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Oxalomalate reduces tumor progression in melanoma via ROS-dependent proapoptotic and antiangiogenic effects

Sung Hwan Kim1, In Sup Kil1, Oh-Shin Kwon1

  • 1School of Life Sciences and Biotechnology, BK21 Plus KNU Creative BioResearch Group, College of Natural Sciences, Kyungpook National University, Taegu, South Korea.

Biochimie
|January 15, 2019
PubMed

Insights

Oxalomalate (OMA) shows promise as a melanoma cancer therapy by inhibiting isocitrate dehydrogenase (IDH) enzymes. This leads to cancer cell death via apoptosis and reduced blood vessel growth, suggesting OMA as a potential drug candidate.

Area of Science:

  • Biochemistry
  • Oncology
  • Cell Biology

Background:

  • Reactive oxygen species (ROS) exhibit potent cytotoxicity but can be harnessed for cancer therapy.
  • Oxalomalate (OMA) is a tricarboxylic acid intermediate and a known inhibitor of NADP+-dependent isocitrate dehydrogenase (IDH) enzymes, crucial for cellular antioxidant defense and redox regulation.

Purpose of the Study:

  • To investigate the therapeutic potential of OMA in melanoma.
  • To elucidate the mechanisms underlying OMA's anti-melanoma effects.

Main Methods:

  • In vitro and in vivo melanoma models were utilized.
  • Investigated OMA's impact on IDH enzyme activity, apoptosis, angiogenesis, and key signaling pathways (p53, ATM-Chk2, E2F1, HIF-1α).

Main Results:

  • OMA suppressed melanoma growth by activating apoptosis and inhibiting angiogenesis.
  • OMA induced p53-mediated apoptosis via ROS-dependent ATM-Chk2 signaling.
  • OMA reduced vascular endothelial growth factor expression through ROS-dependent E2F1-mediated degradation of hypoxia-inducible factor-1α.
  • OMA-induced IDH inhibition led to ROS stress, resulting in apoptotic cell death and antiangiogenic effects.

Conclusions:

  • OMA demonstrates therapeutic efficacy against melanoma by inducing oxidative stress and activating apoptotic pathways.
  • OMA inhibits melanoma progression by suppressing angiogenesis through a ROS-dependent mechanism.
  • OMA is a potential candidate for melanoma skin cancer therapy.
Keywords:
Antiangiogenic effectsIDHOxalomalateROS

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