JS-K

One of the most promising contributions from this group is the use of diazeniumdiolates as potential anticancer leads. The hGSTP1-1 isoform of glutathione (GSH) S-transferase (GST) is overexpressed in many tumor cells, often by 10- to 100-fold.  It is postulated that a drug capable of releasing nitric oxide (NO) selectively on metabolism by hGSTP1-1 might target NO’s potentially cytolytic effect on the hGSTP1-1-overexpressing tumor cells while minimizing exposure of normal tissues.  JS-K is a NO-donor which has shown promising anticancer activity in mouse xenograft models of human leukemia and prostate cancer.  In vitro studies with the HL-60 human leukemia cell line showed that JS-K could induce differentiation toward a more normal monocytic phenotype as well as cause caspase-dependent apoptosis.  Later studies revealed that JS-K induced activation of caspases 3 and 9 as well as cytochrome c release from the mitochondria and down-regulation of Bcl-2.  Further in vitro investigations with human umbilical vein endothelial cells showed promising anti-angiogenic activity, including inhibition of the cells' proliferation, cord formation, and migration in response to vascular endothelial growth factor.  All of these in vitro effects were seen at micromolar or submicromolar concentrations of JS-K, suggesting the existence of a multimodal mechanism of action.

Kiziltepe, T.; Hideshima, T.; Raje, N.; Ishitsuka, K.; Ocio, E. M.; Catley, L.; Li, C. Q.; Trudel, L.; Yasui, H.; Shirashi, N.; Tai, Y. T.; Chauhan, D.; Mitsiades, C.; Saavedra, J. E.; Wogan, G. N.; Keefer, L. K.; Shami, P. J.; Anderson, K. C. Blood 2007,110, 709.

Udupi, V.; Yu, M.; Malaviya, S.; Saavedra, J. E.; Shami, P. J. Leuk. Res. 2006, 30, 1279.

Shami, P. J.; Saavedra, J. E.; Bonifant, C. L.; Chu, J. X.; Udupi, V.; Malaviya, S.; Carr, B. I.; Kar, S.; Wang, M. F.; Jia, L.; Ji, X. H.; Keefer, L. K. J. Med. Chem. 2006,49, 4356.

Liu, J.; Li, C. X.; Qu, W.; Leslie, E.; Bonifant, C. L.; Buzard, G. S.; Saavedra, J. E.; Keefer, L. K.; Waalkes, M. P. Mol. Cancer Ther. 2004, 3, 709.  4.

Ren, Z. G.; Kar, S.; Wang, Z. Q.; Wang, M. F.; Saavedra, J. E.; Carr, B. I. J. Cell. Physiol. 2003,197, 426.

Shami, P. J.; Saavedra, J. E.; Wang, L. Y.; Bonifant, C. L.; Diwan, B. A.; Singh, S. V.; Gu, Y. J.; Fox, S. D.; Buzard, G. S.; Citro, M. L.; Waterhouse, D. J.; Davies, K. M.; Ji, X. H.; Keefer, L. K. Mol. Cancer Ther. 2003, 2, 409.