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Updated: Jul 20, 2026

Spectrophotometric Screening for Potential Inhibitors of Cytosolic Glutathione S-Transferases
14:57

Spectrophotometric Screening for Potential Inhibitors of Cytosolic Glutathione S-Transferases

Published on: October 10, 2020

Pharmacologic inhibitors of extracellular signal-regulated kinase (ERKs) and c-Jun NH(2)-terminal kinase (JNK)

Adrian M Ramos1, Carlos Fernandez, Donna Amrán

  • 1Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Ramiro de Maeztu 9, 28040-Madrid, Spain.

Journal of Cellular Physiology
|September 15, 2006
PubMed

Insights

Arsenic trioxide (As(2)O(3)) combined with MEK/ERK and JNK inhibitors enhances apoptosis in leukemia cells by depleting glutathione. This combination therapy shows promise for improving As(2)O(3) antitumor effects.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Pharmacology

Background:

  • Arsenic trioxide (As(2)O(3)) exhibits modest apoptosis-inducing effects in leukemia cells.
  • Mitogen-activated protein kinases (MAPKs) play a role in cellular signaling pathways relevant to cancer.
  • Glutathione (GSH) is a critical intracellular antioxidant involved in cell survival and drug resistance.

Purpose of the Study:

  • To investigate the potentiation of As(2)O(3)-induced apoptosis by MAPK inhibitors in leukemia cells.
  • To elucidate the role of glutathione depletion and reactive oxygen species (ROS) in this potentiation.
  • To explore the potential of combining As(2)O(3) with kinase inhibitors for enhanced anti-leukemia therapy.

Main Methods:

  • Treatment of U-937 and NB4 leukemia cell lines with As(2)O(3) and various MAPK inhibitors (MEK/ERK, JNK, p38).
  • Assessment of apoptosis induction via caspase activation, Bid cleavage, and mitochondrial pathways.
  • Measurement of intracellular glutathione levels, ROS production, and arsenic accumulation.

Main Results:

  • MEK/ERK and JNK inhibitors, but not p38 inhibitors, potentiated As(2)O(3)-induced apoptosis in U-937 cells.
  • This potentiation involved both intrinsic and extrinsic apoptosis pathways and was linked to GSH depletion.
  • MEK/ERK inhibitors also enhanced apoptosis and reduced GSH in As(2)O(3)-treated NB4 cells; JNK inhibitors did not.

Conclusions:

  • Glutathione is a key target of MEK/ERK and JNK signaling in myeloid leukemia cells.
  • Combining As(2)O(3) with specific MAPK inhibitors (MEK/ERK, JNK) can enhance anti-leukemia effects.
  • These findings provide a rationale for using kinase inhibitors to improve the therapeutic efficacy of As(2)O(3).

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