ROS, an unusual new ally in defeating cancer?

Reactive oxygen species (ROS) are molecules that can be categorized into two groups: free radicals which contain one or more unpaired electron(s) such as superoxide (O₂^-), hydroxyl radical (OH^●), and nitric oxide (NO^●); and non-radical ROS which do not contain unpaired electrons such as hydrogen peroxide (H₂O₂) or singlet oxygen (¹O₂). Tumor cells are highly reactive as they can also be converted into free radical forms of ROS. ROS are naturally produced by the mitochondrial electron transport chain during aerobic respiration, oxidoreductase enzymes and metal ion-catalyzed oxidation. They are essential for several biological functions as they react with and modify the structure of genes and proteins to modulate their functions. They also act as second messenger molecules in a variety of signaling cascades including cell proliferation and differentiation.

Elevated levels of ROS have been found in most cancers with the main putative causes being an increase in metabolic activity, mitochondrial dysfunction, and relative lack of blood supply compared to normal cells (i.e. hypoxia). It is well documented that ROS act in multiple signaling cascades involved in cancer initiation, development, progression, invasion and metastasis. For these reasons, they are deemed to be oncogenic. The use of antioxidants such as polyphenols derived from red wine or green tea has been considered a reasonable therapeutic approach to treat ROS-induced cancers. Interestingly, there is an increasing number of evidence suggesting a totally opposite role for ROS. Indeed, it seems that both extrinsic and intrinsic forms of apoptosis can be triggered by relatively high levels of ROS. As for all types of therapies, efficiency and selectivity of the treatment are essential and the question remains on how tumor cells can be efficiently and selectively killed by ROS. The current hypothesis is that ROS might function as a “double-edged sword”. A moderate increase of ROS may promote cell proliferation and survival whereas an excessive increase of ROS may lead to a toxic threshold and trigger cell death. Because healthy cells maintain redox homeostasis and have lower basal levels of ROS than cancer cells, they can better tolerate a certain level of exogenous stress than cancer cells. The latter reach the critical threshold earlier and ultimately undergo cell death by apoptosis while healthy cells may survive (J. Wang et al., 2008; D. Trachootam et al., 2009). Several ROS-generating agents are currently in clinical trials as single agents or in combination therapy.

Prostate cancer is the most prevalent form of cancer in men worldwide. While some types of prostate cancer grow slowly and may need minimal to no treatment, other types can be very aggressive and spread quickly. Thanks to numerous advances in early diagnosis, the number of prostate cancer-related deaths has steadily decreased in the last decade. Unfortunately, late stage prostate cancers, such as castration-resistant prostate cancer, are virtually incurable as they do not respond to most currently available therapeutic agents or therapies. Consequently, there is an urgent need for novel treatment options for these patients. Recently, Dr. Tang and colleagues from the University of Kansas Medical Center defined a natural compound called Alternol as a promising novel anticancer drug for advanced prostate cancer in a research article published in Molecular Cancer Therapeutics. Alternol is a compound purified from the fermentation products of Alternaria alternate var. monosporus, a microorganism from the bark of the yew tree. Using Enzo’s Total ROS detection kit for microscopy and flow cytometry, the authors demonstrated that Alternol induces prostate cancer cell-specific apoptosis through severe intracellular accumulation of ROS. The functional significance of ROS accumulation in Alternol-induced cytotoxicity was confirmed using two structurally distinct antioxidants: N-acetylcysteine (NAC) and dihydrolipoic acid (DHLA). Treatment with either NAC or DHLA completely abolished Alternol-induced oxidative stress and apoptosis as evidenced by the blockage of PARP cleavage, caspase-3 processing, DNA fragmentation and mitochondria membrane potential perturbation. Alternol-induced apoptosis of prostate cancer cells was shown to be dependent on the expression of the pro-apoptotic protein Bax. Indeed, prostate cancer cells negative for the expression of Bax were insensitive to Alternol-induced ROS accumulation. Finally, using an in vivo model of mouse xenograft, they demonstrated that Alternol significantly suppressed tumor growth in vivo. Overall, these data suggest that Alternol possesses a great potential as an anticancer agent and further preclinical and clinical development should be envisaged to confirm these results not only with prostate cancer but also with other forms of cancer.

Enzo Life Sciences offers comprehensive tools for advancing your research in oxidative stress and cancer such as the Total ROS detection kit for microscopy and flow cytometry and the DNA damage ELISA kit. In addition, Enzo offers activity kits, antibodies, and live cell analysis kits, some of which are listed below:

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