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S1P Signaling Genes as Prominent Drivers of BCR-ABL1-Independent Imatinib Resistance and Six Herbal Compounds as Potential Drugs for Chronic Myeloid Leukemia.
Morang, Sikha; Bisht, Manisha; Upadhyay, Vikas; Thapliyal, Surabhi; Handu, Shailendra.
Afiliación
  • Morang S; Department of Pharmacology, All India Institute of Medical Sciences, Rishikesh, India.
  • Bisht M; Department of Pharmacology, All India Institute of Medical Sciences, Rishikesh, India.
  • Upadhyay V; Department of AYUSH, All India Institute of Medical Sciences, Rishikesh, India.
  • Thapliyal S; School of Neuroscience, Virginia Tech, Blacksburg, United States.
  • Handu S; Department of Pharmacology, All India Institute of Medical Sciences, Rishikesh, India.
OMICS ; 28(7): 367-376, 2024 07.
Article en En | MEDLINE | ID: mdl-38986084
ABSTRACT
Imatinib (IM), a breakthrough in chronic myeloid leukemia (CML) treatment, is accompanied by discontinuation challenges owing to drug intolerance. Although BCR-ABL1 mutation is a key cause of CML resistance, understanding mechanisms independent of BCR-ABL1 is also important. This study investigated the sphingosine-1-phosphate (S1P) signaling-associated genes (SphK1 and S1PRs) and their role in BCR-ABL1-independent resistant CML, an area currently lacking investigation. Through comprehensive transcriptomic analysis of IM-sensitive and IM-resistant CML groups, we identified the differentially expressed genes and found a notable upregulation of SphK1, S1PR2, and S1PR5 in IM-resistant CML. Functional annotation revealed their roles in critical cellular processes such as proliferation and GPCR activity. Their network analysis uncovered significant clusters, emphasizing the interconnectedness of the S1P signaling genes. Further, we identified interactors such as BIRC3, TRAF6, and SRC genes, with potential implications for IM resistance. Additionally, receiver operator characteristic curve analysis suggested these genes' potential as biomarkers for predicting IM resistance. Network pharmacology analysis identified six herbal compounds-ampelopsin, ellagic acid, colchicine, epigallocatechin-3-gallate, cucurbitacin B, and evodin-as potential drug candidates targeting the S1P signaling genes. In summary, this study contributes to efforts to better understand the molecular mechanisms underlying BCR-ABL1-independent CML resistance. Moreover, the S1P signaling genes are promising therapeutic targets and plausible new innovation avenues to combat IM resistance in cancer clinical care in the future.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Leucemia Mielógena Crónica BCR-ABL Positiva / Transducción de Señal / Proteínas de Fusión bcr-abl / Resistencia a Antineoplásicos / Mesilato de Imatinib Límite: Female / Humans Idioma: En Revista: OMICS Asunto de la revista: BIOLOGIA MOLECULAR Año: 2024 Tipo del documento: Article País de afiliación: India Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Leucemia Mielógena Crónica BCR-ABL Positiva / Transducción de Señal / Proteínas de Fusión bcr-abl / Resistencia a Antineoplásicos / Mesilato de Imatinib Límite: Female / Humans Idioma: En Revista: OMICS Asunto de la revista: BIOLOGIA MOLECULAR Año: 2024 Tipo del documento: Article País de afiliación: India Pais de publicación: Estados Unidos