Co-treatment of Salinomycin Sensitizes AZD5363-treated Cancer Cells Through Increased Apoptosis.

AZD5363, an inhibitor of protein kinase B (AKT), is currently in clinical trials assessing the potential of the phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway. The purpose of the present study was to identify conditions that increase the sensitivity of cancer cells to AZD5363. Microscopic examination revealed that treatment of cancer cells with a low concentration of salinomycin reduced cellular growth of AZD5363-treated breast cancer cells. Furthermore, fluorescence-activated cell sorting (FACS) analysis, Hoechst staining, and annexin V staining revealed that co-treatment with salinomycin sensitizes AZD5363-treated cancer cells via increased apoptosis with S-phase arrest. These results suggest that salinomycin can be applied to increase treatment efficacy for AZD5363-treated cancer cells. Our findings may contribute to improving the efficacy of the development of AZD5363-based sensitization therapies for patients with cancer.

Selenate specifically sensitizes drug-resistant cancer cells by increasing apoptosis via G2 phase cell cycle arrest without P-GP inhibition.

The purpose of this study was to identify conditions that will increase the sensitivity of drug-resistant cancer cells. Selenium derivatives have been shown to present anti-cancer properties in the clinic. Currently, selenate, selenite, selenomethionine (SeMet), methyl-selenocysteine (MSC), and methaneselenic acid (MSA) are the most common selenium derivatives used as drugs in humans. Herein, we tested whether these selenium derivatives can sensitize KBV20C cancer cells, which are highly resistant to anti-cancer drugs such as vincristine. All five drugs could sensitize KBV20C cells to the same extent as they sensitized the sensitive parent KB cells, suggesting that selenium-derived drugs can be used for drug-resistant cancer cells. We also observed that these drugs did not inhibit the P-glycoprotein (P-gp) pumping-out ability, suggesting that the sensitization by selenium-derived drugs does not depend on P-gp activity in resistant KBV20C cells. Interestingly, using a cell viability assay, microscopic observation, and Hoechst staining, we found that selenate highly sensitized drug-resistant KBV20C cells by activating the apoptotic pathway, when compared to sensitive KB cells. Furthermore, we investigated why selenate sensitizes resistant KBV20C cells. Selenate-induced toxicity was associated with an increase in G2-phase cell cycle arrest in KBV20C cells, suggesting that the selenate-induced increase in apoptosis resulted from cell cycle arrest in resistant KBV20C cells. Our findings may contribute to the development of selenate-based therapies for patients resistant to cancer drugs.

The TRPA1 agonist, methyl syringate suppresses food intake and gastric emptying.

Transient receptor potential channel ankryn 1 (TRPA1) expressed in the gastrointestinal tract is associated with gastric motility, gastric emptying, and food intake. In this study, we investigated the effects of methyl syringate, a specific and selective TRPA1 agonist, on food intake, gastric emptying, and gut hormone levels in imprinting control region (ICR) mice. The administration of methyl syringate suppressed cumulative food intake and gastric emptying. In addition, treatment with ruthenium red (RR), a general cation channel blocker, and HC-030031, a selective TRPA1 antagonist, inhibited methyl syringate-induced reduction of food intake and delayed gastric emptying in ICR mice. Methyl syringate also increased plasma peptide YY (PYY) levels, but not glucagon-like peptide-1 (GLP-1) levels. The elevation in PYY was blocked by treatment with RR and HC-030031. The present findings indicate that methyl syringate regulates food intake and gastric emptying through a TRPA1-mediated pathway and, by extension, can contribute to weight suppression.