JS‐K, a novel non‐ionic diazeniumdiolate derivative, inhibits Hep 3B hepatoma cell growth and induces c‐Jun phosphorylation via multiple MAP kinase pathways

Abstract

JS-K, a non-ionic diazeniumdiolate derivative, is capable of arylating nucleophiles and spontaneously generating nitric oxide (NO) at physiological pH. This recently synthesized low molecular weight compound is shown here to be an inhibitor of cell growth with concomitant activation of mitogen-activated protein kinase (MAPK) members ERK, JNK, and p38 and their downstream effectors c-Jun and AP-1. Inhibitors of these MAPK pathways abrogated the growth inhibitory actions of JS-K. In addition to the well-described actions of JNK as a kinase for c-Jun, we show that c-Jun is also an ERK target. Furthermore, JS-K generated NO in culture and NO inhibitors antagonized both MAPK induction and the growth inhibitory effects of JS-K. These results suggest two possible mechanisms for the mediation of JS-K growth inhibitory actions, namely NO-induction of MAPK pathway constituents as well as possible arylation reactions. The data support the idea that prolonged MAPK activation by JS-K action is important in mediating its growth-inhibitory actions. JS-K thus represents a promising platform for novel growth inhibitory analog synthesis.

The Nitric Oxide Prodrug JS-K Is Effective against Non–Small-Cell Lung Cancer Cells In Vitro and In Vivo: Involvement of Reactive Oxygen Species

“…Other types of cancer cells were also effectively killed by JS-K, including prostate cancer (Shami et al, 2003) and hepatoma cells (Ren et al, 2003). A survey of the National Cancer Institute panel of 51 cancer cell lines suggested sensitivity of renal cancers, and correspondingly we found approximately 10-fold selectivity observed for renal cancer cells compared with noncancerous renal epithelial cells (Chakrapani et al, 2008).…”

Nitric Oxide-Releasing Molecules for Cancer Therapy and Chemoprevention

“…By installing an aryl group similar to CDNB as the R 1 substituent, the O 2 -arylated diazeniumdiolate JS-K (D.7) becomes an excellent substrate for GST, releasing the NONOate group, and thereby NO, upon activation (Shami et al 2003). While this may be one of the pathways by which JS-K is cytotoxic, results from in vitro studies (Shami et al 2003;Udupi et al 2006) that have been conducted on the anti-tumor effects of JS-K point to the existence of multiple modes of action (Ren et al 2003) including GST inhibition and GSH depletion. Despite the lack of clear-cut evidence about its mode of action, JS-K is a worthy lead in anti-cancer drug discovery .…”

“…Similarly, the biological activity of JS-K has been proposed to result in part from NO-independent actions of the carrier (Ren et al 2003). In all these cases of NO-independent activity, the hybrid NORMs have a common feature, the provision of a thiophilic electrophile Each molecule incorporates at least two component parts: a bioactive carrier and a warhead.…”

Nitric Oxide (NO)- and Nitroxyl (HNO)-Generating Diazeniumdiolates (NONOates): Emerging Commercial Opportunities

“…A separate investigation [20] with a rat hepatoma cell line pointed to activation by JS-K of the mitogen-activated protein kinases ERK, JNK, and p38.…”