title: 3-bromopyruvate enhanced daunorubicin-induced cytotoxicity involved in monocarboxylate transporter 1 in breast cancer cells.
abstract: Increasing evidence demonstrates that the hexokinase inhibitor 3-bromopyruvate (3-BrPA) induces the cell apoptotic death by inhibiting ATP generation in human cancer cells. Interestingly, some tumor cell lines are less sensitive to 3-BrPA-induced apoptosis than others. Moreover, the molecular mechanism of 3-BrPA-trigged apoptosis is unclear. In the present study, we examined the effects of 3-BrPA on the viability of the breast cancer cell lines MDA-MB-231 and MCF-7. We further investigated the potential roles of monocarboxylate transporter 1 (MCT1) in drug accumulation and efflux of breast cancer cells. Finally, we explored whether 3-BrPA enhanced daunorubicin (DNR)-induced cytotoxicity through regulation of MCT1 in breast cancer cells. MTT and colony formation assays were used to measure cell viability. Western blot analysis, flow cytometric analysis and fluorescent microscopy were used to determine the molecular mechanism of actions of MCT1 in different breast cancer cell lines. Whole-body bioluminescence imaging was used to investigate the effect of 3-BrPA in vivo. We found that 3-BrPA significantly inhibited cell growth and induced apoptosis in MCF-7 cell line, but not in MDA-MB-231 cells. Moreover, we observed that 3-BrPA efficiently enhanced DNR-induced cytotoxicity in MCF-7 cells by inhibiting the activity of ATP-dependent efflux pumps. We also found that MCT1 overexpression increased the efficacy of 3-BrPA in MDA-MB-231 cells. 3-BrPA markedly suppressed subcutaneous tumor growth in combination with DNR in nude mice implanted with MCF-7 cells. Lastly, our whole-body bioluminescence imaging data indicated that 3-BrPA promoted DNR accumulation in tumors. These findings collectively suggest that 3-BrPA enhanced DNR antitumor activity in breast cancer cells involved MCT-1, suggesting that inhibition of glycolysis could be an effective therapeutic approach for breast cancer treatment.
authors.affiliation: Faculty of Pharmacy, Bengbu Medical College Bengbu, Anhui, P. R. China.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Faculty of Pharmacy, Bengbu Medical College Bengbu, Anhui, P. R. China.
authors.forename: Yiming
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Allergy and Cancer Center, Otorhinolaryngology Hospital, The First Affiliated Hospital of Sun Yat-Sen University Guangzhou, Guangdong, P. R. China.
authors.forename: Haiyu
authors.initials: H
authors.lastname: Hong
authors.affiliation: Faculty of Pharmacy, Bengbu Medical College Bengbu, Anhui, P. R. China.
authors.forename: Surong
authors.initials: S
authors.lastname: Zhao
authors.affiliation: Faculty of Pharmacy, Bengbu Medical College Bengbu, Anhui, P. R. China.
authors.forename: Xue
authors.initials: X
authors.lastname: Zou
authors.affiliation: Allergy and Cancer Center, Otorhinolaryngology Hospital, The First Affiliated Hospital of Sun Yat-Sen University Guangzhou, Guangdong, P. R. China.
authors.forename: Renqiang
authors.initials: R
authors.lastname: Ma
authors.affiliation: School of Medicine and Public Health, University of Newcastle Newcastle, New South Wales, Australia.
authors.forename: Chenchen
authors.initials: C
authors.lastname: Jiang
authors.affiliation: Department of Biochemistry and Molecular Biology, Bengbu Medical College Bengbu 233030, Anhui, China ; Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School Boston, MA 02215, USA.
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Allergy and Cancer Center, Otorhinolaryngology Hospital, The First Affiliated Hospital of Sun Yat-Sen University Guangzhou, Guangdong, P. R. China.
authors.forename: Huabin
authors.initials: H
authors.lastname: Li
authors.affiliation: Faculty of Pharmacy, Bengbu Medical College Bengbu, Anhui, P. R. China.
authors.forename: Hao
authors.initials: H
authors.lastname: Liu
keywords: 3-BrPA; Breast cancer; DNR; MCT1