Effects of the CK2 inhibitors CX-4945 and CX-5011 on drug-resistant cells.
CK2 is a pleiotropic protein kinase, which regulates many survival pathways and plays a global anti-apoptotic function. It is highly expressed in tumor cells, and is presently considered a promising therapeutic target. Among the many inhibitors available for this kinase, the recently developed CX-49...
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doaj-1628c93d81e54239a1197f03df0b67902021-03-04T12:19:57ZengPublic Library of Science (PLoS)PLoS ONE1932-62032012-01-01711e4919310.1371/journal.pone.0049193Effects of the CK2 inhibitors CX-4945 and CX-5011 on drug-resistant cells.Sofia ZaninChristian BorgoCristina GirardiSean E O'BrienYoshihiko MiyataLorenzo A PinnaArianna Donella-DeanaMaria RuzzeneCK2 is a pleiotropic protein kinase, which regulates many survival pathways and plays a global anti-apoptotic function. It is highly expressed in tumor cells, and is presently considered a promising therapeutic target. Among the many inhibitors available for this kinase, the recently developed CX-4945 and CX-5011 have proved to be very potent, selective and effective in inducing cell death in tumor cells; CX-4945 has recently entered clinical trials. However, no data are available on the efficacy of these compounds to overcome drug resistance, a major reasons of cancer therapy failure. Here we address this point, by studying their effects in several tumor cell lines, each available as variant R resistant to drug-induced apoptosis, and normal-sensitive variant S. We found that the inhibition of endogenous CK2 was very similar in S and R treated cells, with more than 50% CK2 activity reduction at sub-micromolar concentrations of CX-4945 and CX-5011. A consequent apoptotic response was induced both in S and R variants of each pairs. Moreover, the combined treatment of CX-4945 plus vinblastine was able to sensitize to vinblastine R cells that are otherwise almost insensitive to this conventional antitumor drug. Consistently, doxorubicin accumulation in multidrug resistant (MDR) cells was greatly increased by CX-4945.In summary, we demonstrated that all the R variants are sensitive to CX-4945 and CX-5011; since some of the treated R lines express the extrusion pump Pgp, often responsible of the MDR phenotype, we can also conclude that the two inhibitors can successfully overcome the MDR phenomenon.https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23145120/?tool=EBI |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Sofia Zanin Christian Borgo Cristina Girardi Sean E O'Brien Yoshihiko Miyata Lorenzo A Pinna Arianna Donella-Deana Maria Ruzzene |
spellingShingle |
Sofia Zanin Christian Borgo Cristina Girardi Sean E O'Brien Yoshihiko Miyata Lorenzo A Pinna Arianna Donella-Deana Maria Ruzzene Effects of the CK2 inhibitors CX-4945 and CX-5011 on drug-resistant cells. PLoS ONE |
author_facet |
Sofia Zanin Christian Borgo Cristina Girardi Sean E O'Brien Yoshihiko Miyata Lorenzo A Pinna Arianna Donella-Deana Maria Ruzzene |
author_sort |
Sofia Zanin |
title |
Effects of the CK2 inhibitors CX-4945 and CX-5011 on drug-resistant cells. |
title_short |
Effects of the CK2 inhibitors CX-4945 and CX-5011 on drug-resistant cells. |
title_full |
Effects of the CK2 inhibitors CX-4945 and CX-5011 on drug-resistant cells. |
title_fullStr |
Effects of the CK2 inhibitors CX-4945 and CX-5011 on drug-resistant cells. |
title_full_unstemmed |
Effects of the CK2 inhibitors CX-4945 and CX-5011 on drug-resistant cells. |
title_sort |
effects of the ck2 inhibitors cx-4945 and cx-5011 on drug-resistant cells. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS ONE |
issn |
1932-6203 |
publishDate |
2012-01-01 |
description |
CK2 is a pleiotropic protein kinase, which regulates many survival pathways and plays a global anti-apoptotic function. It is highly expressed in tumor cells, and is presently considered a promising therapeutic target. Among the many inhibitors available for this kinase, the recently developed CX-4945 and CX-5011 have proved to be very potent, selective and effective in inducing cell death in tumor cells; CX-4945 has recently entered clinical trials. However, no data are available on the efficacy of these compounds to overcome drug resistance, a major reasons of cancer therapy failure. Here we address this point, by studying their effects in several tumor cell lines, each available as variant R resistant to drug-induced apoptosis, and normal-sensitive variant S. We found that the inhibition of endogenous CK2 was very similar in S and R treated cells, with more than 50% CK2 activity reduction at sub-micromolar concentrations of CX-4945 and CX-5011. A consequent apoptotic response was induced both in S and R variants of each pairs. Moreover, the combined treatment of CX-4945 plus vinblastine was able to sensitize to vinblastine R cells that are otherwise almost insensitive to this conventional antitumor drug. Consistently, doxorubicin accumulation in multidrug resistant (MDR) cells was greatly increased by CX-4945.In summary, we demonstrated that all the R variants are sensitive to CX-4945 and CX-5011; since some of the treated R lines express the extrusion pump Pgp, often responsible of the MDR phenotype, we can also conclude that the two inhibitors can successfully overcome the MDR phenomenon. |
url |
https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23145120/?tool=EBI |
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