Premium
Modulation of mdr‐1 Expression and Activity by Verapamil and Resveratrol Potentiates the Cytotoxicity of Docetaxel and Doxorubicin in Solid Tumor Cell Lines
Author(s) -
El-Moselhy Mohamed Ahmed Mohamed,
El-Sherbiny Gamal Ahmed,
Abd Abdel-Latif Hekma Abdel-Tawab,
Al-Abd Ahmed Mohamed,
Nofal Salwa Mohamed,
El-Eraky Wafaa Ibraheem
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.1038.6
Subject(s) - verapamil , resveratrol , docetaxel , doxorubicin , efflux , pharmacology , hela , cytotoxicity , chemistry , intracellular , p glycoprotein , cancer cell , cell culture , cell , biochemistry , cancer , multiple drug resistance , biology , medicine , chemotherapy , in vitro , calcium , genetics , organic chemistry , antibiotics
P‐glycoprotein (P‐gp) is a member of ATP‐dependent membrane transport protein superfamily encoded by mdr‐1 gene family. In tumor cells, expression of P‐gp results in reduced intracellular drug concentrations, which decreases the cytotoxicity of antitumor drugs. Herein, we evaluated the added value of combining two P‐gp blockers (verapamil and resveratrol) with docetaxel and doxorubicin and the possible underlying mechanism(s) in solid tumor cell lines (MCF‐7, HeLa and HepG2). Verapamil possessed weaker anti‐cancer properties than resveratrol (IC 50 of 92.1 to 107.6 μM and 35.0 to 84μM, respectively). Doxorubicin and docetaxel IC 50 's of 0.48 to 0.72 μM and 25.9 to 77.8 nM, respectively. Verapamil combination with doxorubicin and docetaxel significantly decreased the IC 50 's of both agents to 0.034 to 0.12 μM and 2.5 to 6.0 nM, respectively. Resveratrol increased the potencies of both chemotherapeutic agents to IC 50 of 0.12 to 0.34 μM and 7.2 to 53.02 nM, respectively. The interaction of resveratrol with both agents was additive in HeLa and Hep‐G2 cell lines. Surprisingly, only resveratrol but not verapamil interfered with the expression of mdr‐1 and several apoptotic genes BAX, BcL2 and p53. P‐gp efflux activity was significantly inhibited by resveratrol and verapamil with subsequent accumulation of P‐gp substrate within the intracellular compartment. In conclusion, resveratrol was comparable to verapamil in potentiating the anti‐cancer effects of doxorubicin and docetaxel in solid tumor.