Fenton Reaction Induced Cancer in Wild Type Rats Recapitulates Genomic Alterations Observed in Human Cancer

Abstract

Iron overload has been associated with carcinogenesis in humans. Intraperitoneal administration of ferric nitrilotriacetate initiates a Fenton reaction in renal proximal tubules of rodents that ultimately leads to a high incidence of renal cell carcinoma (RCC) after repeated treatments. We performed high-resolution microarray comparative genomic hybridization to identify characteristics in the genomic profiles of this oxidative stress-induced rat RCCs. The results revealed extensive large-scale genomic alterations with a preference for deletions. Deletions and amplifications were numerous and sometimes fragmented, demonstrating that a Fenton reaction is a cause of such genomic alterations in vivo. Frequency plotting indicated that two of the most commonly altered loci corresponded to a Cdkn2a/2b deletion and a Met amplification. Tumor sizes were proportionally associated with Met expression and/or amplification, and clustering analysis confirmed our results. Furthermore, we developed a procedure to compare whole genomic patterns of the copy number alterations among different species based on chromosomal syntenic relationship. Patterns of the rat RCCs showed the strongest similarity to the human RCCs among five types of human cancers, followed by human malignant mesothelioma, an iron overload-associated cancer. Therefore, an iron-dependent Fenton chemical reaction causes large-scale genomic alterations during carcinogenesis, which may result in distinct genomic profiles. Based on the characteristics of extensive genome alterations in human cancer, our results suggest that this chemical reaction may play a major role during human carcinogenesis.

Cyst fluid hemoglobin species in endometriosis and its malignant transformation: The role of metallobiology

“…Antioxidant activity may be upregulated to address the redox imbalance in a subset of endometriotic cells, which may be exposed to sublethal levels of ROS and able to adapt to cell survival (27)(28)(29). The present data support the idea that excess free radicals may lead to cell damage that culminates in cell death, whereas persistent exposure to sublethal ROS with an increased antioxidant state increases the tumorigenic potential of endometriotic cells (24,30).…”

Modulation of Angiogenesis, Proliferative Response and Apoptosis by β-Sitosterol in Rat Model of Renal Carcinogenesis

“…Moreover, the Fenton reaction occurs faster in male rats when compared to female rats, which have lower whole-kidney and single nephron glomerular filtration rate [4]. Fe-NTA, a well established renal toxicant, its repeated administration leads to renal adenocarcinoma in experimental rats [5].…”

Fenton chemistry at aqueous interfaces

“…The characteristic multiplet patterns arising from natural abundance 35 Cl (75%) and 37 Cl (25%) chlorine isotopes let us establish the number of Cl − contained in each detected species and, hence, the molecular composition of these singly charged ions ( -in bulk water (7), we estimate that less than 0.1% Fe 2+ should have been consumed under present conditions. In other words, reactions R3a and R4 proceed ∼10…”

“…The bactericidal action of antibiotics has been linked to their ability to induce Fenton chemistry in vivo (9,(30)(31)(32)(33)(34). Oxidative damage from exogenous Fenton chemistry likely is responsible for acute and chronic pathologies of the respiratory tract (35)(36)(37)(38).…”