AI Article Synopsis

  • Intracellular ATP is released outside of cells in response to various stimuli and activates purinergic receptors, but its release during radionuclide therapy is not well understood.
  • Researchers developed I-labeled trastuzumab (I-trastuzumab) and found that it significantly increased extracellular ATP levels in HER2-positive cells while showing no effect on HER2-negative cells.
  • The study concluded that I-trastuzumab not only induces ATP release via radiation but also that this release helps enhance its effectiveness in reducing cell viability through the P2Y receptor pathway.

Article Abstract

Intracellular ATP is released outside cells by various stimuli and is involved in cytoprotection by activating purinergic receptors. However, it remains unclear whether targeted radionuclide therapy induces extracellular ATP release. Here, we prepared I-labeled trastuzumab (I-trastuzumab) and examined extracellular ATP release and its roles in I-trastuzumab's growth inhibitory effects. I-trastuzumab was prepared by labeling with the chloramine-T method. The binding of I-trastuzumab to cells was investigated using the human epidermal growth factor receptor 2 (HER2)-positive cells (SKOV3) and the HER2-negative cell (MCF7). Extracellular ATP was determined by measuring chemiluminescence using a luciferin-luciferase reagent. The growth inhibitory effects of I-trastuzumab were investigated by colony formation assay. I-trastuzumab bound exclusively to SKOV3 cells. Treatment with I-trastuzumab at 4 MBq/mL and higher concentrations significantly increased extracellular ATP levels, whereas non-radioactive trastuzumab didn't. This suggested that ATP release was specifically induced by radiation derived from I. The growth inhibitory effects of I-trastuzumab were significantly enhanced by pretreatment with apyrase (ecto-ATPase) or MRS2578 (a P2Y-selective antagonist), whereas they were significantly reduced by treatment with a P2Y-selective agonist. In conclusion, I-trastuzumab induced extracellular ATP release, and the released ATP was shown to be involved in mitigating radiation-induced reduction in cell viability through P2Y receptor.

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http://dx.doi.org/10.1248/bpb.b24-00427DOI Listing

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