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Oncotarget. 2016 Nov 8;7(45):73697-73710. doi: 10.18632/oncotarget.12048.

Second-generation proteasome inhibitor carfilzomib enhances doxorubicin-induced cytotoxicity and apoptosis in breast cancer cells.

Shi Y1,2,3, Yu Y3,4, Wang Z2,3,5, Wang H2,3,6, Bieerkehazhi S2,3,7, Zhao Y8, Suzuk L1, Zhang H2,3.

Author information

1
Department of Pathology, Basic Medicine College, Xinjiang Medical University, Urumqi, Xinjiang 830011, China.
2
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
3
Department of Translational and Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
4
Laboratory of Medical Genetics, Harbin Medical University, Harbin, Heilongjiang 150081, China.
5
Department of Breast Surgery, The Second Hospital of Jilin University, Changchun, Jilin 130041, China.
6
Department of Hepatopancreatobiliary Surgery, the Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, China.
7
College of Public Health, Xinjiang Medical University, Urumqi, Xinjiang 830011, China.
8
Texas Children's Cancer Center, Department of Pediatrics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA.

Abstract

Proteasome inhibition is an attractive approach for anticancer therapy. Doxorubicin (DOX) is widely used for treatment in a number of cancers including breast cancer; however, the development of DOX resistance largely limits its clinical application. One of the possible mechanisms of DOX-resistance is that DOX might induce the activation of NF-κB. In this case, proteasome inhibitors could inhibit the activation of NF-κB by blocking inhibitory factor κB (IκB) degradation. Carfilzomib, a second-generation proteasome inhibitor, overcomes bortezomib resistance and lessens its side-effects. Currently, the effect of carfilzomib on breast cancer cell proliferation remains unclear. In this study, we exploited the role of carfilzomib in seven breast cancer cell lines, MCF7, T-47D, MDA-MB-361, HCC1954, MDA-MB-468, MDA-MB-231, and BT-549, representing all major molecular subtypes of breast cancer. We found that carfilzomib alone had cytotoxic effects on the breast cancer cells and it increased DOX-induced cytotoxic effects and apoptosis in combination by enhancing DOX-induced JNK phosphorylation and inhibiting DOX-induced IκBα degradation. The results suggest that carfilzomib has potent antitumor effects on breast cancer in vitro and can sensitize breast cancer cells to DOX treatment. DOX in combination with carfilzomib may be an effective and feasible therapeutic option in the clinical trials for treating breast cancer.

KEYWORDS:

breast cancer; carfilzomib; doxorubicin; drug resistance; proteasome inhibitor

PMID:
27655642
PMCID:
PMC5342008
DOI:
10.18632/oncotarget.12048
[Indexed for MEDLINE]
Free PMC Article

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