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

Abstract

Adrenocortical carcinoma (ACC) is a rare malignancy, and CTNNB1 is frequently mutated in ACC. Our study aims to screen for effective agents with antineoplastic activity against ACC with CTNNB1 mutation. In‐silico screening of the Genomics of Drug Sensitivity in Cancer (GDSC) database was conducted. Drug sensitivity in cells with CTNNB1 mutation was analyzed and further in vitro and in vivo studies were performed using the compound. Only one compound, Nutlin‐3a, an MDM2 inhibitor, was significantly sensitive in 18 cancer cells with CTNNB1 mutation. Further analysis of the 18 cells revealed no significant efficacy between cells with both CTNNB1 and TP53 mutations indicating concomitant TP53 mutation did not impact on drug efficacy. We verified that Nutlin‐3a inhibited cellular proliferation in ACC cell line NCI‐H295R which harbored CTNNB1 mutation but not in SW13 cells which did not. Nutlin‐3a induced cell apoptosis and G1 cell‐cycle arrest in NCI‐H295R cells. Nutlin‐3a also decreased cellular migration and inhibited epithelial‐to‐mesenchymal transition (EMT) process in terms of EMT index. Nutlin‐3a resulted in decreased β‐catenin level independent of p53 level in NCI‐H295R but not SW13 cells. We also evaluated the effect of Nutlin‐3a on hormonal secretion of NCI‐H295R cells and found it resulted in decreased levels of cortisol, androgen, and progesterone. Nutlin‐3a treatment inhibited ACC tumor growth with no observed toxicity in mice in vivo. Our study has revealed that Nutlin‐3a potently inhibits ACC with CTNNB1 mutation. How p53/MDM2 axis coordinates with Wnt/beta‐Catenin signaling in ACC warrants further study.

Safety evaluation of conditionally immortalized cells for renal replacement therapy

“…This is in line with the mechanism of action of SV40T, which is known to interfere with Rb and p53 pathways thus driving cell proliferation [20]. Finally, the susceptibility of cells to undergo p53-mediated apoptosis at non-permissive temperature was confirmed using nutlin-3a, a compound that selectively induces p53 by inhibiting its degradation via Mdm2 [45, 46], suggesting normal p53 activity and apoptosis regulation at non-permissive temperature.…”

Ultrasound-responsive nutlin-loaded nanoparticles for combined chemotherapy and piezoelectric treatment of glioblastoma cells

“…Nut is known to reduce cancer cell migration and invasion [ 80 , 81 ], and therefore it may be considered surprising that the treatment with the free drug was not able to reduce motility in our experimental conditions. However, the inhibitory effects of Nut on cell motility, which are known to be mediated by cytoskeletal rearrangements, are limited to p53 wild-type cells [ 79 ].…”

MDM2-Recruiting PROTAC Offers Superior, Synergistic Antiproliferative Activity via Simultaneous Degradation of BRD4 and Stabilization of p53

“…In this report, we have revisited the strategy of constructing PROTACs using the small molecule, idasanutlin -- a ligand with high affinity for the E3 ligase, MDM2 (37). Nutlins were initially developed to act as a pharmacological means to elevate expression of the tumor suppressor p53 and there have been numerous reports (47–49) concerning the potential of nutlins as anti-cancer drugs/adjuvants. Our original study (25) indicated that nutlin-based PROTACs were limited in their ability to facilitate degradation: a PROTAC that recruited MDM2 to ubiquitinate the androgen receptor caused only limited target degradation at micromolar concentrations.…”