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Article

BTK and PI3K Inhibitors Reveal Synergistic Inhibitory Anti-Tumoral Effects in Canine Diffuse Large B-Cell Lymphoma Cells

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Department of Medicine Clinic III, Hematology, Oncology and Palliative Medicine, Rostock University Medical Center, 18057 Rostock, Germany
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Small Animal Clinic, University of Veterinary Medicine Hannover, 30559 Hannover, Germany
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Institute of Muscle Biology and Growth, Research Institute for Farm Animal Biology (FBN), 18196 Dummerstorf, Germany
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Institute for Biostatistics and Informatics in Medicine and Ageing Research, Rostock University Medical Center, 18057 Rostock, Germany
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Institute of Biomedical Informatics, Graz University of Technology, 8010 Graz, Austria
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Department for Pathobiology, Clinical Pathology, University of Veterinary Medicine Vienna, Veterinärplatz 1, 1210 Vienna, Austria
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Department of Animal Sciences, Faculty of Agricultural Sciences, University of Goettingen, 37077 Goettingen, Germany
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Chronix Biomedical Goettingen, 37079 Goettingen, Germany
*
Author to whom correspondence should be addressed.
Academic Editor: Alessandro Poggi
Int. J. Mol. Sci. 2021, 22(23), 12673; https://doi.org/10.3390/ijms222312673
Received: 4 October 2021 / Revised: 19 November 2021 / Accepted: 20 November 2021 / Published: 24 November 2021
(This article belongs to the Special Issue Novel Biological Molecules for Cancer Treatments)
Bruton’s tyrosine kinase (BTK) and phosphoinositide 3-kinase (PI3K) in the B-cell receptor (BCR) signaling pathway are considered potential therapeutic targets for the treatment of B-cell lymphomas, among which, diffuse large B-cell lymphoma (DLBCL) is the most common type. Herein, we comparatively evaluated the single and combined application of the BTK inhibitor ibrutinib and the selective PI3Kγ inhibitor AS-605240 in the canine DLBCL cell line CLBL-1. For further comparison, key findings were additionally analyzed in canine B-cell leukemia GL-1 and human DLBCL cell line SU-DHL-4. While ibrutinib alone induced significant anti-proliferative effects on all cell lines in a dose-dependent manner, AS-605240 only induced anti-proliferative effects at high concentrations. Interestingly, ibrutinib and AS-605240 acted synergistically, reducing cell proliferation and increasing apoptosis/necrosis in all cell lines and inducing morphological changes in CLBL-1. Moreover, the combined application of ibrutinib and AS-605240 reduced relative phosphorylation and, in some instances, the levels of the BTK, AKT, GSK3β, and ERK proteins. Comparative variant analysis of RNA-seq data among canine B- and T-lymphoid cell lines and primary B-cell lymphoma samples revealed potentially high-impact somatic variants in the genes that encode PI3K, which may explain why AS-605240 does not singly inhibit the proliferation of cell lines. The combination of ibrutinib and AS-605240 represents a promising approach that warrants further in vivo evaluation in dogs, potentially bearing significant value for the treatment of human DLBCL. View Full-Text
Keywords: BCR signaling pathway; BTK inhibitor; PI3K inhibitor; DLBCL; gene variants BCR signaling pathway; BTK inhibitor; PI3K inhibitor; DLBCL; gene variants
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MDPI and ACS Style

Kong, W.; Sender, S.; Taher, L.; Villa-Perez, S.; Ma, Y.; Sekora, A.; Ruetgen, B.C.; Brenig, B.; Beck, J.; Schuetz, E.; Junghanss, C.; Nolte, I.; Murua Escobar, H. BTK and PI3K Inhibitors Reveal Synergistic Inhibitory Anti-Tumoral Effects in Canine Diffuse Large B-Cell Lymphoma Cells. Int. J. Mol. Sci. 2021, 22, 12673. https://doi.org/10.3390/ijms222312673

AMA Style

Kong W, Sender S, Taher L, Villa-Perez S, Ma Y, Sekora A, Ruetgen BC, Brenig B, Beck J, Schuetz E, Junghanss C, Nolte I, Murua Escobar H. BTK and PI3K Inhibitors Reveal Synergistic Inhibitory Anti-Tumoral Effects in Canine Diffuse Large B-Cell Lymphoma Cells. International Journal of Molecular Sciences. 2021; 22(23):12673. https://doi.org/10.3390/ijms222312673

Chicago/Turabian Style

Kong, Weibo, Sina Sender, Leila Taher, Simon Villa-Perez, Yixuan Ma, Anett Sekora, Barbara C. Ruetgen, Bertram Brenig, Julia Beck, Ekkehard Schuetz, Christian Junghanss, Ingo Nolte, and Hugo Murua Escobar. 2021. "BTK and PI3K Inhibitors Reveal Synergistic Inhibitory Anti-Tumoral Effects in Canine Diffuse Large B-Cell Lymphoma Cells" International Journal of Molecular Sciences 22, no. 23: 12673. https://doi.org/10.3390/ijms222312673

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