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, 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, <i>Psoralea corylifolia</i>, 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.
Authors
- Julie Devin (ORCID: https://orcid.org/0000-0001-8929-6992)
- Domenico Maiorano (ORCID: https://orcid.org/0000-0003-4229-5903)
- Philippe Pasero (ORCID: https://orcid.org/0000-0001-5891-0822)
- Flavie Coquel (ORCID: https://orcid.org/0000-0002-6953-3409)
- Jérôme Moreaux (ORCID: https://orcid.org/0000-0002-5717-3207)
- Keng‐Chang Tsai (ORCID: https://orcid.org/0000-0001-8277-9174)
- Marie Kong-Hap
- Sing-Zong Ho (ORCID: https://orcid.org/0009-0008-9986-6061)
- Philippe Pourquier (ORCID: https://orcid.org/0000-0001-5326-3005)
- Antoine Aze
- Wen‐Chin Yang (ORCID: https://orcid.org/0000-0001-6410-2581)
- Chun‐Yen Yang (ORCID: https://orcid.org/0000-0003-3941-4561)
- Yea‐Lih Lin (ORCID: https://orcid.org/0000-0003-4063-0771)
- Ting-Hsiang Chang
- Audrey Bioteau
Institutions
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- National Chung Hsing University (TW)
- Institut Universitaire de France (FR)
- Université de Montpellier (FR)
- Centre Hospitalier Universitaire de Montpellier (FR)
- National Research Institute of Chinese Medicine (TW)
- Institut de Recherche en Cancérologie de Montpellier (FR)
- Agricultural Biotechnology Research Center, Academia Sinica (TW)
- Institut de Génétique Humaine (FR)
- Taipei Medical University (TW)
- China Medical University (CN)
Publication Details
- Journal
- eLife
- Published
- 2024-12-30
- DOI
- https://doi.org/10.7554/elife.104718
- Citations
- 3
- Primary Topic
- Cancer therapeutics and mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 0.70
Funders
- Fondation ARC pour la Recherche sur le Cancer
- Ligue Contre le Cancer
- Institut National Du Cancer
- Région Occitanie Pyrénées-Méditerranée