Inhibition of protein kinase C by isojacareubin suppresses hepatocellular carcinoma metastasis and induces apoptosis in vitro and in vivo.

Publisher: Nature Publishing Group Country of Publication: England NLM ID: 101563288 Publication Model: Electronic Cited Medium: Internet ISSN: 2045-2322 (Electronic) Linking ISSN: 20452322 NLM ISO Abbreviation: Sci Rep Subsets: MEDLINE

Original Publication: London : Nature Publishing Group, copyright 2011-

Apoptosis/*drug effects ; Carcinoma, Hepatocellular/*drug therapy ; Liver Neoplasms/*drug therapy ; Neoplasm Proteins/*antagonists & inhibitors ; Protein Kinase C/*antagonists & inhibitors ; Xanthenes/*pharmacology; Animals ; Carcinoma, Hepatocellular/enzymology ; Carcinoma, Hepatocellular/pathology ; Hep G2 Cells ; Humans ; Liver Neoplasms/enzymology ; Liver Neoplasms/pathology ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Neoplasm Metastasis ; Neoplasm Proteins/metabolism ; Protein Kinase C/metabolism ; Xenograft Model Antitumor Assays

Targeted inhibition of protein kinase C (PKC) inhibits hepatocellular carcinoma (HCC) proliferation and metastasis. We previously reported the cytotoxicity of a series of synthetic phenyl-substituted polyoxygenated xanthone derivatives against human HCC. In the current study, the most potent natural product, isojacareubin (ISJ), was synthesized, and its cellular-level antihepatoma activities were evaluated. ISJ significantly inhibited cell proliferation and was highly selective for HCC cells in comparison to nonmalignant QSG-7701 hepatocytes. Moreover, ISJ exhibited pro-apoptotic effects on HepG2 hepatoma cells, as well as impaired HepG2 cell migration and invasion. Furthermore, ISJ was a potent inhibitor of PKC, with differential actions against various PKC isotypes. ISJ selectively inhibited the expression of aPKC (PKCζ) in the cytosol and the translocation of cytosolic PKCζ to membrane site. ISJ also directly interacted with cPKC (PKCα) and nPKC (PKCδ, PKCε and PKCμ) and thereby inhibited the early response of major MAPK phosphorylation and the late response of HCC cell invasion and proliferation. In a hepatoma xenograft model, ISJ pretreatment resulted in significant antihepatoma activity in vivo. These findings identify ISJ as a promising lead compound for the development of new antihepatoma agents and may guide the search for additional selective PKC inhibitors.

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0 (Neoplasm Proteins)
0 (Xanthenes)
0 (isojacareubin)
EC 2.7.11.13 (Protein Kinase C)

Date Created: 20150807 Date Completed: 20160801 Latest Revision: 20181113

20231215

PMC4526861

10.1038/srep12889

26245668