title: Next-generation proteasome inhibitor MLN9708 sensitizes breast cancer cells to doxorubicin-induced apoptosis.
abstract: Doxorubicin (Dox), one of the most effective chemotherapy drug for cancer treatment, is limited by its severe side effects and chemoresistance. Dox induces DNA damage and leads to significant proteomic changes in the cancer cells, which makes the ubiquitin-proteasome system a potential target to enhance the efficacy of Dox therapy. The unsuccessful clinical trials of proteasome inhibitor PS-341 (bortezomib) in solid tumors led to the invention of MLN9708 (ixazomib), an orally bioavailable next-generation proteasome inhibitor with improved pharmacokinetic and pharmacodynamic features. In this preclinical study, we used eight human breast cancer cell lines, which represent the major molecular subtypes of breast cancer, to validate the cytotoxic effects of MLN9708, alone and in combination with Dox. We found that MLN9708 had cytotoxic effects, induced autophagy and MKP-1 expression, and enhanced Dox-induced apoptosis in these cell lines. MLN9708 also enhanced Dox-induced JNK and p38 phosphorylation and inhibited Dox-induced IκBα degradation. Our in vitro results suggest that MLN9708 has antitumor effects in breast cancer and can sensitize breast cancer cells to Dox treatment. This promising combination may be an effective and feasible therapeutic option for treating breast cancer and warrants clinical validation.
authors.affiliation: Department of Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, China.|Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.|Laboratory of Medical Genetics, Harbin Medical University, Harbin, Heilongjiang 150081, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.|Department of Colorectal Surgery, Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100021, China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Jiang
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.|Department of Medical Oncology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, China.
authors.forename: Wen-Ming
authors.initials: WM
authors.lastname: Cao
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.|Department of Breast Surgery, Second Hospital of Jilin University, Changchun, Jilin 130041, China.
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.|Xinjiang Key Laboratory of Plant Resources and Natural Products Chemistry, Xinjiang Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Urumqi, Xinjiang 830011, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Dou
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Yanling
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, China.
authors.forename: Yunfu
authors.initials: Y
authors.lastname: Cui
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.|Department of Molecular and Translational Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
mesh_terms: D001343:Autophagy; D001896:Boron Compounds / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D054638:Dual Specificity Phosphatase 1 / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D061986:MCF-7 Cells; D010766:Phosphorylation; D061988:Proteasome Inhibitors / Q000494:pharmacology*
chemical_list: D001896:Boron Compounds; D061988:Proteasome Inhibitors; C548400:ixazomib; D004317:Doxorubicin; C517019:DUSP1 protein, human; D054638:Dual Specificity Phosphatase 1; D005998:Glycine