Combined use of subclinical hydroxyurea and CHK1 inhibitor effectively controls melanoma and lung cancer progression, with reduced normal tissue toxicity compared to gemcitabine
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 sen...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2019-07-01
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| Series: | Molecular Oncology |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/1878-0261.12497 |
| _version_ | 1797987689263267840 |
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| author | Zay Yar Oo Martina Proctor Alexander J. Stevenson Deborah Nazareth Madushan Fernando Sheena M. Daignault Catherine Lanagan Sebastian Walpole Vanessa Bonazzi Dubravka Škalamera Cameron Snell Nikolas K. Haass Jill E. Larsen Brian Gabrielli |
| author_facet | Zay Yar Oo Martina Proctor Alexander J. Stevenson Deborah Nazareth Madushan Fernando Sheena M. Daignault Catherine Lanagan Sebastian Walpole Vanessa Bonazzi Dubravka Škalamera Cameron Snell Nikolas K. Haass Jill E. Larsen Brian Gabrielli |
| author_sort | Zay Yar Oo |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-11T07:52:10Z |
| format | Article |
| id | doaj.art-f030e16cdb874773a4afb382b8266e37 |
| institution | Directory Open Access Journal |
| issn | 1574-7891 1878-0261 |
| language | English |
| last_indexed | 2024-04-11T07:52:10Z |
| publishDate | 2019-07-01 |
| publisher | Wiley |
| record_format | Article |
| series | Molecular Oncology |
| spelling | doaj.art-f030e16cdb874773a4afb382b8266e372022-12-22T04:36:04ZengWileyMolecular Oncology1574-78911878-02612019-07-011371503151810.1002/1878-0261.12497Combined use of subclinical hydroxyurea and CHK1 inhibitor effectively controls melanoma and lung cancer progression, with reduced normal tissue toxicity compared to gemcitabineZay Yar Oo0Martina Proctor1Alexander J. Stevenson2Deborah Nazareth3Madushan Fernando4Sheena M. Daignault5Catherine Lanagan6Sebastian Walpole7Vanessa Bonazzi8Dubravka Škalamera9Cameron Snell10Nikolas K. Haass11Jill E. Larsen12Brian Gabrielli13Smiling for Smiddy Research Group Translational Research Institute Mater Research Institute‐The University of Queensland Brisbane AustraliaSmiling for Smiddy Research Group Translational Research Institute Mater Research Institute‐The University of Queensland Brisbane AustraliaSmiling for Smiddy Research Group Translational Research Institute Mater Research Institute‐The University of Queensland Brisbane AustraliaSmiling for Smiddy Research Group Translational Research Institute Mater Research Institute‐The University of Queensland Brisbane AustraliaSmiling for Smiddy Research Group Translational Research Institute Mater Research Institute‐The University of Queensland Brisbane AustraliaTranslational Research Institute The University of Queensland-Diamantina Institute Brisbane AustraliaSmiling for Smiddy Research Group Translational Research Institute Mater Research Institute‐The University of Queensland Brisbane AustraliaTranslational Research Institute The University of Queensland-Diamantina Institute Brisbane AustraliaTranslational Research Institute The University of Queensland-Diamantina Institute Brisbane AustraliaSmiling for Smiddy Research Group Translational Research Institute Mater Research Institute‐The University of Queensland Brisbane AustraliaSmiling for Smiddy Research Group Translational Research Institute Mater Research Institute‐The University of Queensland Brisbane AustraliaTranslational Research Institute The University of Queensland-Diamantina Institute Brisbane AustraliaQIMR-Berghofer Medical Research Institute The University of Queensland Brisbane AustraliaSmiling for Smiddy Research Group Translational Research Institute Mater Research Institute‐The University of Queensland Brisbane AustraliaDrugs 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.https://doi.org/10.1002/1878-0261.12497CHK1 inhibitorhydroxyureamacrophage infiltrationreplication stress |
| spellingShingle | Zay Yar Oo Martina Proctor Alexander J. Stevenson Deborah Nazareth Madushan Fernando Sheena M. Daignault Catherine Lanagan Sebastian Walpole Vanessa Bonazzi Dubravka Škalamera Cameron Snell Nikolas K. Haass Jill E. Larsen Brian Gabrielli Combined use of subclinical hydroxyurea and CHK1 inhibitor effectively controls melanoma and lung cancer progression, with reduced normal tissue toxicity compared to gemcitabine Molecular Oncology CHK1 inhibitor hydroxyurea macrophage infiltration replication stress |
| title | Combined use of subclinical hydroxyurea and CHK1 inhibitor effectively controls melanoma and lung cancer progression, with reduced normal tissue toxicity compared to gemcitabine |
| title_full | Combined use of subclinical hydroxyurea and CHK1 inhibitor effectively controls melanoma and lung cancer progression, with reduced normal tissue toxicity compared to gemcitabine |
| title_fullStr | Combined use of subclinical hydroxyurea and CHK1 inhibitor effectively controls melanoma and lung cancer progression, with reduced normal tissue toxicity compared to gemcitabine |
| title_full_unstemmed | Combined use of subclinical hydroxyurea and CHK1 inhibitor effectively controls melanoma and lung cancer progression, with reduced normal tissue toxicity compared to gemcitabine |
| title_short | Combined use of subclinical hydroxyurea and CHK1 inhibitor effectively controls melanoma and lung cancer progression, with reduced normal tissue toxicity compared to gemcitabine |
| title_sort | combined use of subclinical hydroxyurea and chk1 inhibitor effectively controls melanoma and lung cancer progression with reduced normal tissue toxicity compared to gemcitabine |
| topic | CHK1 inhibitor hydroxyurea macrophage infiltration replication stress |
| url | https://doi.org/10.1002/1878-0261.12497 |
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