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 language | English (US) |
|---|---|
| Pages (from-to) | 4262-4276 |
| Number of pages | 15 |
| Journal | Journal of Biological Chemistry |
| Volume | 293 |
| Issue number | 12 |
| DOIs | |
| State | Published - Jan 1 2018 |
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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 journal › Article
}
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.
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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
VL - 293
SP - 4262
EP - 4276
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 12
ER -