Effects of palladacycle complex on hematopoietic progenitor cells proliferation in vivo and in vitro and its relation with the inhibitory properties of this compound on the angiotensin-I converting enzyme activity.
In the present study, we introduce a new class of organometallic compound, the Biphosphinic Palladacycle Complex [Pd (C2, N-S(-)(dmpa)(dppf)] Cl (BPC), as an angiotensin-I converting-enzyme inhibitor (ACEI) with hematological regulation properties. When BPC was assayed as a competitive inhibitor over the hydrolysis of Abz-YRK (Dnp)-P-OH (Km = 7.0 microM), it showed a Kiapp = 0.2259 ng and a Ki value of 94.12 pg. Using murine long-term bone marrow cultures (LTBMCs) and clonal culture techniques, we also evaluated the capacity of this drug (1.18 microM) to module haematopoietic progenitor cells proliferation in vitro and in vivo. Our results demonstrated that BPC produces no toxicity to bone marrow cells, as determined by the unchanged cell number in the non-adherent layer at weeks 1, 2, and 8 and the increased number of adherent cells present in the BPC-treated LTBMCs. However, the proportion of CFU-Cs in the non-adherent cell layer was reduced at weeks 5, 6, 8, and 9. In vivo studies using the dose of 1 mg/kg of BPC, administered by subcutaneous route, presented similar result as those found in vitro, in the number of CFU-Cs. This latter finding may be explained by the inhibitory effects of this drug on the ACE activity, which probably result in increased levels of its substrate AcSDKP, a negative regulator of hematopoiesis.
Caires
Antonio C F
AC
Centro Interdisciplinar de Investigação Bioquímica (CIIB), Universidade de Mogi das Cruzes (UMC), São Paulo, Brazil.
Oliveira
Carlos R
CR
Smith
Mickaela C M
MC
Hemerly
Jefferson P
JP
Juliano
Maria A
MA
Bincoletto
Claudia
C
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology / Q000633:toxicity*; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D003114:Colony-Forming Units Assay; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D007279:Injections, Subcutaneous; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009942:Organometallic Compounds / Q000494:pharmacology / Q000633:toxicity*; D010165:Palladium / Q000494:pharmacology / Q000633:toxicity*; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism*; D013154:Spleen / Q000166:cytology / Q000187:drug effects
D000806:Angiotensin-Converting Enzyme Inhibitors; D009942:Organometallic Compounds; D010165:Palladium; D007703:Peptidyl-Dipeptidase A