ExcisaninA, a diterpenoid compound purified from Isodon MacrocalyxinD, induces tumor cells apoptosis and suppresses tumor growth through inhibition of PKB/AKT kinase activity and blockade of its signal pathway.
Isodon diterpenoids have received considerable phytochemical and biological attention for their strong antitumor activity with low toxicity. In this study, ExcisaninA, a diterpenoid compound purified from Isodon MacrocalyxinD, was tested on human Hep3B and MDA-MB-453 cell lines and Hep3B xenograft models. The results showed ExcisaninA could inhibit the proliferation of Hep3B and MDA-MB-453 cells via induction of apoptosis, with the evidence of increasing AnnexinV-positive cells and characteristic morphologic changes of apoptosis in the nucleus. Also, ExcisaninA sensitized Hep3B cells to 5-fluorouracil treatment or MDA-MB-453 cells to ADM treatment in vitro. In Hep3B xenograft models, ExcisaninA at 20 mg/kg/d remarkably decreased the xenograft tumor size and induced tumor cells apoptosis using transferase-mediated FITC-12-dUTP nick-end labeling assay. More importantly, we found that ExcisaninA could inhibit AKT activity and block its signal pathway in vitro and in vivo. And treatment with ExcisaninA significantly reduced the number of viable cells in Hep3B/myr-AKT1 cells more than that in control cells. Together, ExcisaninA might be a potent inhibitor of AKT signaling pathway in tumor cells. These data provide validation for the development of ExcisaninA to treat cancers displaying elevated levels of AKT.
State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen University, 651 Dongfeng Road East, Guangzhou 510060, China.
Rong
R
Deng
Jun
J
Tang
Liang-Ping
LP
Xia
Dan-Dan
DD
Li
Wen-Jun
WJ
Zhou
Lin-Lin
LL
Wang
Gong-Kan
GK
Feng
Yi-Xin
YX
Zeng
You-Heng
YH
Gao
Xiao-Feng
XF
Zhu
D064413:3-Phosphoinositide-Dependent Protein Kinases; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects; D004224:Diterpenes / Q000494:pharmacology*; D004365:Drugs, Chinese Herbal / Q000494:pharmacology; D005455:Fluorescent Antibody Technique; D006801:Humans; D020287:In Situ Nick-End Labeling; D037602:Isodon / Q000737:chemistry*; D008113:Liver Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D004224:Diterpenes; D004365:Drugs, Chinese Herbal; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C047381:excisanin A; D064413:3-Phosphoinositide-Dependent Protein Kinases; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt