Glucose-deprived HT-29 human colon carcinoma cells are sensitive to verrucosidin as a GRP78 down-regulator

Abstract Glucose deprivation, a feature of poorly vascularized solid tumors, activates the unfolded protein response (UPR) which is a stress-signaling pathway in tumor cells that is associated with the molecular chaperone GRP78 and induction of GRP78 has been shown to protect them against programmed cell death. Thus, targeting glucose-deprived conditions may be a novel strategy in anticancer drug development. Based on that, we established a novel screening program for chaperone modulators that preferentially cytotoxic activity in cancer cells under glucose-deprived conditions. During the course of our screening system, we recently isolated an active compound, 326-2, from Penicillium verrucosum var. cyclopium and identified it as a down-regulator of the grp 78 gene. As expected, 326-2 inhibited the expression of the GRP78 promoter under glucose-deprived conditions in a dose-dependent manner with an IC50 value of 50 nM. Furthermore, 326-2 was identified as verrucosidin, a pyrone-type polyketide, by ESI-MS analyses and various NMR spectroscopic methods. We found that verrucosidin prevents UPR-induced expression of protein, such as GRP78, whose expression is induced by glucose-deprived or by 2-deoxyglucose; this effect is not seen under normal growth conditions. The GRP78-inhibitory action of verrucosidin was dependent on strict hypoglycemic conditions and resulted in selective cell death of glucose-deprived HT-29 human colon cancer cells.