title: Sulforaphane inhibits proliferation and invasive activity of everolimus-resistant kidney cancer cells in vitro.
abstract: 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.
authors.affiliation: Department of Urology, Goethe-University, Frankfurt am Main, Germany.|Current address: Department of Urology and Pediatric Urology, University Medical Center Mainz, Mainz, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Juengel
authors.affiliation: Department of Urology, Goethe-University, Frankfurt am Main, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Maxeiner
authors.affiliation: Department of Urology, Goethe-University, Frankfurt am Main, Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Rutz
authors.affiliation: Department of Urology, Goethe-University, Frankfurt am Main, Germany.
authors.forename: Saira
authors.initials: S
authors.lastname: Justin
authors.affiliation: Department of Urology, Goethe-University, Frankfurt am Main, Germany.
authors.forename: Frederik
authors.initials: F
authors.lastname: Roos
authors.affiliation: Department of Urology, Goethe-University, Frankfurt am Main, Germany.
authors.forename: Wael
authors.initials: W
authors.lastname: Khoder
authors.affiliation: Department of Urology, Goethe-University, Frankfurt am Main, Germany.
authors.forename: Igor
authors.initials: I
authors.lastname: Tsaur
authors.affiliation: Department of Vascular and Endovascular Surgery, Goethe-University, Frankfurt am Main, Germany.
authors.forename: Karen
authors.initials: K
authors.lastname: Nelson
authors.affiliation: Department of Urology, Goethe-University, Frankfurt am Main, Germany.|Department of General and Visceral Surgery, Goethe-University, Frankfurt am Main, Germany.
authors.forename: Wolf O
authors.initials: WO
authors.lastname: Bechstein
authors.affiliation: Department of Urology, Goethe-University, Frankfurt am Main, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Haferkamp
authors.affiliation: Department of Urology, Goethe-University, Frankfurt am Main, Germany.
authors.forename: Roman A
authors.initials: RA
authors.lastname: Blaheta
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis; D016203:CDC2 Protein Kinase / Q000235:genetics / Q000378:metabolism; D002448:Cell Adhesion; D002453:Cell Cycle; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D019926:Cyclin B / Q000235:genetics / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D000068338:Everolimus / Q000627:therapeutic use; D006801:Humans; D039482:Integrin alpha5 / Q000378:metabolism; D017879:Isothiocyanates / Q000627:therapeutic use*; D007680:Kidney Neoplasms / Q000188:drug therapy*; D034741:RNA, Small Interfering / Q000235:genetics; D013454:Sulfoxides; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D019926:Cyclin B; D039482:Integrin alpha5; D017879:Isothiocyanates; D034741:RNA, Small Interfering; D013454:Sulfoxides; D000068338:Everolimus; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D016203:CDC2 Protein Kinase; C016766:sulforaphane
keywords: complementary and alternative medicine; invasion; proliferation; renal cell carcinoma; sulforaphane