Inhibiting p53 Acetylation Reduces Cancer Chemotoxicity

Inhibiting p53 Acetylation Reduces Cancer Chemotoxicity
Title:
Inhibiting p53 Acetylation Reduces Cancer Chemotoxicity
Other Titles:
Cancer Research
Publication Date:
27 June 2017
Citation:
Cancer Res August 15 2017 (77) (16) 4342-4354;
Abstract:
Chemotoxicity due to unwanted p53 activation in the bone marrow remains an unmet clinical challenge. Doxorubicin, a first-line chemotherapy drug, often causes myelosuppression in patients, thus limiting its effectiveness. In this study, we discovered that C646, a reversible p300 inhibitor, downregulates p53 transcription and selectively protects noncancerous cells from p53-dependent apoptosis. C646 treatment blocked acetylation of specific lysine residues that regulate p53 activity. Exploitation of differential p53 genetic backgrounds between human hematopoietic and colorectal cancer cells improved the therapeutic index of doxorubicin with C646 cotreatment. C646 administration in mice afflicted with p53-mutant tumors protected them from doxorubicin-induced neutropenia and anemia while retaining antitumor efficacy. We deduce that temporary and reversible inhibition of p53 acetylation in cancer subjects, especially those with p53-mutant tumors, may protect them from severe chemotoxicity while allowing treatment regimens to effectively proceed.
License type:
PublisherCopyrights
Funding Info:
This work was supported by an A*STAR grant (BMSI/15-800001-P53LOOE).
Description:
The full paper is available for download at the publisher's URL: https://doi.org/10.1158/0008-5472.CAN-17-0424
ISSN:
0008-5472
1538-7445
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