title: 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.affiliation: Department of Phytochemistry, School of Pharmacy, Second Military Medical University, Shanghai 200433, China.
authors.forename: Xing
authors.initials: X
authors.lastname: Yuan
authors.affiliation: Department of Phytochemistry, School of Pharmacy, Second Military Medical University, Shanghai 200433, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Chen
authors.affiliation: Department of Phytochemistry, School of Pharmacy, Second Military Medical University, Shanghai 200433, China.
authors.forename: Xia
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Phytochemistry, School of Pharmacy, Second Military Medical University, Shanghai 200433, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Dai
authors.affiliation: Department of Phytochemistry, School of Pharmacy, Second Military Medical University, Shanghai 200433, China.
authors.forename: Huawu
authors.initials: H
authors.lastname: Zeng
authors.affiliation: Department of Phytochemistry, School of Pharmacy, Second Military Medical University, Shanghai 200433, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Shan
authors.affiliation: Department of Organic Chemistry, School of Pharmacy, Second Military Medical University, Shanghai 200433, China.
authors.forename: Qingyan
authors.initials: Q
authors.lastname: Sun
authors.affiliation: 1] Department of Phytochemistry, School of Pharmacy, Second Military Medical University, Shanghai 200433, China [2] Shanghai Institute of Pharmaceutical Industry, Shanghai 200040, China.
authors.forename: Weidong
authors.initials: W
authors.lastname: Zhang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014966:Xanthenes / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D009363:Neoplasm Proteins; D014966:Xanthenes; C458659:isojacareubin; D011493:Protein Kinase C