Combined use of subclinical hydroxyurea and CHK1 inhibitor effectively controls melanoma and lung cancer progression, with reduced normal tissue toxicity compared to gemcitabine.

Autor:	Oo ZY; Smiling for Smiddy Research Group, Translational Research Institute, Mater Research Institute-The University of Queensland, Brisbane, Australia.; Translational Research Institute, The University of Queensland-Diamantina Institute, Brisbane, Australia., Proctor M; Smiling for Smiddy Research Group, Translational Research Institute, Mater Research Institute-The University of Queensland, Brisbane, Australia., Stevenson AJ; Smiling for Smiddy Research Group, Translational Research Institute, Mater Research Institute-The University of Queensland, Brisbane, Australia., Nazareth D; Smiling for Smiddy Research Group, Translational Research Institute, Mater Research Institute-The University of Queensland, Brisbane, Australia., Fernando M; Smiling for Smiddy Research Group, Translational Research Institute, Mater Research Institute-The University of Queensland, Brisbane, Australia., Daignault SM; Translational Research Institute, The University of Queensland-Diamantina Institute, Brisbane, Australia., Lanagan C; Smiling for Smiddy Research Group, Translational Research Institute, Mater Research Institute-The University of Queensland, Brisbane, Australia., Walpole S; Translational Research Institute, The University of Queensland-Diamantina Institute, Brisbane, Australia., Bonazzi V; Translational Research Institute, The University of Queensland-Diamantina Institute, Brisbane, Australia.; Translational Research Institute, Queensland University of Technology, Brisbane, Australia., Škalamera D; Smiling for Smiddy Research Group, Translational Research Institute, Mater Research Institute-The University of Queensland, Brisbane, Australia., Snell C; Smiling for Smiddy Research Group, Translational Research Institute, Mater Research Institute-The University of Queensland, Brisbane, Australia.; Mater Pathology, Mater Adults Hospital, Mater Misericordiae Limited, South Brisbane, Australia., Haass NK; Translational Research Institute, The University of Queensland-Diamantina Institute, Brisbane, Australia., Larsen JE; QIMR-Berghofer Medical Research Institute, The University of Queensland, Brisbane, Australia.; School of Medicine, The University of Queensland, Brisbane, Australia., Gabrielli B; Smiling for Smiddy Research Group, Translational Research Institute, Mater Research Institute-The University of Queensland, Brisbane, Australia.; Translational Research Institute, The University of Queensland-Diamantina Institute, Brisbane, Australia.
Jazyk:	angličtina
Zdroj:	Molecular oncology [Mol Oncol] 2019 Jul; Vol. 13 (7), pp. 1503-1518. Date of Electronic Publication: 2019 Jun 14.
DOI:	10.1002/1878-0261.12497
Abstrakt:	Drugs such as gemcitabine that increase replication stress are effective chemotherapeutics in a range of cancer settings. These drugs effectively block replication and promote DNA damage, triggering a cell cycle checkpoint response through the ATR-CHK1 pathway. Inhibiting this signalling pathway sensitises cells to killing by replication stress-inducing drugs. Here, we investigated the effect of low-level replication stress induced by low concentrations (> 0.2 mm) of the reversible ribonucleotide reductase inhibitor hydroxyurea (HU), which slows S-phase progression but has little effect on cell viability or proliferation. We demonstrate that HU effectively synergises with CHK1, but not ATR inhibition, in > 70% of melanoma and non-small-cell lung cancer cells assessed, resulting in apoptosis and complete loss of proliferative potential in vitro and in vivo. Normal fibroblasts and haemopoietic cells retain viability and proliferative potential following exposure to CHK1 inhibitor plus low doses of HU, but normal cells exposed to CHK1 inhibitor combined with submicromolar concentrations of gemcitabine exhibited complete loss of proliferative potential. The effects of gemcitabine on normal tissue correlate with irreversible ATR-CHK1 pathway activation, whereas low doses of HU reversibly activate CHK1 independently of ATR. The combined use of CHK1 inhibitor and subclinical HU also triggered an inflammatory response involving the recruitment of macrophages in vivo. These data indicate that combining CHK1 inhibitor with subclinical HU is superior to combination with gemcitabine, as it provides equal anticancer efficacy but with reduced normal tissue toxicity. These data suggest a significant proportion of melanoma and lung cancer patients could benefit from treatment with this drug combination. (© 2019 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.)
Databáze:	MEDLINE
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