Resveratrol enhances the cytotoxic profile of docetaxel and doxorubicin in solid tumour cell lines in vitro.
OBJECTIVE
Resveratrol, with its robust antioxidant activity, has frequently been suggested as potentially having activity in cancer prevention and some recent reports have indicated that it has cancer treatment potential for several types of neoplasia. It has been found to block p-glycoprotein and to protect against several chemotherapeutic agents' side effects. In this study, we assessed interactive characteristics of resveratrol with docetaxel and doxorubicin and further investigated molecular bases of this interaction in cells of three different solid tumour lines (MCF-7, HeLa and HepG2).


RESULTS
Resveratrol per se was found to have anti-cancer properties, but with relatively low potency in all tested cell lines (IC(50) ranged from 35.1 to 83.8 μM). Doxorubicin and docetaxel showed IC(50) ranging from 0.48 to 0.72 μM and from 25.9 to 77.8 nM, respectively. Resveratrol in combination with doxorubicin and docetaxel significantly increased potencies of both chemotherapeutic agents showing IC(50) ranging from 0.12 to 0.34 μM and from 7.2 to 53.02 nM, respectively. The combination index showed synergistic interaction between resveratrol and doxorubicin or docetaxel on MCF-7 cells, and additive interactions on HeLa and HepG2 cells. Real time PCR revealed that expression of Bax and Bcl-2 was simultaneously elevated on combination of resveratrol with doxorubicin or docetaxel in all tested cell lines, whereas p53 exhibited marginal elevation in MCF-7 and HepG2 cells. In addition, p-glycoprotein efflux activity was significantly inhibited, with subsequent accumulation of p-glycoprotein substrate in intracellular compartments. Expression level of mdr1 gene was downregulated after resveratrol combined with doxorubicin or docetaxel in all tested cell lines.


CONCLUSIONS
Resveratrol potentiates cytotoxic properties of both cancer drugs used in the study through increasing their intracellular level due to p-glycoprotein inhibition and downregulation of mdr1 gene.
Pharmacology Dept., Medical Division, National Research Center, Dokki, Giza, Egypt.
A M
AM
Al-Abd
A M
AM
Mahmoud
G A
GA
El-Sherbiny
M A
MA
El-Moselhy
S M
SM
Nofal
H A
HA
El-Latif
W I
WI
El-Eraky
H A
HA
El-Shemy
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D043823:Taxoids / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D051028:bcl-2-Associated X Protein / Q000235:genetics
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D013267:Stilbenes; D043823:Taxoids; D051028:bcl-2-Associated X Protein; D000077143:Docetaxel; D004317:Doxorubicin; D000077185:Resveratrol