RITA

Details:

RITA(NSC 652287) induced both DNA-protein and DNA-DNA cross-links with no detectable DNA single-strand breaks. RITA, a drug that, like nutlin-3, can disrupt the p53/Mdm2 interaction.
IC50 Value: 54nM in MCF-7 cells [4]
Target: MDM-2/p53
in vitro: [2,2':5',2"-terthiopene] 5,5"-diyldimethanol (1f) displayed promising antiproliferative activity compared to RITA (IC50=28 nM in MCF-7 cells and 100 nM in colon cancer HCT116 cells, vs. 54 and 0.10 nM, respectively, for RITA) [4]. NSC 652287 induced both DNA-protein and DNA-DNA cross-links with no detectable DNA single-strand breaks. These DNA-protein cross-links (DPC) persisted for at least 12 h after drug removal and their frequency was correlated with cytotoxicity in the renal cell lines studied. The most sensitive renal carcinoma cell line, A498, exhibited cell cycle arrest in G(0)-G(1) and G(2)-M at 10 nM NSC 652287, with increased p53 and p21(WAF1) protein. At higher concentrations, NSC 652287 still induced p53 elevation but with p21(WAF1) reduction and massive apoptosis [1].  RITA induced prominent accumulation and reactivation of p53 in a wild-type TP53-bearing HNC cell line. RITA showed maximal growth suppression in tumor cells showing MDM2-dependent p53 degradation. RITA promoted apoptosis in association with upregulation of p21, BAX, and cleaved caspase-3; notably, the apoptotic response was blocked by pifithrin-α, demonstrating its p53 dependence. With increasing concentrations, RITA strongly induced apoptosis rather than G2-phase arrest [2]. By Western blot analysis we further confirmed that RITA induced activation of p53 in conjunction with up-regulation of phosphorylated ASK-1, MKK-4 and c-Jun [3].
in vivo: