1.PRIMA-1Met induces apoptosis in Waldenström's Macroglobulinemia cells independent of p53.
Sobhani M1, Abdi J, Manujendra SN, Chen C, Chang H. Cancer Biol Ther. 2015;16(5):799-806. doi: 10.1080/15384047.2015.1026482.
PRIMA-1Met has shown promising preclinical activity in various cancer types. However, its effect on Waldenström's Macroglobulinemia (WM) cells as well as its exact mechanism of action is still elusive. In this study, we evaluated the anti- tumor activity of PRIMA-1Met alone and in combination with dexamethasone or bortezomib in WM cell lines and primary samples. Treatment of WM cells with PRIMA-1Met resulted in induction of apoptosis, inhibition of migration and suppression of colony formation. Upon PRIMA-1Met treatment, p73 was upregulated and Bcl-xL was down-regulated while no significant change in expression of p53 was observed. Furthermore, siRNA knockdown of p53 in WM cell line did not influence the PRIMA-1Met-induced apoptotic response whereas silencing of p73 inhibited latter response in WM cells. Importantly, combined treatment of BCWM-1 cells with PRIMA-1Met and dexamethasone or bortezomib induced synergistic reduction in cell survival.
2.APR-246/PRIMA-1Met Inhibits and Reverses Squamous Metaplasia in Human Conjunctival Epithelium.
Li J1, Li C1, Wang G1, Liu Z1, Chen P1, Yang Q1, Dong N2, Wu H2, Liu Z3, Li W3. Invest Ophthalmol Vis Sci. 2016 Feb 1;57(2):444-52. doi: 10.1167/iovs.15-17519.
PURPOSE: Squamous metaplasia is a common pathologic condition in ocular surface diseases for which there is no therapeutic medication in clinic. In this study, we investigated the effect of a small molecule, APR-246/PRIMA-1Met, on squamous metaplasia in human conjunctival epithelium.
3.Targeting of Mutant p53 and the Cellular Redox Balance by APR-246 as a Strategy for Efficient Cancer Therapy.
Bykov VJ1, Zhang Q1, Zhang M1, Ceder S1, Abrahmsen L2, Wiman KG1. Front Oncol. 2016 Feb 3;6:21. doi: 10.3389/fonc.2016.00021. eCollection 2016.
TP53 is the most frequently mutated gene in cancer. The p53 protein activates transcription of genes that promote cell cycle arrest or apoptosis, or regulate cell metabolism, and other processes. Missense mutations in TP53 abolish specific DNA binding of p53 and allow evasion of apoptosis and accelerated tumor progression. Mutant p53 often accumulates at high levels in tumor cells. Pharmacological reactivation of mutant p53 has emerged as a promising strategy for improved cancer therapy. Small molecules that restore wild type activity of mutant p53 have been identified using various approaches. One of these molecules, APR-246, is a prodrug that is converted to the Michael acceptor methylene quinuclidinone (MQ) that binds covalently to cysteines in p53, leading to refolding and restoration of wild type p53 function. MQ also targets the cellular redox balance by inhibiting thioredoxin reductase (TrxR1) and depleting glutathione. This dual mechanism of action may account for the striking synergy between APR-246 and platinum compounds.
4.APR-246 potently inhibits tumour growth and overcomes chemoresistance in preclinical models of oesophageal adenocarcinoma.
Liu DS1, Read M1, Cullinane C2, Azar WJ3, Fennell CM4, Montgomery KG4, Haupt S5, Haupt Y5, Wiman KG6, Duong CP7, Clemons NJ1, Phillips WA8. Gut. 2015 Oct;64(10):1506-16. doi: 10.1136/gutjnl-2015-309770. Epub 2015 Jul 17.
OBJECTIVES: p53 is a critical tumour suppressor and is mutated in 70% of oesophageal adenocarcinomas (OACs), resulting in chemoresistance and poor survival. APR-246 is a first-in-class reactivator of mutant p53 and is currently in clinical trials. In this study, we characterised the activity of APR-246 and its effect on p53 signalling in a large panel of cell line xenograft (CLX) and patient-derived xenograft (PDX) models of OAC.