title: Dopamine enhances the response of sunitinib in the treatment of drug-resistant breast cancer: Involvement of eradicating cancer stem-like cells.
abstract: Growing evidence suggests that the efficacy of sunitinib in breast cancer may be limited by increasing the population of cancer stem-like cells (CSCs). Hence the concurrent use of CSCs-targeting agents is required. Previous results indicated that dopamine receptor (DR) may serve as a potential therapeutic target of anti-CSCs therapies. This study focused on evaluating the effect of dopamine (an agonist of DR) on the enhancement of sunitinib's efficacy in the treatment of drug-resistant breast cancer, investigating the involved activation type of DR pathway and exploring the underlying anti-CSCs mechanisms. MCF-7 cells, MCF-7/Adr cells and breast cancer stem-like cells (BCSCs) were used for in vitro study. Moreover, MCF-7/Adr cells and BCSCs were selected as drug-resistant cell lines and further used for in vivo development of the xenograft animal models. Our results showed that dopamine greatly synergized the inhibitory effect of sunitinib in the drug-resistant cells and strikingly enhanced the response of sunitinib in both xenograft models. It was found that dopamine significantly down-regulated the expression of BCSCs markers (CD44(+)/CD24(-)) in vitro and in vivo. In addition, dopamine remarkably induced the apoptosis of BCSCs, markedly inhibited the Wnt signaling pathway and activated the apoptotic associated signals. The activation of dopamine receptor D1 (D1DR) pathway may be involved in the underlying mechanism as D1DR's antagonist SCH23390 completely reversed the combined effects. In conclusion, dopamine may eradicate CSCs and it significantly enhances the response of sunitinib in the treatment of drug-resistant breast cancer.
authors.affiliation: Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
authors.forename: Siyuan
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
authors.forename: Zhenzhen
authors.initials: Z
authors.lastname: Mou
authors.affiliation: Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
authors.forename: Yuanheng
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
authors.forename: Jingyun
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
authors.forename: Xiwei
authors.initials: X
authors.lastname: Ji
authors.affiliation: Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
authors.forename: Kehua
authors.initials: K
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs (Peking University), Beijing 100191, China; Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Li
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs (Peking University), Beijing 100191, China; Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Lu
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs (Peking University), Beijing 100191, China; Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China. Electronic address: tianyanzhou@vip.sina.com.
authors.forename: Tianyan
authors.initials: T
authors.lastname: Zhou
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D004298:Dopamine / Q000494:pharmacology / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use*; D008856:Microscopy, Fluorescence; D014411:Neoplastic Stem Cells / Q000166:cytology / Q000187:drug effects*; D011758:Pyrroles / Q000494:pharmacology / Q000627:therapeutic use*; D000077210:Sunitinib; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D011758:Pyrroles; D040301:Vascular Endothelial Growth Factor Receptor-2; D000077210:Sunitinib; D004298:Dopamine
keywords: Cancer stem-like cells; Combination therapy; Dopamine; Dopamine receptor; Drug-resistance; Sunitinib