review · Cancer Cell International
Resistance to chemotherapy limits cancer treatment efficacy, leading to recurrence, metastasis, and patient mortality. Tumour cells frequently display high levels of sphingosine kinase-1, an enzyme that produces sphingosine-1 phosphate. Once exported into the tumour microenvironment, sphingosine-1 phosphate promotes anti-apoptotic activity, angiogenesis, epithelial-mesenchymal transition, invasion, and resistance to chemotherapeutic drugs. Elevated levels occur across ovarian, prostate, colorectal, breast, and hepatocellular carcinomas. Targeting this signalling axis offers a strategy to restore sensitivity to chemotherapy. Bioinformatics analysis demonstrates that altered sphingosine kinase-1 expression correlates with patient survival across diverse cancers, while protein interaction networks clarify its broader cellular roles. Furthermore, molecular docking assessments of publicly accessible sphingosine kinase-1 inhibitors confirm their capacity to suppress sphingosine-1 phosphate production, highlighting their prospective value in reducing chemoresistance and improving oncological outcomes.
Chemotherapy resistance remains a critical barrier to effective cancer therapy, frequently leading to disease relapse and death. Demonstrating how sphingosine kinase-1 and sphingosine-1 phosphate drive resistance mechanisms across multiple prevalent cancers helps clarify potential therapeutic targets. By identifying inhibitors capable of disrupting this pathway, researchers can design combination treatments aimed at restoring chemotherapy responsiveness and prolonging patient survival.
This research informs early-stage drug discovery programmes aimed at overcoming chemoresistance in oncology. Pharmaceutical developers and medicinal chemists could utilise the evaluated sphingosine kinase-1 inhibitors and docking profiles to design targeted combination therapies alongside standard chemotherapeutics. Because the findings rely on computational bioinformatic frameworks and molecular docking of existing compounds, the work is at an early exploratory stage, requiring preclinical laboratory validation before clinical development.
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Cancer chemoresistance is a problematic dilemma that significantly restrains numerous cancer management protocols. It can promote cancer recurrence, spreading of cancer, and finally, mortality. Accordingly, enhancing the responsiveness of cancer cells towards chemotherapies could be a vital approach to overcoming cancer chemoresistance. Tumour cells express a high level of sphingosine kinase-1 (SphK1), which acts as a protooncogenic factor and is responsible for the synthesis of sphingosine-1 phosphate (S1P). S1P is released through a Human ATP-binding cassette (ABC) transporter to interact with other phosphosphingolipids components in the interstitial fluid in the tumor microenvironment (TME), provoking communication, progression, invasion, and tumor metastasis. Also, S1P is associated with several impacts, including anti-apoptotic behavior, metastasis, mesenchymal transition (EMT), angiogenesis, and chemotherapy resistance. Recent reports addressed high levels of S1P in several carcinomas, including ovarian, prostate, colorectal, breast, and HCC. Therefore, targeting the S1P/SphK signaling pathway is an emerging therapeutic approach to efficiently attenuate chemoresistance. In this review, we comprehensively discussed S1P functions, metabolism, transport, and signaling. Also, through a bioinformatic framework, we pointed out the alterations of SphK1 gene expression within different cancers with their impact on patient survival, and we demonstrated the protein-protein network of SphK1, elaborating its sparse roles. Furthermore, we made emphasis on different machineries of cancer resistance and the tight link with S1P. We evaluated all publicly available SphK1 inhibitors and their inhibition activity using molecular docking and how SphK1 inhibitors reduce the production of S1P and might reduce chemoresistance, an approach that might be vital in the course of cancer treatment and prognosis.
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DOI: 10.1186/s12935-024-03221-8
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