Synergistic effect of inhibiting CHK2 and DNA replication on cancer cell growth
Cancer cells display high levels of oncogene-induced replication stress (RS) and rely on DNA damage checkpoint for viability. This feature is exploited by cancer therapies to either increase RS to unbearable levels or inhibit checkpoint kinases involved in the DNA damage response. Thus far, treatmen...
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eLife Sciences Publications Ltd
2025-01-01
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| Online Access: | https://elifesciences.org/articles/104718 |
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| author | Flavie Coquel Sing-Zong Ho Keng-Chang Tsai Chun-Yen Yang Antoine Aze Julie Devin Ting-Hsiang Chang Marie Kong-Hap Audrey Bioteau Jerome Moreaux Domenico Maiorano Philippe Pourquier Wen-Chin Yang Yea-Lih Lin Philippe Pasero |
| author_facet | Flavie Coquel Sing-Zong Ho Keng-Chang Tsai Chun-Yen Yang Antoine Aze Julie Devin Ting-Hsiang Chang Marie Kong-Hap Audrey Bioteau Jerome Moreaux Domenico Maiorano Philippe Pourquier Wen-Chin Yang Yea-Lih Lin Philippe Pasero |
| author_sort | Flavie Coquel |
| collection | DOAJ |
| description | Cancer cells display high levels of oncogene-induced replication stress (RS) and rely on DNA damage checkpoint for viability. This feature is exploited by cancer therapies to either increase RS to unbearable levels or inhibit checkpoint kinases involved in the DNA damage response. Thus far, treatments that combine these two strategies have shown promise but also have severe adverse effects. To identify novel, better-tolerated anticancer combinations, we screened a collection of plant extracts and found two natural compounds from the plant, Psoralea corylifolia, that synergistically inhibit cancer cell proliferation. Bakuchiol inhibited DNA replication and activated the checkpoint kinase CHK1 by targeting DNA polymerases. Isobavachalcone interfered with DNA double-strand break repair by inhibiting the checkpoint kinase CHK2 and DNA end resection. The combination of bakuchiol and isobavachalcone synergistically inhibited cancer cell proliferation in vitro. Importantly, it also prevented tumor development in xenografted NOD/SCID mice. The synergistic effect of inhibiting DNA replication and CHK2 signaling identifies a vulnerability of cancer cells that might be exploited by using clinically approved inhibitors in novel combination therapies. |
| format | Article |
| id | doaj-art-8c263bb60f8a421f9b29dbf5e254f232 |
| institution | Kabale University |
| issn | 2050-084X |
| language | English |
| publishDate | 2025-01-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj-art-8c263bb60f8a421f9b29dbf5e254f2322025-01-31T12:27:24ZengeLife Sciences Publications LtdeLife2050-084X2025-01-011310.7554/eLife.104718Synergistic effect of inhibiting CHK2 and DNA replication on cancer cell growthFlavie Coquel0Sing-Zong Ho1https://orcid.org/0009-0008-9986-6061Keng-Chang Tsai2https://orcid.org/0000-0001-8277-9174Chun-Yen Yang3Antoine Aze4Julie Devin5Ting-Hsiang Chang6Marie Kong-Hap7Audrey Bioteau8Jerome Moreaux9https://orcid.org/0000-0002-5717-3207Domenico Maiorano10https://orcid.org/0000-0003-4229-5903Philippe Pourquier11https://orcid.org/0000-0001-5326-3005Wen-Chin Yang12https://orcid.org/0000-0001-6410-2581Yea-Lih Lin13https://orcid.org/0000-0003-4063-0771Philippe Pasero14https://orcid.org/0000-0001-5891-0822Institut de Génétique Humaine, Univ. de Montpellier, CNRS, Montpellier, France; ‘Maintenance of Genome Integrity during DNA replication’ laboratory, équipe labélisée Ligue contre le Cancer, Montpellier, FranceAgricultural Biotechnology Research Center, Academia Sinica, Taipei, TaiwanPh.D. Program in Medical Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan; National Research Institute of Chinese Medicine, Ministry of Health and Welfare, Taipei, TaiwanInstitut de Génétique Humaine, Univ. de Montpellier, CNRS, Montpellier, FranceInstitut de Génétique Humaine, Univ. de Montpellier, CNRS, Montpellier, France; ‘Genome Surveillance and Stability’ Laboratory, IGH, Univ. de Montpellier, CNRS, Montpellier, FranceInstitut de Génétique Humaine, Univ. de Montpellier, CNRS, Montpellier, France; ‘Normal and Malignant B cells’ laboratory', IGH, Univ. de Montpellier, CNRS, Montpellier, FranceAgricultural Biotechnology Research Center, Academia Sinica, Taipei, TaiwanIRCM, Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Université de Montpellier, Institut régional du Cancer de Montpellier, Montpellier, FranceInstitut de Génétique Humaine, Univ. de Montpellier, CNRS, Montpellier, France; ‘Maintenance of Genome Integrity during DNA replication’ laboratory, équipe labélisée Ligue contre le Cancer, Montpellier, FranceInstitut de Génétique Humaine, Univ. de Montpellier, CNRS, Montpellier, France; ‘Normal and Malignant B cells’ laboratory', IGH, Univ. de Montpellier, CNRS, Montpellier, France; Institut Universitaire de France, Paris, France; Department of Biological Hematology, CHU Montpellier, Montpellier, FranceInstitut de Génétique Humaine, Univ. de Montpellier, CNRS, Montpellier, France; ‘Genome Surveillance and Stability’ Laboratory, IGH, Univ. de Montpellier, CNRS, Montpellier, FranceIRCM, Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Université de Montpellier, Institut régional du Cancer de Montpellier, Montpellier, FranceAgricultural Biotechnology Research Center, Academia Sinica, Taipei, Taiwan; Graduate Institute of Integrated Medicine, China Medical University, Taichung, Taiwan; Department of Life Sciences, National Chung-Hsing University, Taichung, Taiwan‘Maintenance of Genome Integrity during DNA replication’ laboratory, équipe labélisée Ligue contre le Cancer, Montpellier, FranceInstitut de Génétique Humaine, Univ. de Montpellier, CNRS, Montpellier, France; ‘Maintenance of Genome Integrity during DNA replication’ laboratory, équipe labélisée Ligue contre le Cancer, Montpellier, FranceCancer cells display high levels of oncogene-induced replication stress (RS) and rely on DNA damage checkpoint for viability. This feature is exploited by cancer therapies to either increase RS to unbearable levels or inhibit checkpoint kinases involved in the DNA damage response. Thus far, treatments that combine these two strategies have shown promise but also have severe adverse effects. To identify novel, better-tolerated anticancer combinations, we screened a collection of plant extracts and found two natural compounds from the plant, Psoralea corylifolia, that synergistically inhibit cancer cell proliferation. Bakuchiol inhibited DNA replication and activated the checkpoint kinase CHK1 by targeting DNA polymerases. Isobavachalcone interfered with DNA double-strand break repair by inhibiting the checkpoint kinase CHK2 and DNA end resection. The combination of bakuchiol and isobavachalcone synergistically inhibited cancer cell proliferation in vitro. Importantly, it also prevented tumor development in xenografted NOD/SCID mice. The synergistic effect of inhibiting DNA replication and CHK2 signaling identifies a vulnerability of cancer cells that might be exploited by using clinically approved inhibitors in novel combination therapies.https://elifesciences.org/articles/104718DNA replicationDNA repaircancer |
| spellingShingle | Flavie Coquel Sing-Zong Ho Keng-Chang Tsai Chun-Yen Yang Antoine Aze Julie Devin Ting-Hsiang Chang Marie Kong-Hap Audrey Bioteau Jerome Moreaux Domenico Maiorano Philippe Pourquier Wen-Chin Yang Yea-Lih Lin Philippe Pasero Synergistic effect of inhibiting CHK2 and DNA replication on cancer cell growth eLife DNA replication DNA repair cancer |
| title | Synergistic effect of inhibiting CHK2 and DNA replication on cancer cell growth |
| title_full | Synergistic effect of inhibiting CHK2 and DNA replication on cancer cell growth |
| title_fullStr | Synergistic effect of inhibiting CHK2 and DNA replication on cancer cell growth |
| title_full_unstemmed | Synergistic effect of inhibiting CHK2 and DNA replication on cancer cell growth |
| title_short | Synergistic effect of inhibiting CHK2 and DNA replication on cancer cell growth |
| title_sort | synergistic effect of inhibiting chk2 and dna replication on cancer cell growth |
| topic | DNA replication DNA repair cancer |
| url | https://elifesciences.org/articles/104718 |
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