NSC59984

NSC59984 is a promising lead compound for anti-cancer therapy that acts by targeting GOF mutant p53 and stimulates p73 to restore the p53 signaling pathway. The p53 is a tumour-suppressor protein which exerts antiproliferative effects, including growth arrest and apoptosis.

In vitro: In SW480 and DLD-1 cells, NSC59984 treatment for 3 hours dose-dependently increased the mRNA levels of p21, Noxa and Puma. NSC59984 was also found to increase p53-responsive reporter activity in both SW480 in a dose-dependent manner. The EC50 values of NSC59984 against a panel of cancer cell lines were different, varying from 8.38 to 110.49 ?M. After incubation with 12 ?M NSC59984 for 8 hours, the level ofγH2AX, a marker of genotoxicity due to DNA double-strand breaks, increased in HCT116 cells. NSC59984 induced cell death in a panel of cancer cells but displayed little or no cytotoxicity towards normal cells. Noxa mRNA slightly increased in response to 25 μM of NSC59984 in HCT116 and 12 μM of NSC59984 in p53-null HCT116 cells [1].

In vivo: In nude mice bearing colon-tumor xenografts, NSC59984 (i.p. injection, 45mg/kg) did not cause an obvious change in mouse body weights and no overt toxic effects. NSC59984 treatment significantly repressed the DLD-1 xenograft tumor growth. Tumor weight measured at day 15 reduced by 34% in DLD-1 xenograft tumors. In p73 knock-down DLD-1 xenograft tumors, NSC59984 didn’t suppress tumor growth. In p73 knock-down DLD-1 xenograft tumors, NSC59984 treatment reduced tumor weight by 18% [1].

Reference:
Zhang S, Zhou L, Hong B, et al.  Small-molecule NSC59984 restores p53 pathway signaling and antitumor effects against colorectal cancer via p73 activation and degradation of mutant p53[J]. Cancer research, 2015, 75(18): 3842-3852.

Small-Molecule NSC59984 Restores p53 Pathway Signaling and Antitumor Effects against Colorectal Cancer via p73 Activation and Degradation of Mutant p53.[Pubmed:26294215]

Cancer Res. 2015 Sep 15;75(18):3842-52.

The tumor-suppressor p53 prevents cancer development via initiating cell-cycle arrest, cell death, repair, or antiangiogenesis processes. Over 50% of human cancers harbor cancer-causing mutant p53. p53 mutations not only abrogate its tumor-suppressor function, but also endow mutant p53 with a gain of function (GOF), creating a proto-oncogene that contributes to tumorigenesis, tumor progression, and chemo- or radiotherapy resistance. Thus, targeting mutant p53 to restore a wild-type p53 signaling pathway provides an attractive strategy for cancer therapy. We demonstrate that small-molecule NSC59984 not only restores wild-type p53 signaling, but also depletes mutant p53 GOF. NSC59984 induces mutant p53 protein degradation via MDM2 and the ubiquitin-proteasome pathway. NSC59984 restores wild-type p53 signaling via p73 activation, specifically in mutant p53-expressing colorectal cancer cells. At therapeutic doses, NSC59984 induces p73-dependent cell death in cancer cells with minimal genotoxicity and without evident toxicity toward normal cells. NSC59984 synergizes with CPT11 to induce cell death in mutant p53-expressing colorectal cancer cells and inhibits mutant p53-associated colon tumor xenograft growth in a p73-dependent manner in vivo. We hypothesize that specific targeting of mutant p53 may be essential for anticancer strategies that involve the stimulation of p73 in order to efficiently restore tumor suppression. Taken together, our data identify NSC59984 as a promising lead compound for anticancer therapy that acts by targeting GOF-mutant p53 and stimulates p73 to restore the p53 pathway signaling.

NSC59984 induces mutant p53 protein degradation via MDM2 and the ubiquitin-proteasome pathway. NSC59984 acts by targeting GOF-mutant p53 and stimulates p73 to restore the p53 pathway signaling.

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