Abstract | OBJECTIVE: METHODS: The inhibitory effects of tanshinones on P-gp function were compared using digoxin bi-directional transport assay in Caco-2 cells. The potentiation of cytotoxicity of anticancer drugs by effective tanshinones were evaluated by MTT assay. Doxorubicin efflux assay by flow cytometry, P-gp protein expression by western blot analysis, immunofluorescence for P-gp by confocal microscopy, quantitative real-time PCR and P-gp ATPase activity assay were used to study the possible underlying mechanisms of action of effective tanshinones. RESULTS: Bi-directional transport assay showed that only cryptotanshinone and dihydrotanshinone decreased digoxin efflux ratio in a concentration-dependent manner, indicating their inhibitory effects on P-gp function; whereas, tanshinone I, tanshinone IIA and miltirone had no inhibitory effects. Moreover, both cryptotanshinone and dihydrotanshinone could potentiate the cytotoxicity of doxorubicin and irinotecan in P-gp overexpressing SW620 Ad300 colon cancer cells. Results from mechanistic studies revealed that these two tanshinones increased intracellular accumulation of the P-gp substrate anticancer drugs, presumably by down-regulating P-gp mRNA and protein levels, and inhibiting P-gp ATPase activity. CONCLUSIONS: Taken together, these findings suggest that cryptotanshinone and dihydrotanshinone could be further developed for sensitizing resistant cancer cells and used as an adjuvant therapy together with anticancer drugs to improve their therapeutic efficacies for colon cancer.
|
Authors | Tao Hu, Kenneth K W To, Lin Wang, Lin Zhang, Lan Lu, Jing Shen, Ruby L Y Chan, Mingxing Li, John H K Yeung, Chi Hin Cho |
Journal | Phytomedicine : international journal of phytotherapy and phytopharmacology
(Phytomedicine)
Vol. 21
Issue 11
Pg. 1264-72
(Sep 25 2014)
ISSN: 1618-095X [Electronic] Germany |
PMID | 25172788
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
|
Copyright | Copyright © 2014 Elsevier GmbH. All rights reserved. |
Chemical References |
- ABCB1 protein, human
- ATP Binding Cassette Transporter, Subfamily B
- Abietanes
- Antineoplastic Agents, Phytogenic
- Drugs, Chinese Herbal
- Furans
- Phenanthrenes
- Quinones
- tanshinone
- dihydrotanshinone I
- cryptotanshinone
- Digoxin
- Irinotecan
- Doxorubicin
- Camptothecin
|
Topics |
- ATP Binding Cassette Transporter, Subfamily B
(metabolism)
- Abietanes
(pharmacology)
- Antineoplastic Agents, Phytogenic
(pharmacology)
- Caco-2 Cells
- Camptothecin
(analogs & derivatives, pharmacology)
- Digoxin
(pharmacology)
- Doxorubicin
(pharmacology)
- Drugs, Chinese Herbal
(pharmacology)
- Furans
- Gene Expression Regulation, Neoplastic
- Humans
- Irinotecan
- Phenanthrenes
(pharmacology)
- Quinones
- Salvia miltiorrhiza
(chemistry)
|