title: Furanodiene alters mitochondrial function in doxorubicin-resistant MCF-7 human breast cancer cells in an AMPK-dependent manner.
abstract: Furanodiene is a bioactive sesquiterpene isolated from the spice-producing Curcuma wenyujin plant (Y. H. Chen and C. Ling) (C. wenyujin), which is a commonly prescribed herb used in clinical cancer therapy by modern practitioners of traditional Chinese medicine. Previously, we have shown that furanodiene inhibits breast cancer cell growth both in vitro and in vivo, however, the mechanism for this effect is not yet known. In this study, therefore, we asked (1) whether cultured breast cancer cells made resistant to the chemotherapeutic agent doxorubicin (DOX) via serial selection protocols are susceptible to furanodiene's anticancer effect, and (2) whether AMP-activated protein kinase (AMPK), which is a regulator of cellular energy homeostasis in eukaryotic cells, participates in this effect. We show here (1) that doxorubicin-resistant MCF-7 (MCF-7/DOX(R)) cells treated with furanodiene exhibit altered mitochondrial function and reduced levels of ATP, resulting in apoptotic cell death, and (2) that AMPK is central to this effect. In these cells, furanodiene (as opposed to doxorubicin) noticeably affects the phosphorylation of AMPK and AMPK pathway intermediates, ACLY and GSK-3β, suggesting that furanodiene reduces mitochondrial function and cellular ATP levels by way of AMPK activation. Finally, we find that the cell permeable agent and AMPK inhibitor compound C (CC), abolishes furanodiene-induced anticancer activity in these MCF-7/DOX(R) cells, with regard to cell growth inhibition and AMPK activation; in contrast, AICAR (5-aminoimidazole-4-carboxamide-1-β-4-ribofuranoside, acadesine), an AMPK activator, augments furanodiene-induced anticancer activity. Furthermore, specific knockdown of AMPK in MCF-7/DOX(R) cells protects these cells from furanodiene-induced cell death. Taken together, these findings suggest that AMPK and its pathway intermediates are promising therapeutic targets for treating chemoresistant breast cancer, and that furanodiene may be an important chemical agent incorporated in next-generation chemotherapy protocols.
authors.affiliation: Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Avenida da Universidade, Taipa, Macao 999078, China. ytwang@umac.mo.
authors.forename: Zhang-Feng
authors.initials: ZF
authors.lastname: Zhong
authors.affiliation: School of Pharmacy, Lanzhou University, Lanzhou, Gansu province 730000, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Tan
authors.affiliation: Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Avenida da Universidade, Taipa, Macao 999078, China. ytwang@umac.mo and Yale University, New Haven, Connecticut 06511, USA.
authors.forename: William W
authors.initials: WW
authors.lastname: Qiang
authors.affiliation: Department of Biomedical Sciences, School of Medicine, University of Texas Rio Grande Valley, Edinburg, Texas 78541, USA.
authors.forename: Virginia L
authors.initials: VL
authors.lastname: Scofield
authors.affiliation: School of Chinese Medicine, Hong Kong Baptist University, Hong Kong 999077, China. wsxk1@126.com and Division of Reproductive Science in Medicine, Department of Obstetrics and Gynecology, Feinberg School of Medicine at Northwestern University, 303 East Superior Street, Lurie 7-250, Chicago, Illinois 60611, USA. W-qiang@northwestern.edu.
authors.forename: Ke
authors.initials: K
authors.lastname: Tian
authors.affiliation: Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Avenida da Universidade, Taipa, Macao 999078, China. ytwang@umac.mo.
authors.forename: Chun-Ming
authors.initials: CM
authors.lastname: Wang
authors.affiliation: Division of Reproductive Science in Medicine, Department of Obstetrics and Gynecology, Feinberg School of Medicine at Northwestern University, 303 East Superior Street, Lurie 7-250, Chicago, Illinois 60611, USA. W-qiang@northwestern.edu.
authors.forename: Wen-An
authors.initials: WA
authors.lastname: Qiang
authors.affiliation: Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Avenida da Universidade, Taipa, Macao 999078, China. ytwang@umac.mo.
authors.forename: Yi-Tao
authors.initials: YT
authors.lastname: Wang
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005663:Furans / Q000494:pharmacology*; D055785:Gene Knockdown Techniques; D006574:Heterocyclic Compounds, 2-Ring / Q000494:pharmacology*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D061986:MCF-7 Cells; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism*; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D005663:Furans; D006574:Heterocyclic Compounds, 2-Ring; D047428:Protein Kinase Inhibitors; C442489:furanodiene; D004317:Doxorubicin; D055372:AMP-Activated Protein Kinases