title: Reversal of multidrug resistance in cancer cells by pyranocoumarins isolated from Radix Peucedani.
abstract: The pyranocoumarins, (+/-)-3'-angeloyl-4'-acetoxy-cis-khellactone, were isolated from Radix Peucedani, the dry root of Peucedanum praeruptorum Dunn, through bioassay-guided fractionation. The chemical structure of pyranocoumarins was determined by mass spectrometry and nuclear magnetic resonance (NMR) spectroscopy. X-ray crystallography showed that there are eight molecules (i.e. two each of four conformers) in each unit cell with their optical activities equally cancelled out. The four conformers are 3'(R)-angeloyl-4'(R)-acetoxy-khellactone in two conformational forms, and 3'(S)-angeloyl-4'(S)-acetoxy-khellactone in two conformational forms. Pyranocoumarins caused apoptotic cell death with IC50 of 41.9+/-2.8 and 17.3+/-8.2 microM for drug-sensitive KB-3-1 and multidrug resistant (MDR) KB-V1, respectively. The two- to threefold sensitivity difference between the two cell lines is interesting considering that the same ratio for doxorubicin is 50-300. Strong synergistic interactions were demonstrated when pyranocoumarins were combined with common anti-tumor drugs including doxorubicin, paclitaxel, puromycin or vincristine in MDR KB-V1 cell line, but not in drug-sensitive KB-3-1 cells. Pyranocoumarins increased doxorubicin accumulation in KB-V1 cells by about 25% after 6 h of incubation. Pyranocoumarins treatment for 24 h down-regulated the expression of P-glycoprotein in KB-V1 cells at both protein and mRNA levels. Pyranocoumarins also transiently reduced the cellular ATP contents in KB-V1 cells in a dose-dependent manner. Our results suggest that pyranocoumarins could be a potential MDR reversing agent.
authors.affiliation: Department of Biology and Chemistry, Bioactive Products Research Group, City University of Hong Kong, Kowloon, Hong Kong SAR, China.
authors.forename: Jimmy Yiu-Cheong
authors.initials: JY
authors.lastname: Wu
authors.forename: Wang-Fun
authors.initials: WF
authors.lastname: Fong
authors.forename: Jin-Xia
authors.initials: JX
authors.lastname: Zhang
authors.forename: Chung-Hang
authors.initials: CH
authors.lastname: Leung
authors.forename: Hoi-Lung
authors.initials: HL
authors.lastname: Kwong
authors.forename: Meng-Su
authors.initials: MS
authors.lastname: Yang
authors.forename: Ding
authors.initials: D
authors.lastname: Li
authors.forename: Hon-Yeung
authors.initials: HY
authors.lastname: Cheung
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis / Q000235:genetics; D000255:Adenosine Triphosphate / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology; D019661:Apiaceae / Q000737:chemistry*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D015536:Down-Regulation; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D010936:Plant Extracts / Q000494:pharmacology; D018517:Plant Roots / Q000737:chemistry; D010946:Plants, Medicinal / Q000737:chemistry; D039681:Pyranocoumarins / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013237:Stereoisomerism
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D010936:Plant Extracts; D039681:Pyranocoumarins; D012333:RNA, Messenger; D000255:Adenosine Triphosphate