New Therapeutic Strategy for Overcoming Multidrug Resistance in Cancer Cells with Pyrazolo[3,4-<i>d</i>]pyrimidine Tyrosine Kinase Inhibitors

Tyrosine kinase inhibitors (TKIs) often interact with the multidrug resistant (MDR) phenotype of cancer cells. In some cases, TKIs increase the susceptibility of MDR cancer cells to chemotherapy. As the overexpression of membrane transporter P-glycoprotein (P-gp) is the most common alteration in MDR...

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Autores principales:	Ana Podolski-Renić, Jelena Dinić, Tijana Stanković, Ivanka Tsakovska, Ilza Pajeva, Tiziano Tuccinardi, Lorenzo Botta, Silvia Schenone, Milica Pešić
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	cancer multidrug resistance P-glycoprotein inhibitors Src family tyrosine kinase inhibitors Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/b9af093a68564137ac115fcfbdaf7a4f
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spelling	oai:doaj.org-article:b9af093a68564137ac115fcfbdaf7a4f2021-11-11T15:27:57ZNew Therapeutic Strategy for Overcoming Multidrug Resistance in Cancer Cells with Pyrazolo[3,4-<i>d</i>]pyrimidine Tyrosine Kinase Inhibitors10.3390/cancers132153082072-6694https://doaj.org/article/b9af093a68564137ac115fcfbdaf7a4f2021-10-01T00:00:00Zhttps://www.mdpi.com/2072-6694/13/21/5308https://doaj.org/toc/2072-6694Tyrosine kinase inhibitors (TKIs) often interact with the multidrug resistant (MDR) phenotype of cancer cells. In some cases, TKIs increase the susceptibility of MDR cancer cells to chemotherapy. As the overexpression of membrane transporter P-glycoprotein (P-gp) is the most common alteration in MDR cancer cells, we investigated the effects of TKI pyrazolo[3,4-<i>d</i>]pyrimidines on P-gp inhibition in two cellular models comprising sensitive and corresponding MDR cancer cells (human non-small cell lung carcinoma and colorectal adenocarcinoma). Tested TKIs showed collateral sensitivity by inducing stronger inhibition of MDR cancer cell line viability. Moreover, TKIs directly interacted with P-gp and inhibited its ATPase activity. Their potential P-gp binding site was proposed by molecular docking simulations. TKIs reversed resistance to doxorubicin and paclitaxel in a concentration-dependent manner. The expression studies excluded the indirect effect of TKIs on P-gp through regulation of its expression. A kinetics study showed that TKIs decreased P-gp activity and this effect was sustained for seven days in both MDR models. Therefore, pyrazolo[3,4-<i>d</i>]pyrimidines with potential for reversing P-gp-mediated MDR even in prolonged treatments can be considered a new therapeutic strategy for overcoming cancer MDR.Ana Podolski-RenićJelena DinićTijana StankovićIvanka TsakovskaIlza PajevaTiziano TuccinardiLorenzo BottaSilvia SchenoneMilica PešićMDPI AGarticlecancermultidrug resistanceP-glycoprotein inhibitorsSrc family tyrosine kinase inhibitorsNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENCancers, Vol 13, Iss 5308, p 5308 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	cancer multidrug resistance P-glycoprotein inhibitors Src family tyrosine kinase inhibitors Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	cancer multidrug resistance P-glycoprotein inhibitors Src family tyrosine kinase inhibitors Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Ana Podolski-Renić Jelena Dinić Tijana Stanković Ivanka Tsakovska Ilza Pajeva Tiziano Tuccinardi Lorenzo Botta Silvia Schenone Milica Pešić New Therapeutic Strategy for Overcoming Multidrug Resistance in Cancer Cells with Pyrazolo[3,4-<i>d</i>]pyrimidine Tyrosine Kinase Inhibitors
description	Tyrosine kinase inhibitors (TKIs) often interact with the multidrug resistant (MDR) phenotype of cancer cells. In some cases, TKIs increase the susceptibility of MDR cancer cells to chemotherapy. As the overexpression of membrane transporter P-glycoprotein (P-gp) is the most common alteration in MDR cancer cells, we investigated the effects of TKI pyrazolo[3,4-<i>d</i>]pyrimidines on P-gp inhibition in two cellular models comprising sensitive and corresponding MDR cancer cells (human non-small cell lung carcinoma and colorectal adenocarcinoma). Tested TKIs showed collateral sensitivity by inducing stronger inhibition of MDR cancer cell line viability. Moreover, TKIs directly interacted with P-gp and inhibited its ATPase activity. Their potential P-gp binding site was proposed by molecular docking simulations. TKIs reversed resistance to doxorubicin and paclitaxel in a concentration-dependent manner. The expression studies excluded the indirect effect of TKIs on P-gp through regulation of its expression. A kinetics study showed that TKIs decreased P-gp activity and this effect was sustained for seven days in both MDR models. Therefore, pyrazolo[3,4-<i>d</i>]pyrimidines with potential for reversing P-gp-mediated MDR even in prolonged treatments can be considered a new therapeutic strategy for overcoming cancer MDR.
format	article
author	Ana Podolski-Renić Jelena Dinić Tijana Stanković Ivanka Tsakovska Ilza Pajeva Tiziano Tuccinardi Lorenzo Botta Silvia Schenone Milica Pešić
author_facet	Ana Podolski-Renić Jelena Dinić Tijana Stanković Ivanka Tsakovska Ilza Pajeva Tiziano Tuccinardi Lorenzo Botta Silvia Schenone Milica Pešić
author_sort	Ana Podolski-Renić
title	New Therapeutic Strategy for Overcoming Multidrug Resistance in Cancer Cells with Pyrazolo[3,4-<i>d</i>]pyrimidine Tyrosine Kinase Inhibitors
title_short	New Therapeutic Strategy for Overcoming Multidrug Resistance in Cancer Cells with Pyrazolo[3,4-<i>d</i>]pyrimidine Tyrosine Kinase Inhibitors
title_full	New Therapeutic Strategy for Overcoming Multidrug Resistance in Cancer Cells with Pyrazolo[3,4-<i>d</i>]pyrimidine Tyrosine Kinase Inhibitors
title_fullStr	New Therapeutic Strategy for Overcoming Multidrug Resistance in Cancer Cells with Pyrazolo[3,4-<i>d</i>]pyrimidine Tyrosine Kinase Inhibitors
title_full_unstemmed	New Therapeutic Strategy for Overcoming Multidrug Resistance in Cancer Cells with Pyrazolo[3,4-<i>d</i>]pyrimidine Tyrosine Kinase Inhibitors
title_sort	new therapeutic strategy for overcoming multidrug resistance in cancer cells with pyrazolo[3,4-<i>d</i>]pyrimidine tyrosine kinase inhibitors
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/b9af093a68564137ac115fcfbdaf7a4f
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New Therapeutic Strategy for Overcoming Multidrug Resistance in Cancer Cells with Pyrazolo[3,4-<i>d</i>]pyrimidine Tyrosine Kinase Inhibitors

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