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

Abstract

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.

• Authors: Xing Yuan, Hao Chen, Xia Li, Ming Dai, Huawu Zeng, Lei Shan, Qingyan Sun, Weidong Zhang
• Journal: Scientific reports (Sci Rep) Vol. 5 Pg. 12889 (Aug 06 2015) ISSN: 2045-2322 [Electronic] England
• PMID: 26245668 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Neoplasm Proteins
• Xanthenes
• isojacareubin
• Protein Kinase C

Topics

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