In vitro radiosensitization of breast cancer with hypoxia-activated prodrugs



Aiyappa-Maudsley, Radhika ORCID: 0000-0003-4900-4013, Elsalem, Lina, Ibrahim, Ali IM, Pors, Klaus and Martin, Stewart G
(2022) In vitro radiosensitization of breast cancer with hypoxia-activated prodrugs. JOURNAL OF CELLULAR AND MOLECULAR MEDICINE, 26 (16). pp. 4577-4590.

Access the full-text of this item by clicking on the Open Access link.
[img] PDF
In vitro radiosensitization of breast cancer with hypoxia-activated prodrugs.pdf - Published version

Download (3MB) | Preview

Abstract

KP167 is a novel hypoxia-activated prodrug (HAP), targeting cancer cells via DNA intercalating and alkylating properties. The single agent and radiosensitizing efficacy of KP167 and its parental comparator, AQ4N, were evaluated in 2D and 3D cultures of luminal and triple negative breast cancer (TNBC) cell lines and compared against DNA damage repair inhibitors. 2D normoxic treatment with the DNA repair inhibitors, Olaparib or KU-55933 caused, as expected, substantial radiosensitization (sensitiser enhancement ratio, SER<sub>0.01</sub> of 1.60-3.42). KP167 induced greater radiosensitization in TNBC (SER<sub>0.01</sub> 2.53 in MDAMB-231, 2.28 in MDAMB-468, 4.55 in MDAMB-436) and luminal spheroids (SER<sub>0.01</sub> 1.46 in MCF-7 and 1.76 in T47D cells) compared with AQ4N. Significant radiosensitization was also obtained using KP167 and AQ4N in 2D normoxia. Although hypoxia induced radioresistance, radiosensitization by KP167 was still greater under 2D hypoxia, yielding SER<sub>0.01</sub> of 1.56-2.37 compared with AQ4N SER<sub>0.01</sub> of 1.13-1.94. Such data show KP167 as a promising single agent and potent radiosensitiser of both normoxic and hypoxic breast cancer cells, with greater efficacy in TNBCs.

Item Type: Article
Uncontrolled Keywords: breast cancer, HAPs, hypoxia, hypoxia-activated prodrugs, luminal, radiotherapy, TNBC, triple negative breast cancer
Divisions: Faculty of Health and Life Sciences
Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology
Depositing User: Symplectic Admin
Date Deposited: 18 Oct 2022 13:56
Last Modified: 18 Jan 2023 19:49
DOI: 10.1111/jcmm.17486
Open Access URL: https://doi.org/10.1111/jcmm.17486
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3165607