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. 2023 Aug;41(4):587-595.
doi: 10.1007/s10637-023-01380-5. Epub 2023 Jul 4.

The p53 reactivator PRIMA-1MET synergises with 5-fluorouracil to induce apoptosis in pancreatic cancer cells

Ibtehal Mohammed  1 , Ali Haider Alhammer  2 , Inam Sameh Arif  1
Affiliations

The p53 reactivator PRIMA-1MET synergises with 5-fluorouracil to induce apoptosis in pancreatic cancer cells

Ibtehal Mohammed et al. Invest New Drugs. 2023 Aug.

Abstract

Pancreatic cancer (PC) is one of the deadliest malignancies; p53 is mutated in approximately 75% of PC patients. Hence, the protein derived from mutant/wild-type TP53 may represent a therapeutic target. Interestingly, a p53 reactivator (PRIMA-1MET) showed promise in clinical trials of haematological malignancies; therefore, it warrants an in vitro evaluation in PC cell lines. To evaluate the antiproliferative effects of PRIMA-1MET, either alone or combined with the common chemotherapy 5-fluorouracil (5-FU), against mutated and wild-type p53 PC cell lines. This study involved p53-mutant (AsPC-1) and p53-wild type (Capan-2) PC cell lines. The cytotoxicity of PRIMA-1MET alone or in combination with 5-FU was evaluated by MTT assay. Synergism was assessed by calculating the combination index (CI) via CalcuSyn software. Fluorescence microscopy was used to analyse apoptosis following acridine orange/ethidium bromide (AO/EB) staining. Morphological changes were investigated with an inverted microscope. Quantitative reverse transcription PCR (RT‒qPCR) was used to measure gene expression. Both PC cell lines were sensitive to PRIMA-1MET monotherapy. Furthermore, PRIMA-1MET and 5-FU had a synergistic effect (CI < 1), reflected by significant enhancement of apoptosis and morphological changes in the combination vs. monotherapy treatments. Moreover, the RT‒qPCR results indicated increased expression of the NOXA and TP73 genes in combination-treated cells. Our data suggested that PRIMA-1MET, whether alone or combined with 5-FU, has an antiproliferative effect on PC cell lines regardless of p53 mutational status. The synergism of the combination was associated with significant apoptosis induction through p53-dependent and p53-independent pathways. Preclinical confirmation of these data in in vivo models is highly recommended.

Keywords: 5-FU; APR-246; Combination; P53 reactivator; PRIMA-1MET; Pancreatic cancer.

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