PI3K/mTOR dual-inhibition with VS-5584 enhances anti-leukemic efficacy of ponatinib in blasts and Ph-negative LSCs of chronic myeloid leukemia*

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dc.authoridGunduz, Cumhur/0000-0002-6593-3237
dc.authoridGASIMLI, Roya/0000-0002-6760-8921
dc.authorscopusid56497855800
dc.authorscopusid57195753943
dc.authorscopusid56441719900
dc.authorscopusid57195759077
dc.authorscopusid57203588534
dc.authorscopusid57203593277
dc.authorscopusid54889084200
dc.authorwosidYelken, Besra Ozmen/AAT-5375-2021
dc.authorwosidGunduz, Cumhur/GOP-0629-2022
dc.authorwosidBiray Avcı, Cigir/GWV-1665-2022
dc.contributor.authorKayabasi, Cagla
dc.contributor.authorYelken, Besra Ozmen
dc.contributor.authorAsik, Aycan
dc.contributor.authorOkcanoglu, Tugce Balci
dc.contributor.authorSogutlu, Fatma
dc.contributor.authorGasimli, Roya
dc.contributor.authorSusluer, Sunde Yilmaz
dc.date.accessioned2023-01-12T19:54:44Z
dc.date.available2023-01-12T19:54:44Z
dc.date.issued2021
dc.departmentN/A/Departmenten_US
dc.description.abstractPonatinib is used for advanced treatment of chronic myeloid leukemia (CML), although low doses to prevent side effects do not suppress survival pathways and eradicate leukemia stem cells (LSCs). We evaluated the potential of ponatinib and PI3K/mTOR dual-inhibitor VS-5584 combination (PoVS) therapy to increase the anti-leukemic effects of ponatinib and investigated the underlying mechanisms at the molecular level. We measured the cytotoxicities of ponatinib, VS-5584, and PoVS (CCK-8 assay), and used the median-effect equation for combination analyses. We investigated the effects of inhibitory concentrations on apoptosis, cell viability and cell-cycle regulation (flow cytometry), protein levels (ELISA, Western blot), transcriptional activities (dual-luciferase reporter assay), gene expressions (qRT-PCR). VS-5584 exerted selective cytotoxic effects against CML and LSC cell lines. VS-5584 inhibited the PI3K/Akt/mTOR pathway, resulting in reduced cell viability, slightly induced caspase-independent apoptosis, prominent G0/G1 cell-cycle blockade that is not a consequence of quiescence. Normal hematopoietic stem cell line was the least affected. Moreover, ponatinib and VS-5584 mediated synergistic anti-leukemic effects on leukemic cells. VS-5584 reduced the ponatinib dose required to target leukemic cells. PoVS treatment inhibited PI3K/Akt/mTOR pathway more consistently than either of the two agents alone through reducing p-Akt, p-mTOR, p-S6K, p-PRAS40, p-S6. The subsequent downstream effects were an increase in C/EBP transcriptional activity and decreases in activities of E2F/DP1, Myc/Max, CREB, STAT3, NF kappa B, AP-1, Elk-1/SRF. Transcriptional regulation resulted in alterations in the expression levels of target mRNAs. Our results highlight PoVS can be a promising treatment strategy for eliminating CML cells and LSCs selectively, with the reduced ponatinib doses.en_US
dc.description.sponsorshipEge University Scientific Research Projects (BAP) Department [15-TIP-019, 2015-TIP-063]en_US
dc.description.sponsorshipThis work was supported by Ege University Scientific Research Projects (BAP) Department (Grand no. 15-TIP-019, 2015-TIP-063).en_US
dc.identifier.doi10.1016/j.ejphar.2021.174446
dc.identifier.issn0014-2999
dc.identifier.issn1879-0712
dc.identifier.pmid34461124en_US
dc.identifier.scopus2-s2.0-85113748409en_US
dc.identifier.scopusqualityQ1en_US
dc.identifier.urihttps://doi.org/10.1016/j.ejphar.2021.174446
dc.identifier.urihttps://hdl.handle.net/11454/76520
dc.identifier.volume910en_US
dc.identifier.wosWOS:000724575000004en_US
dc.identifier.wosqualityQ2en_US
dc.indekslendigikaynakWeb of Scienceen_US
dc.indekslendigikaynakScopusen_US
dc.indekslendigikaynakPubMeden_US
dc.language.isoenen_US
dc.publisherElsevieren_US
dc.relation.ispartofEuropean Journal of Pharmacologyen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/closedAccessen_US
dc.subjectChronic myeloid leukemiaen_US
dc.subjectLeukemia stem cellen_US
dc.subjectPonatiniben_US
dc.subjectPI3Ken_US
dc.subjectmTOR inhibitoren_US
dc.subjectC/Ebp-Alphaen_US
dc.subjectBcr-Ablen_US
dc.subjectKinase Inhibitoren_US
dc.subjectStem-Cellsen_US
dc.subjectImatiniben_US
dc.subjectDifferentiationen_US
dc.subjectResistanceen_US
dc.subjectBiologyen_US
dc.subjectMtoren_US
dc.subjectCombinationen_US
dc.titlePI3K/mTOR dual-inhibition with VS-5584 enhances anti-leukemic efficacy of ponatinib in blasts and Ph-negative LSCs of chronic myeloid leukemia*en_US
dc.typeArticleen_US

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