Induction of apoptosis by the adenosine derivative IB-MECA in parental or multidrug-resistant HL-60 leukemia cells: possible relationship to the effects on inhibitor of apoptosis protein levels.
BACKGROUND
The effects of the A(3) adenosine receptor (A(3)AR) agonist IB-MECA were examined in HL-60 leukemia and in its multidrug-resistant variant HL-60R cells.


METHODS
Cytotoxicity was evaluated by MTS assays and apoptosis by flow cytometry analyses of DNA fragmentation and phosphatidylserine exposure. The mRNAs of A(3)AR and inhibitor of apoptosis proteins (IAPs) were determined by RT-PCR.


RESULTS
A(3)AR expression was similar in HL-60 and HL-60R cells. At > or =100 microM, IB-MECA exhibited strong cytotoxic and apoptotic effects in HL-60, but not in HL-60R cells. This activity was not modified by the A(3)AR antagonist VUF5574, the P-glycoprotein inhibitor verapamil, the adenosine uptake inhibitor NBTI or the anti-Fas antibody ZB4. HL-60R cells showed higher levels of different IAPs than HL-60 cells. IB-MECA 100 microM downregulated HIAP1, NAIP and survivin mRNAs in HL-60, but not in HL-60R cells.


CONCLUSIONS
The antitumor effects of IB-MECA are not mediated by A(3)AR in HL-60 cells, where the proapoptotic mechanism of the compound may involve downregulation of IAPs. The resistance of HL-60R cells to IB-MECA may depend on their elevated levels of IAPs.
Notarbartolo
Monica
M
Dipartimento di Scienze Farmacologiche, Università di Palermo, Italia.
Lo Cicero
Salvina
S
Meli
Maria
M
Poma
Paola
P
Labbozzetta
Manuela
M
Cervello
Melchiorre
M
D'Alessandro
Natale
N
D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005434:Flow Cytometry; D018922:HL-60 Cells; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000187:drug effects*
D051034:Inhibitor of Apoptosis Proteins; C084956:N(6)-(3-iodobenzyl)-5'-N-methylcarboxamidoadenosine; D000241:Adenosine