Biochemistry And Microbial Sciences - Research Publications

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Author: search.filters.author.Singh, PriyankaSubject: search.filters.subject.BCR-ABL oncoprotein

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    MicroRNA based combinatorial therapy against TKIs resistant CML by inactivating the PI3K/Akt/mTOR pathway: a review
    (Springer, 2023-09-15T00:00:00) Singh, Priyanka
    Chronic myeloid leukemia (CML) is characterized by presence of Philadelphia chromosome, which harbors BCR-ABL oncogene responsible for encoding BCR-ABL oncoprotein. This oncoprotein interferes with cellular signaling pathways, resulting in tumor progression. Among these pathways, PI3K/Akt/mTOR pathway is significantly upregulated in CML. Tyrosine kinase inhibitors (TKIs) are current standard therapy for CML, and they have shown remarkable efficacy. However, emergence of TKIs drug resistance has necessitated investigation of novel therapeutic approaches. Components of PI3K/Akt/mTOR pathway have emerged as attractive targets in this context, as this pathway is known to be activated in TKIs-resistant CML cells/patients. Inhibiting this pathway may provide a complementary approach to improving TKIs� efficacy and treatment outcomes. Given previous research indicating that miRNAs play an inhibitory role in cancer, current study used computational tools to identify miRNAs that specifically target pathway�s core components. A comprehensive analysis was performed, resulting in identification of 111 miRNAs that potentially target PI3K/Akt/mTOR pathway. From this extensive list, 7 miRNAs was selected for further investigation based on their consistent downregulation across leukemia subtypes. Except for hsa-miR-199a-3p, remaining six miRNAs have been extensively studied in acute myeloid leukemia (AML). Given high similarity between AML and CML, it is believed that six miRNAs which are not studied in context of CML may also be advantageous for curing chemoresistance in CML. Building upon this knowledge, it is reasonable to speculate that a combination therapy approach involving use of miRNAs alongside TKIs may offer improved therapy for TKIs-resistant CML compared to TKIs monotherapy alone. � 2023, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.
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    Transport and metabolism of tyrosine kinase inhibitors associated with chronic myeloid leukemia therapy: a review
    (Springer, 2022-02-07T00:00:00) Kumar, Veerandra; Singh, Priyanka; Gupta, Sonu Kumar; Ali, Villayat; Verma, Malkhey
    Imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and asciminib are FDA-approved tyrosine kinase inhibitors (TKIs) for chronic myeloid leukemia (CML), each of which has a specific pharmacological profile. Asciminib has been recently (2021) approved for patients resistant to former TKIs, and because the binding site of this drug (the myristoyl pocket in the ABL1 kinase) is different from that of other TKIs (ATP-binding sites), it is, therefore, effective against T315I mutation of BCR-ABL oncoprotein. All TKIs have a different pharmacological profile due to different chemical structures. Imatinib is the only TKI whose absorption depends on both influx (OCT1 and OATP1A2) and efflux (ABCB1 and ABCG2) transporters, whereas the others rely only on efflux transporters. The efflux of dasatinib is also regulated by ABCC4 and ABCC6 transporters. Nilotinib and ponatinib are transported passively, as no role of transporters has been found in their case. A phenomenon common to all in the metabolic aspect is that the CYP3A4 isoform of CYP450 primarily metabolizes TKIs. Not only does CYP3A4, flavin-containing monooxygenase 3 (FMO3), and uridine 5'-diphospho-glucuronosyltransferase (UGT) also metabolize dasatinib, and similarly, by glucuronidation process, asciminib gets metabolized by UGT enzymes (UGT1A3, UGT1A4, UGT2B7, and UGT2B17). Additionally, the side effects of TKIs are categorized as hematological (thrombocytopenia, neutropenia, anemia, and cardiac dysfunction) and non-hematological (diarrhea, nausea, vomiting, pleural effusion, and skin rash). However, few toxicities are drug-specific, like degradation of biomolecules by ponatinib-glutathione (P-GSH) conjugates and clinical pancreatitis (dose-limited toxicity and manageable by dosage alterations) are related to ponatinib and asciminib, respectively. This review focuses on the pharmacokinetics of approved TKIs related to CML therapy to comprehend their specificity, tolerability, and off-target effects, which could help clinicians to make a patient-specific selection of CML drugs by considering concomitant diseases and risk factors to the patients. � 2022, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.