title: Quercetin-3-methyl ether inhibits lapatinib-sensitive and -resistant breast cancer cell growth by inducing G(2)/M arrest and apoptosis.
abstract: Lapatinib, an oral, small-molecule, reversible inhibitor of both EGFR and HER2, is highly active in HER2 positive breast cancer as a single agent and in combination with other therapeutics. However, resistance against lapatinib is an unresolved problem in clinical oncology. Recently, interest in the use of natural compounds to prevent or treat cancers has gained increasing interest because of presumed low toxicity. Quercetin-3-methyl ether, a naturally occurring compound present in various plants, has potent anticancer activity. Here, we found that quercetin-3-methyl ether caused a significant growth inhibition of lapatinib-sensitive and -resistant breast cancer cells. Western blot data showed that quercetin-3-methyl ether had no effect on Akt or ERKs signaling in resistant cells. However, quercetin-3-methyl ether caused a pronounced G(2)/M block mainly through the Chk1-Cdc25c-cyclin B1/Cdk1 pathway in lapatinib-sensitive and -resistant cells. In contrast, lapatinib produced an accumulation of cells in the G(1) phase mediated through cyclin D1, but only in lapatinib-sensitive cells. Moreover, quercetin-3-methyl ether induced significant apoptosis, accompanied with increased levels of cleaved caspase 3, caspase 7, and poly(ADP-ribose) polymerase (PARP) in both cell lines. Overall, these results suggested that quercetin-3-methyl ether might be a novel and promising therapeutic agent in lapatinib-sensitive or -resistant breast cancer patients.
authors.affiliation: The Hormel Institute, University of Minnesota, Austin, Minnesota 55912, USA.
authors.forename: Jixia
authors.initials: J
authors.lastname: Li
authors.forename: Feng
authors.initials: F
authors.lastname: Zhu
authors.forename: Ronald A
authors.initials: RA
authors.lastname: Lubet
authors.forename: Antonella
authors.initials: A
authors.lastname: De Luca
authors.forename: Clinton
authors.initials: C
authors.lastname: Grubbs
authors.forename: Marna E
authors.initials: ME
authors.lastname: Ericson
authors.forename: Amelia
authors.initials: A
authors.lastname: D'Alessio
authors.forename: Nicola
authors.initials: N
authors.lastname: Normanno
authors.forename: Zigang
authors.initials: Z
authors.lastname: Dong
authors.forename: Ann M
authors.initials: AM
authors.lastname: Bode
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D016203:CDC2 Protein Kinase / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000071877:Checkpoint Kinase 1; D056744:Cyclin B1 / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D005260:Female; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D000077341:Lapatinib; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects; D020935:MAP Kinase Signaling System / Q000187:drug effects; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011794:Quercetin / Q000031:analogs & derivatives* / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D020687:cdc25 Phosphatases / Q000378:metabolism
chemical_list: C534699:CCNB1 protein, human; D056744:Cyclin B1; D011799:Quinazolines; C459210:quercetin 3-O-methyl ether; D000077341:Lapatinib; D011794:Quercetin; D011065:Poly(ADP-ribose) Polymerases; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; D051057:Proto-Oncogene Proteins c-akt; D016203:CDC2 Protein Kinase; C517009:CDC25C protein, human; D020687:cdc25 Phosphatases; D053148:Caspase 3; D053179:Caspase 7
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