Relationship between antitumor effects and active oxygen
ROS (Reactive oxygen species) are highly reactive oxygen species mainly generated during the ATP synthesis process in mitochondria. While it is important as a signal substance for information transmission and as part of immune functions such as macrophages, it acts as an oxidizing agent on DNA and proteins, causing various diseases. Recent research has drawn attention to ROS in the field of a new type of cell death (ferroptosis) caused by the Fenton reaction induced by divalent iron as a catalyst, and the significance of detecting ROS is increasing. In this post, we introduce you to some reports regarding tumors and active oxygen.
Tachibana et al.’s group found that the enzyme GGT1 (γ-glutamyltransferase 1) is involved in cell metabolism and glutamylcysteine metabolism, and is the key to the response of myeloid-derived suppressor cells (MDSCs) to G-CSF (granulocyte colony-stimulating factor). They reported that tumor progression in a chemotherapy-induced neutropenia mouse model was promoted by G-CSF and that the specific GGT inhibitor GGsTop prevented G-CSF-induced EL4 lymphoma progression. These results suggest that targeting GGT1 suppresses the tumor-promoting effects of myeloid-derived suppressor cells (MDSCs) and simultaneously reduces their immunosuppressive function.
Assessment of intracellular ROS was performed using the ROS Assay Kit -Highly Sensitive DCFH-DA- (Dojindo Laboratories), and intracellular ROS was detected by BD FACSCanto II flow cytometer (BD Biosciences). As a result, they analyzed the expression of arginase 1, inducible nitric oxide synthase (iNOS), and ROS, which are major immunosuppressive molecules in MDSCs, and found that the mRNA levels of Arg1 and Nos2 were significantly upregulated by G-CSF, showed that ROS also increased.
Wei et al. revealed that ROS-mediated oxidative stress plays an important role as a mechanism for the anticancer activity of plumbazin (5-hydroxy-2-methyl-1,4-naphthoquinone, PLB).
Plumbagin a naturally occurring naphthoquinone mainly isolated from the plant Plumbago zeylanica L., has been proven to possess anticancer activities towards multiple types of cancer.
The present study showed that PLB exposure significantly reduced HCC cell viability and colony formation. In addition, they detected ROS and glutathione (GSH)/oxidized glutathione disulfide (GSSH) levels and confirmed that oxidative stress was increased by PLB in HCC cells. Additionally, PLB-induced G2/M cell cycle arrest and DNA damage were detected. The study demonstrates that plumbagin triggers a DNA damage response by activating cell cycle checkpoints such as ATM, Chk1, Chk2, and p53, leading to G2/M cell cycle arrest.
Taken together, these results indicate that ROS-mediated oxidative stress plays a key role in PLB-induced G2/M cell cycle arrest mediated by the ATM-p53 pathway.
What next?
We introduced two examples this time, but the relationship between reactive oxygen species and cancer is extremely complex. Even if a substance exhibits cancer-suppressing effects under certain conditions, it may have the opposite effect under other conditions.
In the future, advances in personalized treatments and immunotherapy, improvements in early cancer diagnosis technology, and the discovery of new therapeutic targets are anticipated. Among them, reactive oxygen species are a crucial element, and it will be one of the interesting topics to be discussed in the future.
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References
Acknowledgment
Special thanks to our partner from Dojindo Laboratories, JAPAN, for writing this article.
