title: Linalool, a plant-derived monoterpene alcohol, reverses doxorubicin resistance in human breast adenocarcinoma cells.
abstract: Essential oils from various aromatic plants have been reported to exert chemopreventive and/or antitumor effects. In addition, a number of studies have shown the ability of chemopreventive phytochemicals to increase the sensitivity of cancer cells to conventional anticancer drugs. The success of chemotherapeutic agents is often hindered by the development of drug resistance, with multidrug resistant (MDR) phenotypes reported in a number of tumors, generally involving reduced intracellular drug accumulation due to increased drug efflux by membrane transporters. In the present study, the effects of linalool (LIN), a monoterpene alcohol found in the essential oils from many aromatic plants, on the growth of two human breast adenocarcinoma cell lines, MCF7 WT and multidrug resistant MCF7 AdrR, were investigated, both as a single agent and in combination with doxorubicin (DOX). The results reported here show that LIN only moderately inhibits cell proliferation; interestingly, however, subtoxic concentrations of LIN potentiate DOX-induced cytotoxicity and pro-apoptotic effects in both cell lines. A significant synergism can be observed in MCF7 AdrR cells, which may be due, at least in part, to the ability of LIN to increase DOX accumulation and to induce a decrease in Bcl-xL levels. In summary, the results of the present study suggest that LIN may improve the therapeutic index of anthracyclines in the management of breast cancer, especially in MDR tumors.
authors.affiliation: Department of Structural and Functional Biology, Section of Pharmacology, University of Insubria, Via A. da Giussano 10, Busto Arsizio, Varese, Italy.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Ravizza
authors.forename: Marzia B
authors.initials: MB
authors.lastname: Gariboldi
authors.forename: Roberta
authors.initials: R
authors.lastname: Molteni
authors.forename: Elena
authors.initials: E
authors.lastname: Monti
mesh_terms: D000080462:Acyclic Monoterpenes; D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism / Q000556:secondary; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects*; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004317:Doxorubicin / Q000009:adverse effects*; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007124:Immunoenzyme Techniques; D051034:Inhibitor of Apoptosis Proteins; D020128:Inhibitory Concentration 50; D007306:Insecticides / Q000627:therapeutic use*; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D039821:Monoterpenes / Q000627:therapeutic use*; D009363:Neoplasm Proteins / Q000378:metabolism; D020011:Protective Agents / Q000627:therapeutic use*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D000077022:Survivin; D014407:Tumor Cells, Cultured / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D051020:bcl-X Protein / Q000378:metabolism
chemical_list: D000080462:Acyclic Monoterpenes; D000903:Antibiotics, Antineoplastic; C494826:BAX protein, human; C494811:BCL2L1 protein, human; C107489:BIRC5 protein, human; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D051034:Inhibitor of Apoptosis Proteins; D007306:Insecticides; D008869:Microtubule-Associated Proteins; D039821:Monoterpenes; D009363:Neoplasm Proteins; D020011:Protective Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D000077022:Survivin; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D004317:Doxorubicin; C018584:linalool