Faculty Collaboration Database

CID-6033590 inhibits p38MAPK pathway and induces S-phase cell cycle arrest and apoptosis in DU145 and PC-3 cells. Toxicol In Vitro 2019 Oct;60:420-436

Date

06/09/2019

Pubmed ID

31175925

DOI

10.1016/j.tiv.2019.06.003

Scopus ID

2-s2.0-85068364782 (requires institutional sign-in at Scopus site)   12 Citations

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.

Author List

Sharma GP, Gurung SK, Inam A, Nigam L, Bist A, Mohapatra D, Senapati S, Subbarao N, Azam A, Mondal N

Author

Guru Prasad Sharma PhD Research Scientist I in the Radiation Oncology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Antineoplastic Agents
Apoptosis
Catalase
Cell Cycle Checkpoints
Cell Line
Glutathione
Humans
Hydrazones
Male
Mice, Inbred BALB C
Prostatic Neoplasms
Protein Kinase Inhibitors
Reactive Oxygen Species
S Phase
Superoxide Dismutase
p38 Mitogen-Activated Protein Kinases