SPHINX-based combination therapy as a potential novel treatment strategy for acute myeloid leukaemia

Wodi, Chigeru; Belali, Tareg; Morse, Ruth; Porazinski, Sean; Ladomery, Michael

Abstract

Introduction: Dysregulated alternative splicing is a prominent feature of cancer. The inhibition and knockdown of the SR splice factor kinase SRPK1 reduces tumour growth in vivo. As a result several SPRK1 inhibitors are in development including SPHINX, a 3-(trifluoromethyl)anilide scaffold. The objective of this study was to treat two leukaemic cell lines with SPHINX in combination with the established cancer drugs azacitidine and imatinib. Materials and Methods: We selected two representative cell lines; Kasumi-1, acute myeloid leukaemia, and K562, BCR-ABL positive chronic myeloid leukaemia. Cells were treated with SPHINX concentrations up to 10μM, and in combination with azacitidine (up to 1.5 μg/ml, Kasumi-1 cells) and imatinib (up to 20 μg/ml, K562 cells). Cell viability was determined by counting the proportion of live cells and those undergoing apoptosis through the detection of activated caspase 3/7. SRPK1 was knocked down with siRNA to confirm SPHINX results. Results: The effects of SPHINX were first confirmed by observing reduced levels of phosphorylated SR proteins. SPHINX significantly reduced cell viability and increased apoptosis in Kasumi-1 cells, but less prominently in K562 cells. Knockdown of SRPK1 by RNA interference similarly reduced cell viability. Combining SPHINX with azacitidine augmented the effect of azacitidine in Kasumi-1 cells. In conclusion, SPHINX reduces cell viability and increases apoptosis in the acute myeloid leukaemia cell line Kasumi-1, but less convincingly in the chronic myeloid leukaemia cell line K562. Conclusion: We suggest that specific types of leukaemia may present an opportunity for the development of SRPK1-targeted therapies to be used in combination with established chemotherapeutic drugs.

Citation

Wodi, C., Belali, T., Morse, R., Porazinski, S., & Ladomery, M. (2023). SPHINX-based combination therapy as a potential novel treatment strategy for acute myeloid leukaemia. British Journal of Biomedical Science, 80, 11041. https://doi.org/10.3389/bjbs.2023.11041

• Journal Article Type: Article
• Acceptance Date: Feb 8, 2023
• Online Publication Date: Feb 21, 2023
• Publication Date: Feb 21, 2023
• Deposit Date: Mar 2, 2023
• Publicly Available Date: Mar 2, 2023
• Journal: British Journal of Biomedical Science
• Print ISSN: 0967-4845
• Electronic ISSN: 2474-0896
• Peer Reviewed: Peer Reviewed
• Volume: 80
• Pages: 11041
• DOI: https://doi.org/10.3389/bjbs.2023.11041
• Keywords: Health Archive, acute myeloid leukemia, splice factor kinases, SRPK1, alternative splicing, SPHINX
• Public URL: https://uwe-repository.worktribe.com/output/10483406
• Publisher URL: https://www.frontierspartnerships.org/articles/10.3389/bjbs.2023.11041/full