P53 activation suppresses irinotecan metabolite SN-38-induced cell damage in non-malignant but not malignant epithelial colonic cells.

Autor: Gunasegaran B; Discipline of Pharmacology, Adelaide Medical School, Faculty of Health and Medical Sciences, The University of Adelaide, South Australia, Australia., Neilsen PM; School of Health, Medical and Applied Sciences, Central Queensland University, Queensland, Australia; Centre for Personalized Cancer Medicine, Adelaide Medical School, Faculty of Health and Medical Sciences, The University of Adelaide, South Australia, Australia., Smid SD; Discipline of Pharmacology, Adelaide Medical School, Faculty of Health and Medical Sciences, The University of Adelaide, South Australia, Australia. Electronic address: scott.smid@adelaide.edu.au.
Jazyk: angličtina
Zdroj: Toxicology in vitro : an international journal published in association with BIBRA [Toxicol In Vitro] 2020 Sep; Vol. 67, pp. 104908. Date of Electronic Publication: 2020 Jun 02.
DOI: 10.1016/j.tiv.2020.104908
Abstrakt: Nutlin-3a is a p53 activator and potential cyclotherapy approach that may also mitigate side effects of chemotherapeutic drugs in the treatment of colorectal cancer. We investigated cell proliferation in a panel of colorectal cancer (CRC) cell lines with wild-type or mutant p53, as well as a non-tumorigenic fetal intestinal cell line following Nutlin-3a treatment (10 μM). We then assessed apoptosis at 24 and 48 h following administration of the active irinotecan metabolite, SN-38 (0.001 μM - 1 μM), alone or following pre-treatment with Nutlin-3a (10 μM). Nutlin-3a treatment (10 μM) significantly reduced proliferation in wild-type p53 expressing cell lines (FHS 74 and HCT116 +/+ ) at 72 and 96 h, but was without effect in cell lines with mutated or deleted p53 (Caco-2, SW480, and HCT 116 -/- ). SN-38 treatment induced significant apoptosis in all cell lines after 48 h. Nutlin-3a unexpectedly increased cell death in the p53 wild-type CRC cell line, HCT116 +/+ , while Nutlin-3a pre-treatment provided protection from SN-38 in the p53 wild-type normal cell line, FHs 74. These results demonstrate Nutlin-3a's selective growth-arresting efficacy in p53 wild-type non-malignant intestinal cell lines, enabling the selective targeting of malignant cells with chemotherapy drugs. These studies highlight the potential of Nutlin-3a to minimise intestinal mucosal damage following chemotherapy.
Competing Interests: Declaration of Competing Interest None.
(Crown Copyright © 2020. Published by Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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