title: Attenuation of nucleoside and anti-cancer nucleoside analog drug uptake in prostate cancer cells by Cimicifuga racemosa extract BNO-1055.
abstract: This study aimed to investigate the mechanisms underlying the anti-proliferative effects of the ethanolic Cimicifuga racemosa extract BNO-1055 on prostate cells and evaluate its therapeutic potential. BNO-1055 dose-dependently attenuated cellular uptake and incorporation of thymidine and BrdU and significantly inhibited cell growth after long-time exposure. Similar results were obtained using saponin-enriched sub-fractions of BNO-1055. These inhibitory effects of BNO-1055 could be mimicked using pharmacological inhibitors and isoform-specific siRNAs targeting the equilibrative nucleoside transporters ENT1 and ENT2. Moreover, BNO-1055 attenuated the uptake of clinically relevant nucleoside analogs, e.g. the anti-cancer drugs gemcitabine and fludarabine. Consistent with inhibition of the salvage nucleoside uptake pathway BNO-1055 potentiated the cytotoxicity of the de novo nucleotide synthesis inhibitor 5-FU without significantly altering its uptake. Collectively, these data show for the first time that the anti-proliferative effects of BNO-1055 result from hindered nucleoside uptake due to impaired ENT activity and demonstrate the potential therapeutic use of BNO-1055 for modulation of nucleoside transport.
authors: Department of Urology, Medical University of Innsbruck, Innsbruck, Austria; Oncotyrol GmbH, Center for Personalized Medicine, Innsbruck, Austria.
authors: Andrea
authors: A
authors: Dueregger
authors: Fabian
authors: F
authors: Guggenberger
authors: Jan
authors: J
authors: Barthelmes
authors: Günther
authors: G
authors: Stecher
authors: Markus
authors: M
authors: Schuh
authors: Daniel
authors: D
authors: Intelmann
authors: Gudrun
authors: G
authors: Abel
authors: Jutta
authors: J
authors: Haunschild
authors: Helmut
authors: H
authors: Klocker
authors: Reinhold
authors: R
authors: Ramoner
authors: Natalie
authors: N
authors: Sampson
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology / Q000627:therapeutic use; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology / Q000627:therapeutic use*; D001973:Bromodeoxyuridine / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D031885:Cimicifuga; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D033705:Equilibrative Nucleoside Transport Proteins / Q000378:metabolism*; D005472:Fluorouracil / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D008297:Male; D009705:Nucleosides / Q000378:metabolism*; D008517:Phytotherapy; D010936:Plant Extracts / Q000494:pharmacology / Q000627:therapeutic use*; D011467:Prostate / Q000187:drug effects*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D012503:Saponins / Q000494:pharmacology / Q000627:therapeutic use; D013936:Thymidine / Q000378:metabolism; D014740:Vidarabine / Q000031:analogs & derivatives / Q000378:metabolism; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; C475575:Cimicifuga extract BNO 1055; D033705:Equilibrative Nucleoside Transport Proteins; D009705:Nucleosides; D010936:Plant Extracts; D034741:RNA, Small Interfering; D012503:Saponins; D003841:Deoxycytidine; D014740:Vidarabine; D001973:Bromodeoxyuridine; C024352:fludarabine; D005472:Fluorouracil; D013936:Thymidine; D000093542:Gemcitabine
keywords: 5-FU; 5-Fluorouracil; 5-bromo-2′-deoxyuridine; 5-fluorouracil; BCa; Black cohosh; BrdU; CNT; CR; Cimicifuga racemosa; ENT; Gemcitabine; HPLC; N-methyl-d-glucamine; NBTI; NMG; NT; Nucleoside transport; PCa; Saponin; breast cancer; cimicifuga racemosa; concentrative nucleoside transporter; equilibrative nucleoside transporter; high-pressure liquid chromatography; nitrobenzylthioinosine; nucleoside transporter; prostate cancer; qPCR; real-time quantitative polymerase chain reaction; short-interfering RNA; siRNA