Abstract：
:The potent cytotoxicity of reactive oxygen species (ROS) can cause various diseases, however, it may also serve as a powerful chemotherapeutic strategy capable of killing cancer cells. Oxalomalate (OMA, α-hydroxy-β-oxalosuccinic acid), a tricarboxylic acid intermediate, is a well-known competitive inhibitor of two classes of NADP+-dependent isocitrate dehydrogenase (IDH) isoenzymes, which serve as the major antioxidants and redox regulators in the mitochondria and cytosol. In this study, we investigated the therapeutic effects of OMA in melanoma and elucidated the associated underlying mechanisms of action using in vitro and in vivo models. OMA targeting IDH enzymes suppressed melanoma growth through activation of apoptosis and inhibition of angiogenesis. Mechanistically, our findings showed that OMA activated p53-mediated apoptosis through ROS-dependent ATM-Chk2 signaling and reduced the expression of vascular endothelial growth factor through ROS-dependent E2F1-mediated hypoxia inducible factor-1α degradation. In particular, OMA-induced suppression of IDH activity resulted in induction of ROS stress response, ultimately leading to apoptotic cell death and antiangiogenic effects in melanoma cells. Thus, OMA might be a potential candidate drug for melanoma skin cancer therapy.
journal_name
Biochimiejournal_title
Biochimieauthors
Kim SH,Kil IS,Kwon OS,Kang BS,Lee DS,Lee HS,Lee JH,Park JWdoi
10.1016/j.biochi.2019.01.004subject
Has Abstractpub_date
2019-03-01 00:00:00pages
165-171eissn
0300-9084issn
1638-6183pii
S0300-9084(19)30004-5journal_volume
158pub_type
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