title: Ferrocene and (arene)ruthenium(II) complexes of the natural anticancer naphthoquinone plumbagin with enhanced efficacy against resistant cancer cells and a genuine mode of action.
abstract: A series of ferrocene and (arene)ruthenium(II) complexes attached to the naturally occurring anticancer naphthoquinones plumbagin and juglone was tested for efficacy against various cancer cell lines and for alterations in the mode of action. The plumbagin ferrocene and (p-cymene)Ru(II) conjugates 1c and 2a overcame the multi-drug drug resistance of KB-V1/Vbl cervix carcinoma cells and showed IC50 (72 h) values around 1 μM in growth inhibition assays using 3-(4,5-dimethyl-2-yl)-2,5-diphenyltetrazolium bromide (MTT). They were further investigated for their influence on the cell cycle of KB-V1/Vbl and HCT-116 colon carcinoma cells, on the generation of reactive oxygen species (ROS) by the latter cell line, for their substrate character for the P-glycoprotein drug eflux pump via the calcein-AM efflux assays, and for DNA affinity by the electrophoretic mobility shift assay (EMSA). The derivatives 1c and 2a increased the number of dead cancer cells (sub-G0/G1 fraction) in a dose- and time-dependent manner. ROS levels were significantly increased upon treatment with 1c and 2a. These compounds also showed a greater affinity to linear DNA than plumbagin. While plumbagin did not affect calcein-AM transport by P-glycoprotein the derivatives 1c and 2a exhibited a 50% or 80% inhibition of the P-glycoprotein-mediated calcein-AM efflux relative to the clinically established sensitizer verapamil.
authors.affiliation: Organic Chemistry Laboratory, University of Bayreuth, Universitätsstrasse 30, 95447, Bayreuth, Germany.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Spoerlein-Guettler
authors.affiliation: Organic Chemistry Laboratory, University of Bayreuth, Universitätsstrasse 30, 95447, Bayreuth, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Mahal
authors.affiliation: Organic Chemistry Laboratory, University of Bayreuth, Universitätsstrasse 30, 95447, Bayreuth, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Schobert
authors.affiliation: Organic Chemistry Laboratory, University of Bayreuth, Universitätsstrasse 30, 95447, Bayreuth, Germany. Electronic address: bernhard.biersack@yahoo.com.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Biersack
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D002453:Cell Cycle; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy; D056831:Coordination Complexes / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D000081007:Cymenes; D004247:DNA / Q000737:chemistry; D005260:Female; D005296:Ferrous Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use*; D006801:Humans; D000075163:Metallocenes; D039821:Monoterpenes; D009285:Naphthoquinones / Q000627:therapeutic use*; D012428:Ruthenium / Q000737:chemistry / Q000627:therapeutic use*; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy
chemical_list: C000595583:((11E)-N'-(5-hydroxy-2-methyl-1-oxonaphthalen-4(1H)-ylidene)nicotinohydrazide)ruthenium(II); C000595582:(11E)-N'-(5-hydroxy-2-methyl-1-oxonaphthalen-4(1H)-ylidene)ferrocenecarboxylic hydrazide; D018435:ATP Binding Cassette Transporter, Subfamily B; D000972:Antineoplastic Agents, Phytogenic; D056831:Coordination Complexes; D000081007:Cymenes; D005296:Ferrous Compounds; D000075163:Metallocenes; D039821:Monoterpenes; D009285:Naphthoquinones; C007210:4-cymene; D012428:Ruthenium; D004247:DNA; C004998:ferrocene; C005134:juglone; C014758:plumbagin
keywords: Anticancer drugs; Ferrocene; Multi-drug resistance; Plumbagin; Ruthenium