title: Salvianolic acid A shows selective cytotoxicity against multidrug-resistant MCF-7 breast cancer cells.
abstract: Multidrug resistance (MDR) is a major cause for incurable breast cancer. Salvianolic acid A (SAA), the hydrophilic polyphenolic derivative of Salvia miltiorrhiza Bunge (Danshen/Red Sage), was examined for cytotoxicities to MDR MCF-7 human breast cancer cells and their parental counterparts. We have shown that SAA inhibited proliferation, caused cell cycle arrest at the S phase, and induced apoptosis dose dependently to the two kinds of cancer cells. However, the resistant cells were significantly susceptible to the inhibition of SAA compared with the parental cells. SAA increased the level of reactive oxygen species (ROS) by 6.2-fold in the resistant cells, whereas the level of SAA-induced ROS changed only by 1.6-fold in their parental counterparts. Thus, the data showed that the selective cytotoxicity resulted from the hypersensitivity of the resistant cells to the strongly elevated ROS by SAA. In addition, SAA-triggered apoptosis was associated with increased caspase-3 activity, disrupted mitochondrial membrane potential, downregulated Bcl-2 expression, and upregulated Bax expression in the resistant cells. Moreover, SAA downregulated the level of P-glycoprotein, which was overexpressed in the resistant cells. This indicated that SAA modulated MDR. Furthermore, SAA showed higher antitumor activity than did doxorubicin in xenografts established from the resistant cells. The present work raised a possibility that SAA might be considered a potential choice to overcome MDR for the selective susceptibility of the resistant breast cancer cells to SAA treatment.
authors.affiliation: Departments of aRadiology bPathology, Jinling Hospital, Nanjing University School of Medicine cNanjing Federation of Natural Medicine Societies, Nanjing, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.forename: Chunyan
authors.initials: C
authors.lastname: Wang
authors.forename: Longjiang
authors.initials: L
authors.lastname: Zhang
authors.forename: Yanjun
authors.initials: Y
authors.lastname: Li
authors.forename: Shouju
authors.initials: S
authors.lastname: Wang
authors.forename: Jiandong
authors.initials: J
authors.lastname: Wang
authors.forename: Caiyun
authors.initials: C
authors.lastname: Yuan
authors.forename: Jia
authors.initials: J
authors.lastname: Niu
authors.forename: Chengsheng
authors.initials: C
authors.lastname: Wang
authors.forename: Guangming
authors.initials: G
authors.lastname: Lu
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002109:Caffeic Acids / Q000494:pharmacology*; D053148:Caspase 3 / Q000378:metabolism; D059447:Cell Cycle Checkpoints; D018432:Drug Resistance, Multiple / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D007773:Lactates / Q000494:pharmacology*; D061986:MCF-7 Cells / Q000187:drug effects; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008807:Mice, Inbred BALB C; D017382:Reactive Oxygen Species / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic; D002109:Caffeic Acids; D007773:Lactates; D017382:Reactive Oxygen Species; C066201:salvianolic acid A; D053148:Caspase 3; D005978:Glutathione