The curcumin analog HO-3867 selectively kills cancer cells by converting mutant p53 protein to transcriptionally active wildtype p53

Esha Madan, Taylor M. Parker, Matthias R. Bauer, Alisha Dhiman, Christopher J. Pelham, Masaki Nagane, M. Lakshmi Kuppusamy, Matti Holmes, Thomas R. Holmes, Kranti Shaik, Kevin Shee, Salome Kiparoidze, Sean D. Smith, Yu Soon A. Park, Jennifer J. Gomm, Louise J. Jones, Ana R. Tomás, Ana C. Cunha, Karuppaiyah Selvendiran, Laura A. HansenAlan R. Fersht, Kálmán Hideg, Rajan Gogna, Periannan Kuppusamy

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

p53 is an important tumor-suppressor protein that is mutated in more than 50% of cancers. Strategies for restoring normal p53 function are complicated by the oncogenic properties of mutant p53 and have not met with clinical success. To counteract mutant p53 activity, a variety of drugs with the potential to reconvert mutant p53 to an active wildtype form have been developed. However, these drugs are associated with various negative effects such as cellular toxicity, nonspecific binding to other proteins, and inability to induce a wildtype p53 response in cancer tissue. Here, we report on the effects of a curcumin analog, HO-3867, on p53 activity in cancer cells from different origins. We found that HO-3867 covalently binds to mutant p53, initiates a wildtype p53-like anticancer genetic response, is exclusively cytotoxic toward cancer cells, and exhibits high anticancer efficacy in tumor models. In conclusion, HO-3867 is a p53 mutant–reactivating drug with high clinical anticancer potential.

Original languageEnglish (US)
Pages (from-to)4262-4276
Number of pages15
JournalJournal of Biological Chemistry
Volume293
Issue number12
DOIs
StatePublished - Jan 1 2018

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All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Madan, E., Parker, T. M., Bauer, M. R., Dhiman, A., Pelham, C. J., Nagane, M., Lakshmi Kuppusamy, M., Holmes, M., Holmes, T. R., Shaik, K., Shee, K., Kiparoidze, S., Smith, S. D., Park, Y. S. A., Gomm, J. J., Jones, L. J., Tomás, A. R., Cunha, A. C., Selvendiran, K., ... Kuppusamy, P. (2018). The curcumin analog HO-3867 selectively kills cancer cells by converting mutant p53 protein to transcriptionally active wildtype p53. Journal of Biological Chemistry, 293(12), 4262-4276. https://doi.org/10.1074/jbc.RA117.000950