A novel compound modified from tanshinone inhibits tumor growth in vivo via activation of the intrinsic apoptotic pathway.
A novel compound, acetyltanshinone IIA (ATA) was obtained from chemical modifications of tanshinone TIIA (TIIA) isolated from a medicinal plant, Salvia miltiorrhiza. ATA exhibited increased water solubility and stronger apoptotic activity on multiple cancer cell lines than TIIA. ATA displayed a higher growth inhibition ability on breast cancer especially HER2 positive cells than normal cells and it inhibited xenografted tumor growth in mice. Mechanistic studies showed that ATA could induce significant reactive oxygen species (ROS) generation, Bax translocation to mitochondria, resulting in mitochondria damage, cytochrome c release, caspase-3 activation and apoptotic cell death. ATA-mediated ROS production and its downstream apoptotic events could be blocked by an antioxidant agent, propyl gallate, indicating the prominent role of ROS in ATA-induced apoptosis. Overexpression of Bcl-2 protein reduced ATA-induced cell death. In conclusion, ATA is a novel anticancer agent with potent in vitro and in vivo anticancer ability. ROS-mediated Bax activation should be the mechanism by which ATA induces apoptosis and inhibits tumor growth.
Tian
Hong-Lei
HL
Department of Biochemistry, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong.
Yu
Ting
T
Xu
Nai-Ning
NN
Feng
Chao
C
Zhou
Li-Ying
LY
Luo
Hou-Wei
HW
Chang
Donald C
DC
Le
Xiao-Feng
XF
Luo
Kathy Qian
KQ
D045784:Abietanes; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000138:chemical synthesis / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology; D005260:Female; D018922:HL-60 Cells; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D017239:Paclitaxel / Q000494:pharmacology; D010616:Phenanthrenes / Q000138:chemical synthesis / Q000494:pharmacology*; D011435:Propyl Gallate / Q000494:pharmacology; D021381:Protein Transport; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D012995:Solubility; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D045784:Abietanes; D000972:Antineoplastic Agents, Phytogenic; D000975:Antioxidants; D053148:Caspase 3; D045304:Cytochromes c; D004317:Doxorubicin; D017239:Paclitaxel; D010616:Phenanthrenes; D011435:Propyl Gallate; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D018719:Erb-b2 Receptor Tyrosine Kinases; D051028:bcl-2-Associated X Protein; C494826:BAX protein, human; C552419:acetyltanshinone IIA; C021751:tanshinone; C508053:ERBB2 protein, human; C505407:CASP3 protein, human