title: Anticancer and chemosensitizing abilities of cycloviolacin 02 from Viola odorata and psyle cyclotides from Psychotria leptothyrsa.
abstract: Cycloviolacin O2 (CyO2), a cyclotide from Viola odorata (Violaceae) has antitumor effects and causes cell death by membrane permeabilization. In the breast cancer line, MCF-7 and its drug resistant subline MCF-7/ADR, the cytotoxic effects of CyO2 (0.2-10 microM) were monitored in the presence and absence of doxorubicin (0.1-5 microM) using cell proliferation assays to establish its chemosensitizing abilities. SYTOX Green assays were Sperformed to verify membrane permeabilization and showed cellular disruption correlates with cyclotide chemosensitization. Fluorescence microscopy studies demonstrated increased cellular internalization of doxorubicin in drug resistant cells when coexposed to CyO2. Interestingly, CyO2 did not produce significant membrane disruption in primary human brain endothelial cells, which suggested cyclotide specificity toward induced pore formation in highly proliferating tumor cells. Furthermore, three novel cyclotides (psyle A, C and E) from Psychotria leptothyrsa (Rubiaceae) were also monitored for cytotoxic activity. The cyclotides displayed potent cytotoxicity (IC50 = 0.64->10 microM), and coexposure to cyclotides significantly enhanced doxorubicin induced toxicity (IC50 = 0.39-0.76 microM). This study documents several cyclotides with robust cytotoxicity that may be promising chemosensitizing agents against drug resistant breast cancer.
authors.affiliation: Department of Ecology and Evolutionary Biology, Tulane University, 2863 St. Charles Avenue, 400 Boggs Center for Energy and Biotechnology, New Orleans, LA 70118, USA. sgerlach@tulane.edu
authors.forename: Samantha L
authors.initials: SL
authors.lastname: Gerlach
authors.forename: Ramesh
authors.initials: R
authors.lastname: Rathinakumar
authors.forename: Geetika
authors.initials: G
authors.lastname: Chakravarty
authors.forename: Ulf
authors.initials: U
authors.lastname: Göransson
authors.forename: William C
authors.initials: WC
authors.lastname: Wimley
authors.forename: Steven P
authors.initials: SP
authors.lastname: Darwin
authors.forename: Debasis
authors.initials: D
authors.lastname: Mondal
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor / Q000187:drug effects*; D047169:Cyclotides / Q000737:chemistry / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D020128:Inhibitory Concentration 50; D010940:Plant Proteins / Q000737:chemistry / Q000494:pharmacology; D032413:Viola / Q000737:chemistry*
chemical_list: D000970:Antineoplastic Agents; D047169:Cyclotides; D010940:Plant Proteins; C551602:psyle C; C473355:cycloviolacin O2