Combination of bazedoxifene with chemotherapy and SMAC-mimetics for the treatment of colorectal cancer.

Autor: Dmello RS; Olivia Newton-John Cancer Research Institute and School of Cancer Medicine, La Trobe University, Heidelberg, VIC, 3084, Australia., Palmieri M; Walter and Eliza Hall Institute of Medical Research (WEHI), Parkville, VIC, 3010, Australia., Thilakasiri PS; Olivia Newton-John Cancer Research Institute and School of Cancer Medicine, La Trobe University, Heidelberg, VIC, 3084, Australia., Doughty L; Department of Biochemistry and Pharmacology, and ACRF Facility for Innovative Cancer Drug Discovery, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, VIC, 3010, Australia., Nero TL; Department of Biochemistry and Pharmacology, and ACRF Facility for Innovative Cancer Drug Discovery, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, VIC, 3010, Australia., Poh AR; Olivia Newton-John Cancer Research Institute and School of Cancer Medicine, La Trobe University, Heidelberg, VIC, 3084, Australia., To SQ; Olivia Newton-John Cancer Research Institute and School of Cancer Medicine, La Trobe University, Heidelberg, VIC, 3084, Australia., Lee EF; Olivia Newton-John Cancer Research Institute and School of Cancer Medicine, La Trobe University, Heidelberg, VIC, 3084, Australia.; Department of Biochemistry and Chemistry, School of Agriculture, Biomedicine and Environment, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, VIC, 3083, Australia., Douglas Fairlie W; Olivia Newton-John Cancer Research Institute and School of Cancer Medicine, La Trobe University, Heidelberg, VIC, 3084, Australia.; Department of Biochemistry and Chemistry, School of Agriculture, Biomedicine and Environment, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, VIC, 3083, Australia., Mielke L; Olivia Newton-John Cancer Research Institute and School of Cancer Medicine, La Trobe University, Heidelberg, VIC, 3084, Australia., Parker MW; Department of Biochemistry and Pharmacology, and ACRF Facility for Innovative Cancer Drug Discovery, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, VIC, 3010, Australia.; ACRF Rational Drug Discovery Centre, St. Vincent's Institute of Medical Research, Fitzroy, VIC, 3065, Australia., Poon IKH; Department of Biochemistry and Chemistry, School of Agriculture, Biomedicine and Environment, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, VIC, 3083, Australia., Batlle E; Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology (BIST), 08028, Barcelona, Spain., Ernst M; Olivia Newton-John Cancer Research Institute and School of Cancer Medicine, La Trobe University, Heidelberg, VIC, 3084, Australia., Chand AL; Olivia Newton-John Cancer Research Institute and School of Cancer Medicine, La Trobe University, Heidelberg, VIC, 3084, Australia. ashwini.chand@onjcri.org.au.
Jazyk: angličtina
Zdroj: Cell death & disease [Cell Death Dis] 2024 Apr 10; Vol. 15 (4), pp. 255. Date of Electronic Publication: 2024 Apr 10.
DOI: 10.1038/s41419-024-06631-8
Abstrakt: Excessive STAT3 signalling via gp130, the shared receptor subunit for IL-6 and IL-11, contributes to disease progression and poor survival outcomes in patients with colorectal cancer. Here, we provide evidence that bazedoxifene inhibits tumour growth via direct interaction with the gp130 receptor to suppress IL-6 and IL-11-mediated STAT3 signalling. Additionally, bazedoxifene combined with chemotherapy synergistically reduced cell proliferation and induced apoptosis in patient-derived colon cancer organoids. We elucidated that the primary mechanism of anti-tumour activity conferred by bazedoxifene treatment occurs via pro-apoptotic responses in tumour cells. Co-treatment with bazedoxifene and the SMAC-mimetics, LCL161 or Birinapant, that target the IAP family of proteins, demonstrated increased apoptosis and reduced proliferation in colorectal cancer cells. Our findings provide evidence that bazedoxifene treatment could be combined with SMAC-mimetics and chemotherapy to enhance tumour cell apoptosis in colorectal cancer, where gp130 receptor signalling promotes tumour growth and progression.
(© 2024. The Author(s).)
Databáze: MEDLINE
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