Hint from an Enzymatic Reaction: Superoxide Dismutase Models Efficiently Suppress Colorectal Cancer Cell Proliferation

Abstract

Superoxide dismutases (SODs) are essential antioxidant enzymes that prevent massive superoxide radical production and thus protect cells from damage induced by free radicals. However, this concept has rarely been applied to directly impede the function of driver oncogenes, thus far. Here, leveraging efforts from SOD model complexes, we report the novel finding of biomimetic copper complexes that efficiently scavenge intracellularly generated free radicals and, thereby, directly access the core consequence of colorectal cancer suppression. We conceived four structurally different SOD-mimicking copper complexes that showed distinct disproportionation reaction rates of intracellular superoxide radical anions. By replenishing SOD models, we observed a dramatic reduction of intracellular reactive oxygen species (ROS) and adenine 5′-triphosphate (ATP) concentrations that led to cell cycle arrest at the G2/M stage and induced apoptosis in vitro and in vivo. Our results showcase how nature-mimicking models can be designed and fine-tuned to serve as a viable chemotherapeutic strategy for cancer treatment.

Effects of Dietary Eucommia ulmoides Leaf Extract Supplementation on Growth Performance, Meat Quality, Antioxidant Capacity, and Lipid Metabolism of Finishing Pigs

“…We know that the antioxidant enzyme system, including SOD, GSH-PX, and CAT, constitutes a critical component for maintaining cellular redox homeostasis, serving as the first line of antioxidant defenses [ 44 ]. SOD scavenges harmful superoxide free radicals (O 2 · − ) in cells [ 45 ]. GSH-PX and CAT cooperate with SOD to reduce toxic peroxides into non-toxic hydroxyl compounds and promote the decomposition of H 2 O 2 , thus protecting the structure and function of cell membranes from the damage of peroxides [ 46 ].…”

Copper in colorectal cancer: From copper‐related mechanisms to clinical cancer therapies

“… 206 , 207 The key molecular mechanisms involve the inhibition of topoisomerase IIa activity 208 and interaction with DNA to induce double‐stranded pDNA cleavage. 209 Additionally, copper‐based complexes also promote cancer cell apoptosis through various mechanisms, 210 , 211 including influencing ROS production, 212 , 213 , 214 , 215 inhibiting the activity of the NF‐κB 215 and JAK2/STAT5 signalling pathway, 216 activating the p53 signalling pathway, 217 , 218 , 219 and activating caspase‐related proteins. 220 Moreover, copper‐based complexes can reverse chemoresistance in CRC treatment, particularly against drugs such as oxaliplatin, cisplatin and doxorubicin.…”

The temperature-controlled optimization of g-C3N4 structure significantly enhances the efficiency of photothermal catalytic NO removal

“…10 Finally, disproportionation reactions make controlling product selectivity difficult as observed by Han et al 's use of B(C 6 F 5 ) 3 catalyst in a series of reactions between indole and various hydro silanes resulting in different products with difficult-to-control selectivity requiring appropriate substrate selection or methods to inhibit side reactions. 11–14…”