Sulforaphane inhibits proliferation and invasive activity of everolimus-resistant kidney cancer cells in vitro
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Eva Juengel1,2, Sebastian Maxeiner1, Jochen Rutz1, Saira Justin1, Frederik Roos1, Wael Khoder1, Igor Tsaur1, Karen Nelson3, Wolf O. Bechstein1,4, Axel Haferkamp1, Roman A. Blaheta1
1Department of Urology, Goethe-University, Frankfurt am Main, Germany
2Current address: Department of Urology and Pediatric Urology, University Medical Center Mainz, Mainz, Germany
3Department of Vascular and Endovascular Surgery, Goethe-University, Frankfurt am Main, Germany
4Department of General and Visceral Surgery, Goethe-University, Frankfurt am Main, Germany
Roman A. Blaheta, email: [email protected]
Keywords: renal cell carcinoma, complementary and alternative medicine, sulforaphane, proliferation, invasion
Received: July 16, 2016 Accepted: October 24, 2016 Published: November 17, 2016
Although the mechanistic target of rapamycin (mTOR) inhibitor, everolimus, has improved the outcome of patients with renal cell carcinoma (RCC), improvement is temporary due to the development of drug resistance. Since many patients encountering resistance turn to alternative/complementary treatment options, an investigation was initiated to evaluate whether the natural compound, sulforaphane (SFN), influences growth and invasive activity of everolimus-resistant (RCCres) compared to everolimus-sensitive (RCCpar) RCC cell lines in vitro. RCC cells were exposed to different concentrations of SFN and cell growth, cell proliferation, apoptosis, cell cycle, cell cycle regulating proteins, the mTOR-akt signaling axis, adhesion to human vascular endothelium and immobilized collagen, chemotactic activity, and influence on surface integrin receptor expression were investigated. SFN caused a significant reduction in both RCCres and RCCpar cell growth and proliferation, which correlated with an elevation in G2/M- and S-phase cells. SFN induced a marked decrease in the cell cycle activating proteins cdk1 and cyclin B and siRNA knock-down of cdk1 and cyclin B resulted in significantly diminished RCC cell growth. SFN also modulated adhesion and chemotaxis, which was associated with reduced expression of the integrin subtypes α5, α6, and β4. Distinct differences were seen in RCCres adhesion and chemotaxis (diminished by SFN) and RCCpar adhesion (enhanced by SFN) and chemotaxis (not influenced by SFN). Functional blocking of integrin subtypes demonstrated divergent action on RCC binding and invasion, depending on RCC cell sensitivity to everolimus. Therefore, SFN administration could hold potential for treating RCC patients with established resistance towards everolimus.
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