4-Aryl-1,3,2-oxathiazolylium-5-olate: a novel GST inhibitor to release JNK and activate c-Jun for cancer therapy

Purpose: The over-expression of glutathion S-transferase Pi (GSTpi) in tumors and inhibitory effect of GSTpi to JNK are two possible causes of the development of drug-resistance in chemotherapy. This research is to develop a novel pH-controlled NO donor to inhibit GSTpi(and to activate the JNK/c-Jun pathway (omit "to induce apoptosis").

Methods: Four 4-Aryl-1,3,2-oxathiazolylium-5-olate (OZO) derivatives with varying aryl para-substitutions (-H, -CF(3), -Cl, and -OCH(3)) were synthesized. Anticancer activity was determined by MTS assay. GST activity was measured with spectrophotometry using 1-chlro-2,4-dinitrobenzene (CDNB) and GSH as substrates. (omit "Apoptosis was evaluated by annexin V staining and flow cytometry"). c-Jun N-terminal kinase 1 (JNK1) association with GSTpi and activation of c-Jun were evaluated with immunoprecipitation and western blot.

Results: OZO derivatives showed Anticancer effect against leukemia and breast Cancer cells by MTS assay. The relative potency of their Anticancer effects is OZO-H > OZO-Cl, OZO-OMe > OZO-CF(3). The Anticancer activity of these compounds was correlated with their inhibition of GST activity in Cancer cells. The immunoprecipitation result showed that the treatment of OZO-H released JNK1 from GSTpi-JNK1 complex. Consequently, the treatment of OZO-H in Cancer cells induced JNK1 phophorylation and activated c-Jun in Cancer cells.

Conclusion: OZO-H is a novel GST inhibitor to release JNK1 for activation of JNK/c-Jun pathway (original is "c-Jun to trigger Apoptosis in Cancer cells"). It provides a new class of GST target compound for Anticancer therapy.