Effects of Corchorusoside C on NF-κB and PARP-1 Molecular Targets and Toxicity Profile in Zebrafish.

Autor: Mirtallo Ezzone NP; Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA., Anaya-Eugenio GD; Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA., Addo EM; Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA., Ren Y; Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA., Kinghorn AD; Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA., Carcache de Blanco EJ; Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA.
Jazyk: angličtina
Zdroj: International journal of molecular sciences [Int J Mol Sci] 2022 Nov 22; Vol. 23 (23). Date of Electronic Publication: 2022 Nov 22.
DOI: 10.3390/ijms232314546
Abstrakt: The present study aims to continue the study of corchorusoside C ( 1 ), a cardenolide isolated from Streptocaulon juventas , as a potential anticancer agent. A mechanistic study was pursued in a zebrafish model and in DU-145 prostate cancer cells to investigate the selectivity of 1 towards NF-κB and PARP-1 pathway elements. Compound 1 was found to inhibit the expression of IKKα and NF-κB p65 in TNF-α induced zebrafish and inhibit the expression of NIK in vitro. The protein expression levels of XRCC-1 were increased and p53 decreased in DU-145 cells. XIAP protein expression was initially decreased after treatment with 1 , followed by an increase in expression at doses higher than the IC 50 value. The activity of caspase-1 and the protein expression levels of IL-18 were both decreased following treatment of 1 . The binding interactions for 1 to NIK, XRCC-1, p53, XIAP, and caspase-1 proteins were explored in molecular docking studies. Additionally, the toxicity profile of 1 in zebrafish was favorable in comparison to its analog digoxin and other anticancer drugs at the same MTD in zebrafish. Overall, 1 targets the noncanconical NF-κB pathway in vivo and in vitro, and is well tolerated in zebrafish supporting its potential in the treatment of prostate cancer.
Competing Interests: The authors declare that there are no conflict of interest.
Databáze: MEDLINE
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