Concomitant Use of Sulforaphane Enhances Antitumor Efficacy of Sunitinib in Renal Cell Carcinoma In Vitro

SIMPLE SUMMARY: Despite recent advances in treating metastatic renal cell carcinoma (RCC), many patients develop resistance to therapy, resulting in treatment failure. Sunitinib is one drug used to treat metastasized RCC and resistance eventually develops in most patients. In the present in vitro investigation, sulforaphane, a natural compound known to possess antitumor properties without inducing severe side effects, enhanced the efficacy of sunitinib by preventing tumor growth and proliferation in sunitinib-resistant RCC. Sulforaphane, therefore, could prove beneficial as an integrative component in treating metastasized RCC with sunitinib. Further investigation is required to verify these in vitro findings and to evaluate sulforaphane’s clinical value. ABSTRACT: Chronic treatment of renal cell carcinoma (RCC) with the tyrosine kinase inhibitor sunitinib (ST) inevitably induces resistance and tumor re-activation. This study investigated whether adding the natural compound sulforaphane (SFN) with its anti-cancer properties could improve ST efficacy in vitro. The RCC cell lines A498, Caki1, KTCTL26, and 786O were exposed to ST, SFN, or both (dual therapy, DT) before (short-term exposure) and during ST-resistance buildup (long-term 8-week exposure). Tumor growth, proliferation, and clone formation were evaluated, as was cell cycle progression and cell cycle regulating proteins. In nonresistant cells (short-term), DT induced a higher reduction in cell viability in three cell lines as compared to monotherapy with either ST or SFN. Long-term SFN or DT significantly reduced tumor growth and proliferation, whereas ST alone had no effect or even elevated proliferation in three cell lines. SFN or DT (but not ST alone) also blocked clonogenic growth. Both long-term SFN and DT enhanced the number of cells in the S- and/or G2/M-phase. Protein analysis in 786O cells revealed a down-regulation of cyclin dependent kinase (CDK) 1 and 2. CDK2 or Cyclin A knockdown caused reduced 786O growth activity. SFN therefore inhibits or delays resistance to chronic ST treatment.