JKST6, a novel multikinase modulator of the BCR-ABL1/STAT5 signaling pathway that potentiates direct BCR-ABL1 inhibition and overcomes imatinib resistance in chronic myelogenous leukemia

Chronic myelogenous leukemia (CML) is a hematological malignancy that highly depends on the BCR-ABL1/STAT5 signaling pathway for cell survival. First-line treatments for CML consist of tyrosine kinase inhibitors that efficiently target BCR-ABL1 activity. However, drug resistance and intolerance are...

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Autores principales:	Haidée Aranda-Tavío, Carlota Recio, Pedro Martín-Acosta, Miguel Guerra-Rodríguez, Yeray Brito-Casillas, Rosa Blanco, Vanessa Junco, Javier León, Juan Carlos Montero, Lucía Gandullo-Sánchez, Grant McNaughton-Smith, Juan Manuel Zapata, Atanasio Pandiella, Angel Amesty, Ana Estévez-Braun, Leandro Fernández-Pérez, Borja Guerra
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	Chronic myelogenous leukemia BCR-ABL1 Synergism Imatinib resistance Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/92342ec5291144c1b598681c8beb4683
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spelling	oai:doaj.org-article:92342ec5291144c1b598681c8beb46832021-11-14T04:29:48ZJKST6, a novel multikinase modulator of the BCR-ABL1/STAT5 signaling pathway that potentiates direct BCR-ABL1 inhibition and overcomes imatinib resistance in chronic myelogenous leukemia0753-332210.1016/j.biopha.2021.112330https://doaj.org/article/92342ec5291144c1b598681c8beb46832021-12-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S0753332221011148https://doaj.org/toc/0753-3322Chronic myelogenous leukemia (CML) is a hematological malignancy that highly depends on the BCR-ABL1/STAT5 signaling pathway for cell survival. First-line treatments for CML consist of tyrosine kinase inhibitors that efficiently target BCR-ABL1 activity. However, drug resistance and intolerance are still therapeutic limitations in Ph+ cells. Therefore, the development of new anti-CML drugs that exhibit alternative mechanisms to overcome these limitations is a desirable goal. In this work, the antitumoral activity of JKST6, a naphthoquinone-pyrone hybrid, was assessed in imatinib-sensitive and imatinib-resistant human CML cells. Live-cell imaging analysis revealed JKST6 potent antiproliferative activity in 2D and 3D CML cultures. JKST6 provoked cell increase in the subG1 phase along with a reduction in the G0/G1 phase and altered the expression of key proteins involved in the control of mitosis and DNA damage. Rapid increases in Annexin V staining and activation/cleavage of caspases 8, 9 and 3 were observed after JKST6 treatment in CML cells. Of interest, JKST6 inhibited BCR-ABL1/STAT5 signaling through oncokinase downregulation that was preceded by rapid polyubiquitination. In addition, JKST6 caused a transient increase in JNK and AKT phosphorylation, whereas the phosphorylation of P38-MAPK and Src was reduced. Combinatory treatment unveiled synergistic effects between imatinib and JKST6. Notably, JKST6 maintained its antitumor efficacy in BCR-ABL1-T315I-positive cells and CML cells that overexpress BCR-ABL and even restored imatinib efficacy after a short exposure time. These findings, together with the observed low toxicity of JKST6, reveal a novel multikinase modulator that might overcome the limitations of BCR-ABL1 inhibitors in CML therapy.Haidée Aranda-TavíoCarlota RecioPedro Martín-AcostaMiguel Guerra-RodríguezYeray Brito-CasillasRosa BlancoVanessa JuncoJavier LeónJuan Carlos MonteroLucía Gandullo-SánchezGrant McNaughton-SmithJuan Manuel ZapataAtanasio PandiellaAngel AmestyAna Estévez-BraunLeandro Fernández-PérezBorja GuerraElsevierarticleChronic myelogenous leukemiaBCR-ABL1SynergismImatinib resistanceTherapeutics. PharmacologyRM1-950ENBiomedicine & Pharmacotherapy, Vol 144, Iss , Pp 112330- (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Chronic myelogenous leukemia BCR-ABL1 Synergism Imatinib resistance Therapeutics. Pharmacology RM1-950
spellingShingle	Chronic myelogenous leukemia BCR-ABL1 Synergism Imatinib resistance Therapeutics. Pharmacology RM1-950 Haidée Aranda-Tavío Carlota Recio Pedro Martín-Acosta Miguel Guerra-Rodríguez Yeray Brito-Casillas Rosa Blanco Vanessa Junco Javier León Juan Carlos Montero Lucía Gandullo-Sánchez Grant McNaughton-Smith Juan Manuel Zapata Atanasio Pandiella Angel Amesty Ana Estévez-Braun Leandro Fernández-Pérez Borja Guerra JKST6, a novel multikinase modulator of the BCR-ABL1/STAT5 signaling pathway that potentiates direct BCR-ABL1 inhibition and overcomes imatinib resistance in chronic myelogenous leukemia
description	Chronic myelogenous leukemia (CML) is a hematological malignancy that highly depends on the BCR-ABL1/STAT5 signaling pathway for cell survival. First-line treatments for CML consist of tyrosine kinase inhibitors that efficiently target BCR-ABL1 activity. However, drug resistance and intolerance are still therapeutic limitations in Ph+ cells. Therefore, the development of new anti-CML drugs that exhibit alternative mechanisms to overcome these limitations is a desirable goal. In this work, the antitumoral activity of JKST6, a naphthoquinone-pyrone hybrid, was assessed in imatinib-sensitive and imatinib-resistant human CML cells. Live-cell imaging analysis revealed JKST6 potent antiproliferative activity in 2D and 3D CML cultures. JKST6 provoked cell increase in the subG1 phase along with a reduction in the G0/G1 phase and altered the expression of key proteins involved in the control of mitosis and DNA damage. Rapid increases in Annexin V staining and activation/cleavage of caspases 8, 9 and 3 were observed after JKST6 treatment in CML cells. Of interest, JKST6 inhibited BCR-ABL1/STAT5 signaling through oncokinase downregulation that was preceded by rapid polyubiquitination. In addition, JKST6 caused a transient increase in JNK and AKT phosphorylation, whereas the phosphorylation of P38-MAPK and Src was reduced. Combinatory treatment unveiled synergistic effects between imatinib and JKST6. Notably, JKST6 maintained its antitumor efficacy in BCR-ABL1-T315I-positive cells and CML cells that overexpress BCR-ABL and even restored imatinib efficacy after a short exposure time. These findings, together with the observed low toxicity of JKST6, reveal a novel multikinase modulator that might overcome the limitations of BCR-ABL1 inhibitors in CML therapy.
format	article
author	Haidée Aranda-Tavío Carlota Recio Pedro Martín-Acosta Miguel Guerra-Rodríguez Yeray Brito-Casillas Rosa Blanco Vanessa Junco Javier León Juan Carlos Montero Lucía Gandullo-Sánchez Grant McNaughton-Smith Juan Manuel Zapata Atanasio Pandiella Angel Amesty Ana Estévez-Braun Leandro Fernández-Pérez Borja Guerra
author_facet	Haidée Aranda-Tavío Carlota Recio Pedro Martín-Acosta Miguel Guerra-Rodríguez Yeray Brito-Casillas Rosa Blanco Vanessa Junco Javier León Juan Carlos Montero Lucía Gandullo-Sánchez Grant McNaughton-Smith Juan Manuel Zapata Atanasio Pandiella Angel Amesty Ana Estévez-Braun Leandro Fernández-Pérez Borja Guerra
author_sort	Haidée Aranda-Tavío
title	JKST6, a novel multikinase modulator of the BCR-ABL1/STAT5 signaling pathway that potentiates direct BCR-ABL1 inhibition and overcomes imatinib resistance in chronic myelogenous leukemia
title_short	JKST6, a novel multikinase modulator of the BCR-ABL1/STAT5 signaling pathway that potentiates direct BCR-ABL1 inhibition and overcomes imatinib resistance in chronic myelogenous leukemia
title_full	JKST6, a novel multikinase modulator of the BCR-ABL1/STAT5 signaling pathway that potentiates direct BCR-ABL1 inhibition and overcomes imatinib resistance in chronic myelogenous leukemia
title_fullStr	JKST6, a novel multikinase modulator of the BCR-ABL1/STAT5 signaling pathway that potentiates direct BCR-ABL1 inhibition and overcomes imatinib resistance in chronic myelogenous leukemia
title_full_unstemmed	JKST6, a novel multikinase modulator of the BCR-ABL1/STAT5 signaling pathway that potentiates direct BCR-ABL1 inhibition and overcomes imatinib resistance in chronic myelogenous leukemia
title_sort	jkst6, a novel multikinase modulator of the bcr-abl1/stat5 signaling pathway that potentiates direct bcr-abl1 inhibition and overcomes imatinib resistance in chronic myelogenous leukemia
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/92342ec5291144c1b598681c8beb4683
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JKST6, a novel multikinase modulator of the BCR-ABL1/STAT5 signaling pathway that potentiates direct BCR-ABL1 inhibition and overcomes imatinib resistance in chronic myelogenous leukemia

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