Withaferin A, a steroidal lactone from Withania somnifera, induces mitotic catastrophe and growth arrest in prostate cancer cells.
Cell cycle deregulation is strongly associated with the pathogenesis of prostate cancer. Clinical trials of cell cycle regulators that target either the G0/G1 or G2/M phase to inhibit the growth of cancers including prostate cancer are increasing. The present study focused on the cell cycle regulatory potential of the withanolide withaferin A (1) on prostate cancer cells. Compound 1 induced G2/M arrest in both prostate cancer cell lines (PC-3 and DU-145) when treated for 48 h. The G2/M arrest was accompanied by upregulation of phosphorylated Wee-1, phosphorylated histone H3, p21, and Aurora B. On the other hand, downregulation of cyclins (A2, B1, and E2) and a reduction in phosphorylated Cdc2 (Tyr15) were observed in 1-treated prostate cancer cells. In addition, decreased levels of phosphorylated Chk1 (Ser345) and Chk2 (Thr68) were evident in prostate cancer cells on treatment with 1. These results suggest that activation of Cdc2 leads to arrest in the M phase, with abnormal duplication, and initiation of mitotic catastrophe that results in cell death. In conclusion, these results show clearly the potential of 1 as a regulator of the G2/M phase of the cell cycle and as a therapeutic agent for prostate cancer.
Department of Biomedical Sciences, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center , El Paso, Texas 79905, United States.
Ram V
RV
Roy
Suman
S
Suman
Trinath P
TP
Das
Joe E
JE
Luevano
Chendil
C
Damodaran
D017209:Apoptosis / Q000187:drug effects; D016203:CDC2 Protein Kinase / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D016213:Cyclins / Q000378:metabolism; D016195:G2 Phase / Q000187:drug effects; D006657:Histones / Q000378:metabolism; D006801:Humans; D008297:Male; D008938:Mitosis / Q000187:drug effects; D015394:Molecular Structure; D011471:Prostatic Neoplasms / Q000188:drug therapy; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D032341:Withania / Q000737:chemistry*; D054358:Withanolides / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*
D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D006657:Histones; D016159:Tumor Suppressor Protein p53; D054358:Withanolides; D017346:Protein Serine-Threonine Kinases; D016203:CDC2 Protein Kinase; C009684:withaferin A