title: 20(S)-Protopanaxadiol (PPD) analogues chemosensitize multidrug-resistant cancer cells to clinical anticancer drugs.
abstract: Novel 20(S)-protopanoxadiol (PPD) analogues were designed, synthesized, and evaluated for the chemosensitizing activity against a multidrug resistant (MDR) cell line (KBvcr) overexpressing P-glycoprotein (P-gp). Structure-activity relationship analysis showed that aromatic substituted aliphatic amine at the 24-positions (groups V) effectively and significantly sensitized P-gp overexpressing multidrug resistant (MDR) cells to anticancer drugs, such as docetaxel (DOC), vincristine (VCR), and adriamycin (ADM). PPD derivatives 12 and 18 showed 1.3-2.6 times more effective reversal ability than verapamil (VER) for DOC and VCR. Importantly, no cytotoxicity was observed by the active PPD analogues (5μM) against both non-MDR and MDR cells, suggesting that PPD analogues serve as novel lead compounds toward a potent and safe resistance modulator. Moreover, a preliminary mechanism study demonstrated that the chemosensitizing activity of PPD analogues results from inhibition of P-glycoprotein (P-gp) overexpressed in MDR cancer cells.
authors.affiliation: Shanghai Research Center for Modernization of Traditional Chinese Medicine, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China.
authors.forename: Junhua
authors.initials: J
authors.lastname: Liu
authors.forename: Xu
authors.initials: X
authors.lastname: Wang
authors.forename: Peng
authors.initials: P
authors.lastname: Liu
authors.forename: Rongxin
authors.initials: R
authors.lastname: Deng
authors.forename: Min
authors.initials: M
authors.lastname: Lei
authors.forename: Wantao
authors.initials: W
authors.lastname: Chen
authors.forename: Lihong
authors.initials: L
authors.lastname: Hu
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000737:chemistry*; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology; D015195:Drug Design; D018432:Drug Resistance, Multiple / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy*; D012502:Sapogenins / Q000494:pharmacology; D043823:Taxoids / Q000494:pharmacology; D014700:Verapamil / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D012502:Sapogenins; D043823:Taxoids; D000077143:Docetaxel; D004317:Doxorubicin; D014700:Verapamil; C062916:protopanaxadiol