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

8 Citations (Scopus)

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

Fingerprint

Curcumin
Mutant Proteins
Cells
Pharmaceutical Preparations
Tumor Suppressor Proteins
Neoplasms
Proteins
Toxicity
Tumors
Tissue
(3,5-bis((4-fluorophenyl)methylidene)-1-((1-hydroxy-2,2,5,5-tetramethyl-2,5-dihydro-1H-pyrrol-3-yl)methyl)piperidin-4-one)

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

The curcumin analog HO-3867 selectively kills cancer cells by converting mutant p53 protein to transcriptionally active wildtype p53. / Madan, Esha; Parker, Taylor M.; Bauer, Matthias R.; Dhiman, Alisha; Pelham, Christopher J.; Nagane, Masaki; Lakshmi Kuppusamy, M.; Holmes, Matti; Holmes, Thomas R.; Shaik, Kranti; Shee, Kevin; Kiparoidze, Salome; Smith, Sean D.; Park, Yu Soon A.; Gomm, Jennifer J.; Jones, Louise J.; Tomás, Ana R.; Cunha, Ana C.; Selvendiran, Karuppaiyah; Hansen, Laura A.; Fersht, Alan R.; Hideg, Kálmán; Gogna, Rajan; Kuppusamy, Periannan.

In: Journal of Biological Chemistry, Vol. 293, No. 12, 01.01.2018, p. 4262-4276.

Research output: Contribution to journalArticle

Madan, E, Parker, TM, Bauer, MR, Dhiman, A, Pelham, CJ, Nagane, M, Lakshmi Kuppusamy, M, Holmes, M, Holmes, TR, Shaik, K, Shee, K, Kiparoidze, S, Smith, SD, Park, YSA, Gomm, JJ, Jones, LJ, Tomás, AR, Cunha, AC, Selvendiran, K, Hansen, LA, Fersht, AR, Hideg, K, Gogna, R & 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, vol. 293, no. 12, pp. 4262-4276. https://doi.org/10.1074/jbc.RA117.000950
Madan, Esha ; Parker, Taylor M. ; Bauer, Matthias R. ; Dhiman, Alisha ; Pelham, Christopher J. ; Nagane, Masaki ; Lakshmi Kuppusamy, M. ; Holmes, Matti ; Holmes, Thomas R. ; Shaik, Kranti ; Shee, Kevin ; Kiparoidze, Salome ; Smith, Sean D. ; Park, Yu Soon A. ; Gomm, Jennifer J. ; Jones, Louise J. ; Tomás, Ana R. ; Cunha, Ana C. ; Selvendiran, Karuppaiyah ; Hansen, Laura A. ; Fersht, Alan R. ; Hideg, Kálmán ; Gogna, Rajan ; Kuppusamy, Periannan. / The curcumin analog HO-3867 selectively kills cancer cells by converting mutant p53 protein to transcriptionally active wildtype p53. In: Journal of Biological Chemistry. 2018 ; Vol. 293, No. 12. pp. 4262-4276.
@article{03a34f2cca924986b0ab631e812675d8,
title = "The curcumin analog HO-3867 selectively kills cancer cells by converting mutant p53 protein to transcriptionally active wildtype p53",
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.",
author = "Esha Madan and Parker, {Taylor M.} and Bauer, {Matthias R.} and Alisha Dhiman and Pelham, {Christopher J.} and Masaki Nagane and {Lakshmi Kuppusamy}, M. and Matti Holmes and Holmes, {Thomas R.} and Kranti Shaik and Kevin Shee and Salome Kiparoidze and Smith, {Sean D.} and Park, {Yu Soon A.} and Gomm, {Jennifer J.} and Jones, {Louise J.} and Tom{\'a}s, {Ana R.} and Cunha, {Ana C.} and Karuppaiyah Selvendiran and Hansen, {Laura A.} and Fersht, {Alan R.} and K{\'a}lm{\'a}n Hideg and Rajan Gogna and Periannan Kuppusamy",
year = "2018",
month = "1",
day = "1",
doi = "10.1074/jbc.RA117.000950",
language = "English (US)",
volume = "293",
pages = "4262--4276",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "12",

}

TY - JOUR

T1 - The curcumin analog HO-3867 selectively kills cancer cells by converting mutant p53 protein to transcriptionally active wildtype p53

AU - Madan, Esha

AU - Parker, Taylor M.

AU - Bauer, Matthias R.

AU - Dhiman, Alisha

AU - Pelham, Christopher J.

AU - Nagane, Masaki

AU - Lakshmi Kuppusamy, M.

AU - Holmes, Matti

AU - Holmes, Thomas R.

AU - Shaik, Kranti

AU - Shee, Kevin

AU - Kiparoidze, Salome

AU - Smith, Sean D.

AU - Park, Yu Soon A.

AU - Gomm, Jennifer J.

AU - Jones, Louise J.

AU - Tomás, Ana R.

AU - Cunha, Ana C.

AU - Selvendiran, Karuppaiyah

AU - Hansen, Laura A.

AU - Fersht, Alan R.

AU - Hideg, Kálmán

AU - Gogna, Rajan

AU - Kuppusamy, Periannan

PY - 2018/1/1

Y1 - 2018/1/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85044425478&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85044425478&partnerID=8YFLogxK

U2 - 10.1074/jbc.RA117.000950

DO - 10.1074/jbc.RA117.000950

M3 - Article

C2 - 29382728

AN - SCOPUS:85044425478

VL - 293

SP - 4262

EP - 4276

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 12

ER -