Exploring Prima-1MET as a single agent or in combination with tamoxifen in breast cancer cells in vitro

Abstract

The mutant tumor suppressor p53 (p53-mut) is expressed in approximately 1/3 of breast cancer cases and 2/3 of triple-negative breast cancer (TNBC). It is linked to metastasis and resistance to various cancer therapies. A p53 reactivator, Prima-1^MET (or APR-246), has shown potential synergy with certain conventional therapies against cancer cells with various p53 statuses across a range of cancer types. Moreover, the clinical form eprenetapopt is showing promise in clinical trials. Thus, we examined the cytotoxic effects of Prima-1^MET against a TNBC-derived p53-mut cell line (MDA-MB231) and an estrogen receptor-positive (ER+) cell line (MCF7) that expresses wild-type p53 (p53-wt), either as a monotherapy or in combination with tamoxifen (Tam). Viability, migration, morphology, apoptosis, and expression of the cell cycle gene CCND1 were detected via standard in vitro methods. With CalcuSyn, the combination index (CI) was calculated to assess synergy. Both MDA-MB231 and MCF7 cells cocultured with Prima-1^MET alone exhibited an antiproliferative effect, which was linked to apoptosis and reduced migratory potential. Furthermore, upon exposure to the combination of 10 μM Prima-1^MET and 10 μM Tam, synergistic effects were detected, reflected by decreased viability, migration, altered morphology, and induction of apoptosis, along with downregulation of CCND1. Hence, these results emphasize the attractiveness of the combination of Prima-1^MET and Tam as a therapeutic approach for TNBC and ER + breast cancer, irrespective of p53 mutational status; therefore, these results encourage further preclinical and clinical studies, considering that the effective dose of Prima-1^MET is less than the reported clinically achievable plasma level (∼80 μg/ml).