The dioxonapthoimidazolium
YM155 is a
survivin suppressant which has been investigated as an
anticancer agent in clinical trials. Here, we investigated its growth inhibitory properties on a panel of immortalized and patient derived
renal cell carcinoma (RCC) cell lines which were either deficient in the tumour suppressor von Hippel-Lindau (VHL)
protein or possessed a functional copy. Neither the VHL status nor the
survivin expression levels of these cell lines influenced their susceptibility to growth inhibition by
YM155. Of the various RCC lines, the papillary subtype was more resistant to
YM155, suggesting that the therapeutic efficacy of
YM155 may be restricted to clear cell subtypes.
YM155 was equally potent in cells (RCC786.0) in which
survivin expression had been stably silenced or overexpressed, implicating a limited reliance on
survivin in the mode of action of
YM155. A follow-up in-vitro high throughput
RNA microarray identified possible targets of
YM155 apart from
survivin. Selected genes (ID1, FOXO1, CYLD) that were differentially expressed in YM155-sensitive RCC cells and relevant to RCC pathology were validated with real-time PCR and western immunoblotting analyses. Thus, there is corroboratory evidence that the growth inhibitory activity of
YM155 in RCC cell lines is not exclusively mediated by its suppression of
survivin. In view of the growing importance of combination
therapy in oncology, we showed that a combination of
YM155 and
sorafenib at ½ x IC50 concentrations was synergistic on RCC786.0 cells. However, when tested intraperitoneally on a murine xenograft model derived from a nephrectomised patient with clear cell RCC, a combination of suboptimal doses of both drugs failed to arrest tumour progression. The absence of synergy in vivo highlighted the need to further optimize the dosing schedules of
YM155 and
sorafenib, as well as their routes of administration. It also implied that the expression of other oncogenic
proteins which
YM155 may target is either low or absent in this clear cell RCC.