Research Papers:

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

Yonghua Shi, Yang Yu, Zhenyu Wang, Hao Wang, Shayahati Bieerkehazhi, Yanling Zhao, Lale Suzuk and Hong Zhang _

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Oncotarget. 2016; 7:73697-73710. https://doi.org/10.18632/oncotarget.12048

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Yonghua Shi1,2,3, Yang Yu3,4, Zhenyu Wang2,3,5, Hao Wang2,3,6, Shayahati Bieerkehazhi2,3,7, Yanling Zhao8, Lale Suzuk1, Hong Zhang2,3

1Department of Pathology, Basic Medicine College, Xinjiang Medical University, Urumqi, Xinjiang 830011, China

2Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA

3Department of Translational and Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA

4Laboratory of Medical Genetics, Harbin Medical University, Harbin, Heilongjiang 150081, China

5Department of Breast Surgery, The Second Hospital of Jilin University, Changchun, Jilin 130041, China

6Department of Hepatopancreatobiliary Surgery, the Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, China

7College of Public Health, Xinjiang Medical University, Urumqi, Xinjiang 830011, China

8Texas Children's Cancer Center, Department of Pediatrics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA

Correspondence to:

Hong Zhang, email: [email protected]

Keywords: proteasome inhibitor, carfilzomib, doxorubicin, drug resistance, breast cancer

Abbreviations: PI, proteasome inhibitor; CFZ, carfilzomib; DOX, doxorubicin; DMSO, dimethyl sulfoxide; FDA, Food and Drug Administration

Received: June 07, 2016    Accepted: August 26, 2016    Published: September 15, 2016


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.

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