title: (-)-Hinokinin Induces G2/M Arrest and Contributes to the Antiproliferative Effects of Doxorubicin in Breast Cancer Cells.
abstract: Breast cancer incidence rises worldwide and new chemotherapeutical strategies have been investigated to overcome chemoresistance. (-)-Hinokinin is a dibenzylbutyrolactone lignan derived from the partial synthesis of (-)-cubebin extracted from Piper cubeba seeds. Biological effects of dibenzylbutyrolactone lignans include antiviral, antitumor, anti-inflammatory, and trypanocidal activities. In the present study, we evaluated the ability of (-)-hinokinin to modulate the antiproliferative effects of doxorubicin intumoral (MCF-7 and SKBR-3) and normal (MCF-10 A) breast cell lines. Treatment with (-)-hinokinin did not affect the cellular proliferation or contribute to the antitproliferative effects of doxorubicin in MCF-10 A cells. After 24 and 48 hours of treatment with (-)-hinokinin, MCF-7 and SKBR-3 were accumulated in G2/M and, when combined with doxorubicin, (-)-hinokinin contributed to the antiproliferative effects of this chemotherapic by modulation of the cyclin-dependent kinase inhibitor 1. Apoptotic cell death was observed in response to (-)-hinokinin alone in MCF-7, but not in SKBR-3 even 72 hours after treatment. In MCF-7, doxorubicin-induced apoptosis was not increased by (-)-hinokinin. The findings of the present study suggest (-)-hinokinin as an antiproliferative agent that contributes to the effects of doxorubicin. (-)-Hinokinin modulates apoptotic cell death via the molecular regulation of the cell cycle and apoptotic control genes, but the cellular genetic background directly affects the cell fate decision in response to treatment.
authors.affiliation: University of Franca, Franca, SP, Brazil.
authors.forename: Nayanne Larissa
authors.initials: NL
authors.lastname: Cunha
authors.affiliation: University of Franca, Franca, SP, Brazil.
authors.forename: Gabriella Machado
authors.initials: GM
authors.lastname: Teixeira
authors.affiliation: University of Franca, Franca, SP, Brazil.
authors.forename: Thomás Duzzi
authors.initials: TD
authors.lastname: Martins
authors.affiliation: University of Franca, Franca, SP, Brazil.
authors.forename: Anderson Roberto
authors.initials: AR
authors.lastname: Souza
authors.affiliation: University of Franca, Franca, SP, Brazil.
authors.forename: Pollyana Francieli
authors.initials: PF
authors.lastname: Oliveira
authors.affiliation: University of Franca, Franca, SP, Brazil.
authors.forename: Guilherme Venâncio
authors.initials: GV
authors.lastname: Símaro
authors.affiliation: University of Franca, Franca, SP, Brazil.
authors.forename: Karen Cristina Souza
authors.initials: KC
authors.lastname: Rezende
authors.affiliation: University of Franca, Franca, SP, Brazil.
authors.forename: Natália Dos Santos
authors.initials: Ndos S
authors.lastname: Gonçalves
authors.affiliation: University of Franca, Franca, SP, Brazil.
authors.forename: Daniel Gottardo
authors.initials: DG
authors.lastname: Souza
authors.affiliation: University of Franca, Franca, SP, Brazil.
authors.forename: Denise Crispim
authors.initials: DC
authors.lastname: Tavares
authors.affiliation: University of Franca, Franca, SP, Brazil.
authors.forename: Marcio Luís Andrade
authors.initials: ML
authors.lastname: Silva
authors.affiliation: University of Franca, Franca, SP, Brazil.
authors.forename: Raquel Alves
authors.initials: RA
authors.lastname: Dos Santos
mesh_terms: D015107:4-Butyrolactone / Q000008:administration & dosage / Q000031:analogs & derivatives; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D052117:Benzodioxoles / Q000008:administration & dosage; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000008:administration & dosage; D005260:Female; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D017705:Lignans / Q000008:administration & dosage; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects / Q000235:genetics
chemical_list: D052117:Benzodioxoles; D017705:Lignans; C475934:hinokinin; D004317:Doxorubicin; D053148:Caspase 3; D015107:4-Butyrolactone