Modulation of the A3 adenosine receptor by low agonist concentration induces antitumor and myelostimulatory effects

Ofer Merimsky, Sara Bar-Yehuda, Lea Madi, Pnina Fishman

Research output: Contribution to journalArticlepeer-review

Abstract

The A3 adenosine receptor (A3AR) agonists IB-MECA and CI-IB-MECA act as anticancer agents by inhibiting the growth of melanoma and colon carcinoma cells both in vitro and in vivo. The A3AR is highly expressed in these tumor cells and upon agonist binding receptor internalization and recycling occurs. The downstream signaling pathways that follow these events include a decrease in the expression level of protein kinase A (PKA) and protein kinase B/Akt (PKB/Akt) leading to the deregulation of the Wnt and the NF-κB signaling pathways. Interestingly, IB-MECA and CI-IB-MECA generate the opposite, beneficial effect on myeloid cells. These agonists induce the production of granulocyte colony-stimulating factor (G-CSF) by murine splenocytes. The molecular mechanisms underlying the events prior to G-CSF production include the upregulation of NF-κB and the upstream kinases phosphoinositide 3-kinase (PI3K), PKB/Akt, and IKK. In addition, a myeloprotective effect is noted upon administration of IB-MECA and CI-IB-MECA to chemotherapy-treated mice. This was expressed by accelerated recovery of white blood cells and neutrophil counts in cyclophosphamide-treated mice following agonist administration. Taken together, activation of the A3AR on tumor and normal cells generates opposing responses: in tumor cells, NF-κB expression level decreases, resulting in tumor growth inhibition, while in normal cells it is upregulated, leading to G-CSF production and the induction of myelostimulation. It thus appears that A3AR agonists act as tumor growth inhibitors, simultaneously maintaining the myeloid system, capable of preventing the damage of chemotherapeutic agents.

Original languageEnglish
Pages (from-to)386-389
Number of pages4
JournalDrug Development Research
Volume58
Issue number4
DOIs
StatePublished - 1 Apr 2003
Externally publishedYes

Keywords

  • A adenosine receptor
  • Cancer
  • Chemotherapy
  • Myelostimulation

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