Cytotoxic effects of tanshinones from Salvia miltiorrhiza on doxorubicin-resistant human liver cancer cells.
P-Glycoprotein (Pgp) overexpression and alterations in p53 oncogene expression are known to affect chemotherapeutic efficacy in the treatment of human hepatocellular carcinoma (HCC). The present study has demonstrated the anti-HCC potential of cryptotanshinone (1), dihydrotanshinone (2), tanshinone I (3), and tanshinone IIA (4), the active lipophilic constituents of Salvia miltiorrhiza, using MTT and caspase-3 activity assays and poly(ADP-ribose) polymerase cleavage in HepG2, Hep3B, and PLC/PRF/5 cells. THLE-3, a normal human immortalized liver cell line, was used to demonstrate the selective growth inhibitory effect of 3 for a HCC cell line. Compound 1 suppressed doxorubicin efflux, a process mediated by P-glycoprotein, in a Pgp-overexpressed HepG2 subclone (R-HepG2 cells). Despite its moderate cytostatic and pro-apoptotic effects and minimal influence on doxorubicin efflux, 4 provided the best synergism with doxorubicin as determined by the Combination Index, the Loewe additivity model, and the Bliss independence criterion.
Lee
Wayne Y W
WY
School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, People's Republic of China.
Cheung
Chartia C M
CC
Liu
Ken W K
KW
Fung
K P
KP
Wong
John
J
Lai
Paul B S
PB
Yeung
John H K
JH
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D045784:Abietanes; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000473:pathology; D004317:Doxorubicin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006801:Humans; D008954:Models, Biological; D015394:Molecular Structure; D010616:Phenanthrenes / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D010946:Plants, Medicinal / Q000737:chemistry*; D027561:Salvia miltiorrhiza / Q000737:chemistry*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D045784:Abietanes; D010616:Phenanthrenes; C021751:tanshinone; D004317:Doxorubicin