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Low dose dinaciclib enhances doxorubicin-induced senescence in myeloma RPMI8226 cells by transformation of the p21 and p16 pathways

Multiple myeloma (MM) is a hematological malignancy that lacks a cure. However, novel combination therapy is a current anti-MM strategy. Doxorubicin (DOX) is a type of anthracycline which is a first-line chemotherapeutic for treating MM and induces senescence in many types of cancer. Dinaciclib is a...

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Autores principales: Tang, Hailong, Xu, Li, Liang, Xue, Gao, Guangxun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: D.A. Spandidos 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6202540/
https://www.ncbi.nlm.nih.gov/pubmed/30405800
http://dx.doi.org/10.3892/ol.2018.9474
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author Tang, Hailong
Xu, Li
Liang, Xue
Gao, Guangxun
author_facet Tang, Hailong
Xu, Li
Liang, Xue
Gao, Guangxun
author_sort Tang, Hailong
collection PubMed
description Multiple myeloma (MM) is a hematological malignancy that lacks a cure. However, novel combination therapy is a current anti-MM strategy. Doxorubicin (DOX) is a type of anthracycline which is a first-line chemotherapeutic for treating MM and induces senescence in many types of cancer. Dinaciclib is a potent, small molecule CDK inhibitor with promise for treating several types of cancer in I/II phase clinical trials. In the present study the anticancer effects and underlying mechanisms of dinaciclib combined with DOX in MM RPMI-8226 cells were investigated. Results indicated that DOX induced cell viability inhibition, cell cycle arrest and senescence. Furthermore, DOX resulted in increased alterations in DNA damage-related proteins such as p-ATM, p-Chk2, p-p53, p21 and γH2AX, but not p16. Notably, the combination of dinaciclib and DOX inhibited cell growth and promoted senescence by transforming the suppressive effects of the ATM/Chk2/p53/p21 signaling pathway and enhancing the p16 signaling pathway. Thus, low-dose dinaciclib enhanced anti-MM effects mediated by DOX via transformation of p21-p16 signaling pathways, leading to accelerated senescence, but not apoptosis. The present findings suggest this approach may be a promising therapeutic strategy for the treatment of MM.
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spelling pubmed-62025402018-11-07 Low dose dinaciclib enhances doxorubicin-induced senescence in myeloma RPMI8226 cells by transformation of the p21 and p16 pathways Tang, Hailong Xu, Li Liang, Xue Gao, Guangxun Oncol Lett Articles Multiple myeloma (MM) is a hematological malignancy that lacks a cure. However, novel combination therapy is a current anti-MM strategy. Doxorubicin (DOX) is a type of anthracycline which is a first-line chemotherapeutic for treating MM and induces senescence in many types of cancer. Dinaciclib is a potent, small molecule CDK inhibitor with promise for treating several types of cancer in I/II phase clinical trials. In the present study the anticancer effects and underlying mechanisms of dinaciclib combined with DOX in MM RPMI-8226 cells were investigated. Results indicated that DOX induced cell viability inhibition, cell cycle arrest and senescence. Furthermore, DOX resulted in increased alterations in DNA damage-related proteins such as p-ATM, p-Chk2, p-p53, p21 and γH2AX, but not p16. Notably, the combination of dinaciclib and DOX inhibited cell growth and promoted senescence by transforming the suppressive effects of the ATM/Chk2/p53/p21 signaling pathway and enhancing the p16 signaling pathway. Thus, low-dose dinaciclib enhanced anti-MM effects mediated by DOX via transformation of p21-p16 signaling pathways, leading to accelerated senescence, but not apoptosis. The present findings suggest this approach may be a promising therapeutic strategy for the treatment of MM. D.A. Spandidos 2018-11 2018-09-20 /pmc/articles/PMC6202540/ /pubmed/30405800 http://dx.doi.org/10.3892/ol.2018.9474 Text en Copyright: © Tang et al. This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
spellingShingle Articles
Tang, Hailong
Xu, Li
Liang, Xue
Gao, Guangxun
Low dose dinaciclib enhances doxorubicin-induced senescence in myeloma RPMI8226 cells by transformation of the p21 and p16 pathways
title Low dose dinaciclib enhances doxorubicin-induced senescence in myeloma RPMI8226 cells by transformation of the p21 and p16 pathways
title_full Low dose dinaciclib enhances doxorubicin-induced senescence in myeloma RPMI8226 cells by transformation of the p21 and p16 pathways
title_fullStr Low dose dinaciclib enhances doxorubicin-induced senescence in myeloma RPMI8226 cells by transformation of the p21 and p16 pathways
title_full_unstemmed Low dose dinaciclib enhances doxorubicin-induced senescence in myeloma RPMI8226 cells by transformation of the p21 and p16 pathways
title_short Low dose dinaciclib enhances doxorubicin-induced senescence in myeloma RPMI8226 cells by transformation of the p21 and p16 pathways
title_sort low dose dinaciclib enhances doxorubicin-induced senescence in myeloma rpmi8226 cells by transformation of the p21 and p16 pathways
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6202540/
https://www.ncbi.nlm.nih.gov/pubmed/30405800
http://dx.doi.org/10.3892/ol.2018.9474
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