HM015k, a Novel Silybin Derivative, Multi-Targets Metastatic Ovarian Cancer Cells and Is Safe in Zebrafish Toxicity Studies

This study was designed to determine the mechanisms by which the novel silybin derivative, (E)-3-(3-(benzyloxy) phenyl)-1-(4-hydroxyphenyl)prop-2-en-1-one ( or ), produces its anticancer efficacy in ovarian cancer cells. Compound induced apoptosis in ovarian cancer cells in a time-dependent manner by significantly upregulating the expression of Bax and Bak and downregulating the expression of Bcl-2. Interestingly, induced the cleavage of Bax p21 into its more efficacious cleaved form, Bax p18. In addition, caspase 3 and caspase 9 were cleaved to their active forms, inducing the cleavage of poly ADP ribose polymerase (PARP) and β-catenin. Furthermore, in OV2008 cells, induced significant cleavage in nuclear β-catenin to primarily inactive fragments of lower molecular weight. Furthermore, reversed the metastatic potential of OV2008 cells by inhibiting their migration and invasiveness. The mesenchymal phenotype in OV2008 was reversed by , causing cells to be rounder with epithelial-like phenotypes. The -induced reversal was further confirmed by significant upregulation of the E-cadherin expression, an epithelial marker, while N-cadherin, a mesenchymal marker, was downregulated in OV2008 cells. Compound inhibited the expression of the oncogenic c-Myc protein, downregulated proteins DVL3 and DVL2 and significantly upregulated cyclin B1. Also, significantly downregulated the expression levels of ABCG2 and ABCB1 transporters in resistant ABCG2 overexpressing H460/MX20 and resistant ABCB1 overexpressing MDCK/MDR1 cells, respectively. Finally, was safe in zebrafish model at concentrations up to 10 μM and induced no major toxicities in cardiac, morphology and swimming position parameters. Overall, is a multi-targeted inhibitor with efficacy against metastatic and resistant ovarian cancer. Future studies will be conducted to determine the efficacy of in tumor-bearing animals.