Disruption of the UPR may provide a novel therapeutic approach to targeting glucose-deprived solid tumors.

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The cytotoxic and antitumor activity of methanolic extract of rice hulls (MERH) were evaluated by the MTT-dye reduction assay against human colon cancer cells and the colonic aberrant crypt foci (ACF) assay in 1,2-dimethylhydrazine (DMH)-injected F344 male rats, respectively. MERH was found to be highly cytotoxic, with IC50 values of 0.5 microg/mL in vitro. Forty weeks of MERH supplementation (50 mg/kg of body weight/day) reduced colonic pre-neoplastic ACF formation by 35% (p < 0.01). An active compound, momilactone B, was isolated from MERH by silica gel chromatography, Sephadex LH-20 chromatography, and HPLC. The cytotoxic activity of momilactone B was evaluated by the MTT-dye reduction, lactate dehydrogenase (LDH), and colony-forming ability assays in human colon cancer HT-29 and SW620 cells. The results indicated that momilactone B from rice hulls might be a new candidate for chemotherapeutic agent against human colon cancer.

Cancer cells in poorly vascularized solid tumors are constantly or intermittently exposed to stressful microenvironments, including glucose deprivation, hypoxia, and other forms of nutrient starvation. These tumor-specific conditions, especially glucose deprivation, activate a signaling pathway called the unfolded protein response (UPR), which enhances cell survival by induction of the stress proteins. We have established a screening method to discover anticancer agents that could preferentially inhibit tumor cell viability under glucose-deprived conditions. Here we identify arctigenin (ARC-G) as an active compound that shows selective cytotoxicity and inhibits the UPR during glucose deprivation. Indeed, ARC-G blocked expression of UPR target genes such as phosphorylated-PERK, ATF4, CHOP, and GRP78, which was accompanied by enhanced phosphorylation of eIF2 alpha during glucose deprivation. The UPR inhibition led to apoptosis involving a mitochondrial pathway by activation of caspase-9 and -3. Furthermore, ARC-G suppressed tumor growth of colon cancer HT-29 xenografts. Our results demonstrate that ARC-G can be served as a novel type of antitumor agent targeting the UPR in glucose-deprived solid tumors.