TAK1 inhibitor NG25 enhances doxorubicin-mediated apoptosis in breast cancer cells.
Doxorubicin (Dox, Adriamycin) has been widely used in breast cancer treatment. But its severe cardio-toxic side effects limited the clinical use. Dox treatment can induce DNA damage and other accompanying effects in cancer cells, and subsequently activates nuclear factor κB (NF-κB) pathway which has a strong pro-survival role in different types of malignancy. We hypothesize that blocking NF-κB pathway may sensitize breast cancer cells to Dox chemotherapy. TGFβ-activated kinase-1 (TAK1) is a key intracellular molecule participating in genotoxic stresses-induced NF-κB activation. Targeting TAK1 as a strategy to enhance cancer treatment efficacy has been studied in several malignancies. We showed that NG25, a synthesized TAK1 inhibitor, greatly enhanced Dox treatment efficacy in a panel of breast cancer cell lines. In this pre-clinical study, we found that NG25 partially blocked Dox-induced p38 phosphorylation and IκBα degradation and enhanced Dox-induced cytotoxic effects and apoptosis in all breast cancer cell lines tested. Taken together, we provided clear evidence that NG25 sensitizes the breast cancer cells to Dox treatment in vitro. This combination may be an effective and feasible therapeutic option maximizing Dox efficacy and meanwhile minimizing Dox side effects in treating breast cancer.
Department of Breast Surgery, the Second Hospital of Jilin University, Changchun, Jilin 130041, China.|Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.|Department of Translational and Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Zhenyu
Z
Wang
Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Huiyuan
H
Zhang
Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.|Department of Blood Transfusion, the Second Hospital of Jilin University, Changchun, Jilin 130041, China.
Minghao
M
Shi
Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Yang
Y
Yu
Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.|Department of Hepatopancreatobiliary Surgery, the Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, China.
Hao
H
Wang
Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.|Department of Medical Oncology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, China.
Wen-Ming
WM
Cao
Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Yanling
Y
Zhao
Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.|Department of Translational and Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Hong
H
Zhang
D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology*; D004357:Drug Synergism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D061986:MCF-7 Cells; D016328:NF-kappa B / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D000099151:MAP Kinase Kinase Kinase 7
D004317:Doxorubicin; D020930:MAP Kinase Kinase Kinases; D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D000099151:MAP Kinase Kinase Kinase 7