The bisbenzylisoquinoline alkaloids, tetrandine and fangchinoline, enhance the cytotoxicity of multidrug resistance-related drugs via modulation of P-glycoprotein.
The occurrence of resistance to chemotherapeutic drugs is a major problem for successful cancer treatment and reducing drug accumulation by P-glycoprotein (P-gp) is one of the major mechanisms of multidrug resistance (MDR). The present study was performed to evaluate the MDR-reversal abilities of two bisbenzylisoquinoline alkaloids, tetrandine (TET) and fangchinoline (FAN), compared with verapamil (VER), a well-known P-gp modulator. TET (3.0 microM), FAN (3.0 microM) and VER (10.0 microM) reduced the paclitaxel (TAX) concentration required to achieve 50% inhibition of cell growth (EC50) to HCT15 (P-gp-positive) cells about 3100-, 1900- and 410-fold, and these compounds also reduced the EC50 value of actinomycin D (AMD) about 36.0-, 45.9- and 18.2-fold in the cells, respectively. Meanwhile, TET, FAN and VER had no effect on the cytotoxicity of the drugs to SK-OV-3 (P-gp-negative) cells. On the other hand, TET (3.0 microM), FAN (3.0 microM) and VER (10.0 microM) similarly enhanced the accumulation rates of rhodamine 123, a well known P-gp substrate, in HCT15 cells (200-250%). After efflux for 2 h with fresh medium, TET and FAN also enhanced the residual rate of rhodamine 123 about 5.0- and 2.6-fold in comparison with control, respectively. TET, FAN and VER could not affect the accumulation and residual rate of rhodamine 123 in SK-OV-3 cells. From the result, we conclude that TET and FAN enhanced the cytotoxicity of MDR-related drugs via modulation of P-gp.
Choi
S U
SU
Screening and Toxicology Research Center, Korea Research Institute of Chemical Technology, Yusong, Taejon.
Park
S H
SH
Kim
K H
KH
Choi
E J
EJ
Kim
S
S
Park
W K
WK
Zhang
Y H
YH
Kim
H S
HS
Jung
N P
NP
Lee
C O
CO
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000187:drug effects / Q000378:metabolism*; D000470:Alkaloids / Q000633:toxicity*; D000972:Antineoplastic Agents, Phytogenic / Q000633:toxicity*; D044182:Benzylisoquinolines; D002470:Cell Survival / Q000187:drug effects*; D015179:Colorectal Neoplasms; D003609:Dactinomycin / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D004354:Drug Screening Assays, Antitumor; D004365:Drugs, Chinese Herbal / Q000633:toxicity*; D005260:Female; D006801:Humans; D007546:Isoquinolines / Q000633:toxicity*; D015394:Molecular Structure; D010051:Ovarian Neoplasms; D014700:Verapamil / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000470:Alkaloids; D000972:Antineoplastic Agents, Phytogenic; D044182:Benzylisoquinolines; D004365:Drugs, Chinese Herbal; D007546:Isoquinolines; D003609:Dactinomycin; C009438:tetrandrine; C060802:fangchinoline; D014700:Verapamil