3’-hydroxy-4’-methoxy-β-methyl-β-nitrostyrene inhibits tumorigenesis in colorectal cancer cells through ROS-mediated DNA damage and mitochondrial dysfunction

Abstract

The β-nitrostyrene family has been shown to suppress cell proliferation and induce apoptosis in types of various cancers. However, the mechanisms underlying the anticancer effects of β-nitrostyrenes in colorectal cancer remain poorly understood. In this study, we synthesized a β-nitrostyrene derivative, CYT-Rx20 (3’-hydroxy-4’-methoxy-β-methyl-β-nitrostyrene), and investigated its anticancer activities in human colorectal cancer cells both in vitro and in vivo. Our findings showed that treatment with CYT-Rx20 reduced cell viability and induced DNA damage in colorectal cancer cells. In addition, CYT-Rx20 induced cell cycle arrest of colorectal cancer cells at the G2/M phase and upregulated the protein expression of phospho-ERK, cyclin B1, phospho-cdc2 (Tyr15), aurora A, and aurora B, while it downregulated the expression of cdc25A and cdc25C. Furthermore, we found that CYT-Rx20 caused accumulation of intracellular reactive oxygen species (ROS) and reduction of mitochondrial membrane potential. The effects of CYT-Rx20 on cell viability, DNA damage, and mitochondrial membrane potential were reversed by pretreatment with the thiol antioxidant N-acetyl-L-cysteine (NAC), suggesting that ROS-mediated DNA damage and mitochondrial dysregulation play a critical role in these events. Finally, the nude mice xenograft study showed that CYT-Rx20 significantly reduced tumor growth of implanted colorectal cancer cells accompanied by elevated protein expression of aurora A, aurora B, γH2AX, phosphor-ERK, and MDA in the tumor tissues. Taken together, these results suggest that CYT-Rx20 may potentially be developed as a novel β-nitrostyrene-based anticancer agent for colorectal cancer.

Anti-Inflammatory Potential of 1-Nitro-2-Phenylethylene

“…NPe and its derivatives have been found to exert various biological effects, including anti-edema [ 35 ], vasorelaxant [ 13 ], antiplatelet [ 36 , 37 ] , anti-inflammatory [ 35 , 38 ], and anticancer activities [ 39 , 40 ]. Despite the several therapeutic actions described for NPe derivatives, they are also recognized to reduce cell viability [ 37 , 40 , 41 ]. In many cases, apoptosis, a programmed cell death, was identified as the mechanism of cell death induced by NPe and its derivatives [ 40 , 41 , 42 ].…”

“…Despite the several therapeutic actions described for NPe derivatives, they are also recognized to reduce cell viability [ 37 , 40 , 41 ]. In many cases, apoptosis, a programmed cell death, was identified as the mechanism of cell death induced by NPe and its derivatives [ 40 , 41 , 42 ]. Apoptosis-inducing cytotoxic activity associated with caspase-3 activation was also identified for hybrid analogs of NPe, nitrovinylstilbene and flavanone scaffolds in breast cancer cells [ 41 ].…”

Design, Synthesis and Biochemical Evaluation of Novel Ethanoanthracenes and Related Compounds to Target Burkitt’s Lymphoma

“…In contrast, the endemic BL is commonly associated with infection by the oncogenic Epstein-Barr virus (EBV), which interrupts cellular pathways regulating cell proliferation and thus prevents apoptosis [4]. Treatment of BL Nitrostyrenes and related nitrovinyl compounds induce anti-cancer effects and stimulate an apoptotic response in cancer cell lines e.g., oral and colon cancers, osteosarcoma and Erlich ascetic tumour cell lines [37][38][39][40][41][42], modulating tumorigenesis in colon and breast cancer via reactive oxygen species (ROS) mediated pathways [43][44][45]. Inhibition of telomerase, protein tyrosine phosphatase (PTP), phospholipase A2 and tubulin have been demonstrated for simple nitrostyrenes, while Pharmaceuticals 2020, 13, 16 4 of 58 In the present work, a structurally diverse library of 9,10-dihydro-9,10-ethanoanthracene compounds related in structure to the previous lead nitrostyrene compounds 10a-c and the tetracyclic antidepressant maprotiline 8 were synthesised.…”

“…From this study we identified the 9,10-dihydro-9,10-ethanoanthracene scaffold e.g., compound 9 as favourable for anti-proliferative activity in these cell lines while the (E)-9-(2-nitrovinyl)anthracene was also shown to elicit a potent pro-apoptotic effect [27]. The ethanoanthracene scaffold was previously reported to demonstrate activity as L-type Ca 2+ channel blockers [28], glucocorticoid and cannabinoid receptor modulators [29,30], inhibitors of drug efflux in multidrug resistance [31,32] together with antimicrobial [33] antimalarial [34], anti-inflammatory [35] and cytotoxic activity [36].Nitrostyrenes and related nitrovinyl compounds induce anti-cancer effects and stimulate an apoptotic response in cancer cell lines e.g., oral and colon cancers, osteosarcoma and Erlich ascetic tumour cell lines [37][38][39][40][41][42], modulating tumorigenesis in colon and breast cancer via reactive oxygen species (ROS) mediated pathways [43][44][45]. Inhibition of telomerase, protein tyrosine phosphatase (PTP), phospholipase A2 and tubulin have been demonstrated for simple nitrostyrenes, while antimicrobial, anti-inflammatory and immunosuppressive effects are also reported [37,46,47].…”

“…Nitrostyrenes and related nitrovinyl compounds induce anti-cancer effects and stimulate an apoptotic response in cancer cell lines e.g., oral and colon cancers, osteosarcoma and Erlich ascetic tumour cell lines [37][38][39][40][41][42], modulating tumorigenesis in colon and breast cancer via reactive oxygen species (ROS) mediated pathways [43][44][45]. Inhibition of telomerase, protein tyrosine phosphatase (PTP), phospholipase A2 and tubulin have been demonstrated for simple nitrostyrenes, while antimicrobial, anti-inflammatory and immunosuppressive effects are also reported [37,46,47].…”