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.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacology , Breast Neoplasms/drug therapy , 4-Butyrolactone/administration & dosage , 4-Butyrolactone/analogs & derivatives , Benzodioxoles/administration & dosage , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Caspase 3/genetics , Caspase 3/metabolism , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Doxorubicin/administration & dosage , Female , G2 Phase Cell Cycle Checkpoints/drug effects , G2 Phase Cell Cycle Checkpoints/genetics , Gene Expression Regulation, Neoplastic/drug effects , Humans , Inhibitory Concentration 50 , Lignans/administration & dosage , M Phase Cell Cycle Checkpoints/drug effects , M Phase Cell Cycle Checkpoints/geneticsABSTRACT
The use of poly(L-lactic acid) (PLA) has been considered an important alternative for medical devices once this polyester presents biomechanical, optical and biodegradable properties. Moreover, the use of PLA results in less inflammatory reactions and more recently it has been proposed its application in drug delivery systems. Genotoxicological evaluations are considered part of the battery assays in toxicological analysis. Considering the wide applications of PLA, the present work evaluated the potential cytotoxic and genotoxic effects of PLA in CHO-K1 cells, as well as its physicochemical properties. No cytotoxic effects of PLA were detected by colorimetric tetrazolium assay (XTT) analysis, and the clonogenic survival assay showed that PLA did not disrupt the replicative cell homeostasis, neither exhibited genotoxic effects as evidenced by comet and micronucleus assays. Thermogravimetric properties of PLA were not altered after contact with cells and this film exhibited ability in absorb and release Europium(III) complex. All these data suggest genotoxicological safety of PLA for further applications in drug delivery systems.
