai, 200040, China.

Cancer Medicine
|March 14, 2018
PubMed

Insights

Nutlin-3a, an MDM2 inhibitor, effectively targets adrenocortical carcinoma (ACC) with CTNNB1 mutations. This compound inhibits tumor growth, proliferation, and hormone secretion while inducing apoptosis and cell cycle arrest in vitro and in vivo.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Adrenocortical carcinoma (ACC) is a rare cancer with frequent CTNNB1 mutations.
  • Targeted therapies for ACC, especially those with CTNNB1 mutations, are limited.

Purpose of the Study:

  • To screen for effective antineoplastic agents against ACC harboring CTNNB1 mutations.
  • To evaluate the efficacy and mechanism of action of potential drug candidates.

Main Methods:

  • In-silico screening of the Genomics of Drug Sensitivity in Cancer (GDSC) database.
  • In vitro studies using ACC cell lines (NCI-H295R, SW13) and in vivo xenograft models.
  • Analysis of cell proliferation, apoptosis, cell cycle, migration, epithelial-to-mesenchymal transition (EMT), beta-catenin levels, and hormone secretion.

Main Results:

  • Nutlin-3a, an MDM2 inhibitor, showed significant sensitivity in ACC cells with CTNNB1 mutations.
  • Nutlin-3a inhibited proliferation, induced apoptosis and G1 cell-cycle arrest, decreased migration, and suppressed EMT in NCI-H295R cells.
  • Nutlin-3a reduced hormone secretion (cortisol, androgen, progesterone) and tumor growth in vivo without observed toxicity.
  • TP53 mutation status did not impact Nutlin-3a efficacy.

Conclusions:

  • Nutlin-3a is a potent inhibitor of adrenocortical carcinoma with CTNNB1 mutations.
  • Nutlin-3a demonstrates therapeutic potential for CTNNB1-mutated ACC.
  • Further investigation into the p53/MDM2 and Wnt/beta-Catenin signaling interplay in ACC is warranted.
Keywords:
CTNNB1TP53Adrenocortical carcinomaMDM2Nutlin-3a

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