Fig. 9

Effect of the combination on orthotopic kidney tumor growth and metastasis and a schematic model of the mechanism of SF and MU combination for mRCC. A, B: Orthotopic kidney tumors were established in athymic mice (n = 5; males) from Caki-1 (EV, HAS3) transfectants. From day nine, animals were treated with vehicle or SF (30 mg/kg) and MU (200 mg/kg) combination, until visible metastasis in the vehicle group of EV cells and in HAS3 groups (both vehicle and treatment). Tumor development as monitored by bioluminescence imaging. C: Tissue histology to evaluate kidney tumors, metastasis, and organ toxicity (treatment group). In mRCC, D: Schematic models: Tumor cells express high levels of both HAS3 and UGT-1A9. Elevated HAS3 expression drives RCC growth and metastasis. By downregulating HAS3 expression, SF can potentially halt mRCC. However, elevated UGT-1A9 levels inactivate SF, and therefore, at pharmacological dose, SF is ineffective against mRCC. Low dose MU downregulates UGT-1A9 and prevents the inactivation of SF by RCC cells. Therefore, SF + MU combination shows high efficacy in inhibiting/eliminating RCC growth and metastasis in preclinical models