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

Abstract

Background: The effects of the A₃ adenosine receptor (A₃AR) 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 A₃AR and inhibitor of apoptosis proteins (IAPs) were determined by RT-PCR. Results: A₃AR expression was similar in HL-60 and HL-60R cells. At ≧100 µM, IB-MECA exhibited strong cytotoxic and apoptotic effects in HL-60, but not in HL-60R cells. This activity was not modified by the A₃AR 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 µM 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 A₃AR 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.

Effect of P38 MAPK on the apoptosis of human lung adenocarcinoma cell induced by the spider venom

“…In addition, our data suggested that P38 MAPK may be involved in A549 cell death. MAP kinases, especially P38 MAPK, have been reported to play important roles in the pathways that regulate both cell cycle and apoptosis 22 . The observation that p38 MAPK facilitates apoptosis through regulation of cell cycle is consistent with these reports 23 …”

Purinergic signalling and cancer

“…Static magnetic field exposure of HL-60 cells increased the increase in [Ca 2+ ] i produced by ATP [457,458]. A 3 receptor agonists were shown to inhibit proliferation and induce apoptosis of HL-60 leukaemia cells [459,460]. ADP and ATP increased [Ca 2+ ] i in CB1 cells, isolated from a patient with T-acute lymphoblastic leukaemia [461], probably via P2Y 1 , P2Y 12 or P2Y 13 receptors.…”

Molecular mechanisms of adenosine-induced apoptosis in human HepG2 cells1

“…Recent evidence suggests that apoptosis of cells is closely related to the occurrence, progress and metastasis of tumors [1][2][3] . Study of the mechanisms of apoptosis in tumor cells is an important field of tumor therapy and cancer molecular biology [4][5][6][7] . Adenosine has been shown to induce apoptosis in various systems [8,9] and in the clinical setting, adenosine has also been used to treat some diseases, including arrhythmia.…”