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Identification of Intracellular Signaling Events Induced in Viable Cells by Interaction with Neighboring Cells Undergoing Apoptotic Cell Death
09:18

Identification of Intracellular Signaling Events Induced in Viable Cells by Interaction with Neighboring Cells Undergoing Apoptotic Cell Death

Published on: December 27, 2016

Rapid decrease of intracellular pH associated with inhibition of Na+/H+ exchanger precedes apoptotic events in the

Hiroyuki Nagata1, Xiao-Fang Che, Keisuke Miyazawa

  • 1Fourth Department of Surgery, Tokyo Medical University, Ibaragi Medical Center, 3-20-1 Chuo, Ami, Inashiki, Ibaraki 300-0395, Japan.

Oncology Reports
|December 15, 2010
PubMed

Insights

2-aminophenoxazine-3-one (Phx-3) rapidly decreases intracellular pH in gastric cancer cells by inhibiting the Na+/H+ exchanger 1 (NHE1). This pH disruption leads to apoptosis and cell death, suggesting Phx-3 as a potential gastric cancer therapeutic.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Oncology

Background:

  • Gastric cancer remains a significant health challenge, often resistant to conventional therapies.
  • Understanding the mechanisms of novel therapeutic agents is crucial for developing effective treatments.

Purpose of the Study:

  • To investigate the mechanism behind the proapoptotic effects of 2-aminophenoxazine-3-one (Phx-3) in human gastric cancer cell lines (MKN45 and MKN74).
  • To evaluate the impact of Phx-3 on intracellular pH (pHi) and its correlation with cytotoxicity.

Main Methods:

  • Treatment of MKN45 and MKN74 cells with varying concentrations of Phx-3.
  • Measurement of intracellular pH (pHi) using established methods.
  • Assessment of Na+/H+ exchanger isoform 1 (NHE1) activity.
  • Morphological analysis of cells for apoptotic indicators.
  • Viability assays to determine cytotoxicity.

Main Results:

  • Phx-3 significantly and rapidly reduced pHi in both cell lines in a dose-dependent manner.
  • The decrease in pHi was strongly correlated with the inhibition of NHE1 activity.
  • Phx-3 induced characteristic apoptotic morphology, including cell shrinkage and nuclear chromatin condensation.
  • Extensive cytotoxicity was observed, with significant cell death at clinically relevant Phx-3 concentrations.

Conclusions:

  • Phx-3 induces apoptosis and cytotoxicity in gastric cancer cells by causing a rapid and substantial decrease in pHi, linked to NHE1 inhibition.
  • This disruption of intracellular homeostasis highlights Phx-3's potential as a therapeutic agent for gastric cancer, particularly for treatment-resistant cases.

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