title: Synergistic and additive antiproliferative effects on human leukemia cell lines induced by combining acetylenehexacarbonyldicobalt complexes with the tyrosine kinase inhibitor imatinib.
abstract: The tyrosine kinase inhibitor imatinib is successfully used in the treatment of chronic myeloid leukemia, but the occurrence of resistance phenomena can significantly limit therapeutic impact. Imatinib shows synergistic effects with cisplatin, suggesting that the coadministration of different cytostatics might reestablish the efficacy of treatment. We recently demonstrated that cobalt alkyne (or acetylenehexacarbonyldicobalt) complexes induce antiproliferative activity in human leukemia and lymphoma cells. The present study evaluates the effects of cobalt alkyne compounds containing propargylic acid esters on human acute (HL-60) and chronic myeloid (LAMA-84 and CML-T1) leukemia cell lines. The cell growth inhibitory activities (IC(50) values of 9.5 microM and higher) and induction of apoptosis (maximum 5.5-fold increase of single-stranded DNA at a drug concentration of 50 microM) achieved with the single agents were moderate. Interestingly, suboptimal concentrations of the cobalt complexes (10 microM) together with imatinib (0.1 microM), when coadministered, showed an additive or synergistic effect on cellular proliferation inhibition. The most promising results were obtained with complexes containing ligands derived from the nonsteroidal antiinflammatory drugs acetylsalicylic acid and naproxene.
authors.affiliation: Institute of Pharmacy, Free University of Berlin, Koenigin-Luise-Strasse 2+4, 14195 Berlin, Germany. ottingo@zedat.fu-berlin.de
authors.forename: Ingo
authors.initials: I
authors.lastname: Ott
authors.forename: Angelika
authors.initials: A
authors.lastname: Abraham
authors.forename: Petra
authors.initials: P
authors.lastname: Schumacher
authors.forename: Hashem
authors.initials: H
authors.lastname: Shorafa
authors.forename: Guenther
authors.initials: G
authors.lastname: Gastl
authors.forename: Ronald
authors.initials: R
authors.lastname: Gust
authors.forename: Brigitte
authors.initials: B
authors.lastname: Kircher
mesh_terms: D001549:Benzamides; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D003035:Cobalt / Q000737:chemistry*; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D004357:Drug Synergism; D018922:HL-60 Cells; D006801:Humans; D000068877:Imatinib Mesylate; D020128:Inhibitory Concentration 50; D007938:Leukemia / Q000188:drug therapy / Q000473:pathology; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000737:chemistry / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*
chemical_list: D001549:Benzamides; D009942:Organometallic Compounds; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D003035:Cobalt; D000068877:Imatinib Mesylate