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Toxicol In Vitro ; 60: 420-436, 2019 Oct.
Article in English | MEDLINE | ID: mdl-31175925

ABSTRACT

Metastatic prostate cancer, with no effective treatment, is among the leading causes of cancer-associated deaths in men. Overexpression of p38αMAPK has been observed in neuroendocrine prostate cancer patients and in both DU145 and PC-3 cell lines and represents a good drug target. Sulfonamide derivatives have shown biological activities against many human diseases, including cancer. CID-6033590, a sulfonylhydrazide compound, screened from PubChem database by molecular docking with p38αMAPK, was evaluated for anti-cancerous activities. CID-6033590 induced toxicity in both DU145 and PC-3 cells in a concentration and time-dependent manner with an IC50 value of 60 µM and 66 µM, respectively. Sub-cytotoxic concentrations of the compound significantly induced S-phase cell cycle arrest, inhibited cyclinA/CDK2 complex and blocked cell proliferation. Further, CID-6033590 downregulated phosphorylation of p38MAPK (P-p38) as well as its downstream targets, Activating transcription factor 2 (ATF-2) and Heat shock protein 27 (Hsp27). The compound increased ROS and decreased mitochondrial membrane potential (Δψm), downregulated Bcl-2 and survivin and cleaved poly ADP ribose polymerase (PARP) and caspase-3, indicating the induction of apoptosis. The evaluaion of the compound on noncancerous, human prostatic epithelial cell line RWPE-1, and healthy murine tissues yielded no significant toxicity. Taken together, we suggest CID-6033590 as a potential candidate for prostate cancer therapy.


Subject(s)
Antineoplastic Agents/pharmacology , Hydrazones/pharmacology , Prostatic Neoplasms/drug therapy , Protein Kinase Inhibitors/pharmacology , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors , Animals , Apoptosis/drug effects , Catalase/metabolism , Cell Cycle Checkpoints/drug effects , Cell Line , Glutathione/metabolism , Humans , Male , Mice, Inbred BALB C , Prostatic Neoplasms/metabolism , Reactive Oxygen Species/metabolism , S Phase/drug effects , Superoxide Dismutase/metabolism , p38 Mitogen-Activated Protein Kinases/metabolism
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