1. Academic Validation
  2. Elacridar enhances the cytotoxic effects of sunitinib and prevents multidrug resistance in renal carcinoma cells

Elacridar enhances the cytotoxic effects of sunitinib and prevents multidrug resistance in renal carcinoma cells

  • Eur J Pharmacol. 2015 Jan 5;746:258-66. doi: 10.1016/j.ejphar.2014.11.021.
Hiromi Sato 1 Sana Siddig 2 Miaki Uzu 2 Sayumi Suzuki 2 Yuki Nomura 3 Tatsuro Kashiba 2 Keisuke Gushimiyagi 3 Yuko Sekine 3 Tomoya Uehara 4 Yasushi Arano 4 Katsunori Yamaura 2 Koichi Ueno 5
Affiliations

Affiliations

  • 1 Department of Geriatric Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan. Electronic address: hiromi-s@chiba-u.jp.
  • 2 Department of Geriatric Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan.
  • 3 Department of Practical Pharmacology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan.
  • 4 Department of Molecular Imaging and Radiotherapy, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan.
  • 5 Center for Preventive Medical Science, Chiba University, Chiba, Japan.
Abstract

Intrinsic drug resistance occurs in many renal carcinomas and is associated with increased expression of multidrug resistant proteins, which inhibits intracellular drug accumulation. Multidrug resistant protein 1, also known as P-glycoprotein, is a membrane drug efflux pump belonging to the ATP-binding cassette (ABC) transporter superfamily. ABC Sub-family B Member 2 (ABCG2) is widely distributed and is involved in the multidrug resistant phenotype. Sunitinib is a tyrosine kinase inhibitor used to treat kidney Cancer that disrupts signaling pathways responsible for abnormal Cancer cell proliferation and tumor angiogenesis. Multiple drug resistance is important in tyrosine kinase inhibitor-induced resistance. We hypothesized that inhibition of multidrug resistant transporters by elacridar (dual inhibitor of P-glycoprotein and ABCG 2) might overcome sunitinib resistance in experimental renal cell carcinoma. Human renal carcinoma cell lines 786-O, ACHN, and Caki-1 were treated with sunitinib or elacridar alone, or in combination. We showed that elacridar significantly enhanced sunitinib cytotoxicity in 786-O cells. P-glycoprotein activity, confirmed by P-glycoprotein function assay, was found to be inhibited by elacridar. ABCG2 expression was low in all renal carcinoma cell lines, and was suppressed only by combination treatment in 786-O cells. ABCG2 function was inhibited by sunitinib alone or combination with elacridar but not elacridar alone. These findings suggest that sunitinib resistance involves multidrug resistance transporters, and in combination with elacridar, can be reversed in renal carcinoma cells by P-glycoprotein inhibition.

Keywords

ABCG2; Drug resistance; P-glycoprotein; Renal cell carcinoma; Sunitinib; Sunitinib (Sutent) (PubChem CID: 5329102).

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