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Purpose: hERG1 channels are aberrantly expressed in several types of human cancers, where they affect different aspects of cancer cell behavior. A thorough analysis of the functional role and clinical significance of hERG1 channels in gastric cancer is still lacking. Experimental Design: hERG1 expression was tested in a wide (508 samples) Italian cohort of surgically resected patients with gastric cancer, by immunohistochemistry and real-time quantitative PCR. The functional link between hERG1 and the VEGF-A was studied in different gastric cancer cell lines. The effects of hERG1 and VEGF-A inhibition were evaluated in vivo in xenograft mouse models. Results: hERG1 was positive in 69% of the patients and positivity correlated with Lauren's intestinal type, fundus localization of the tumor, G1–G2 grading, I and II tumor—node—metastasis stage, and VEGF-A expression. hERG1 activity modulated VEGF-A secretion, through an AKT-dependent regulation of the transcriptional activity of the hypoxia inducible factor. Treatment of immunodeficient mice xenografted with human gastric cancer cells, with a combination of hERG1 blockers and anti-VEGF-A antibodies, impaired tumor growth more than single-drug treatments. Conclusion: Our results show that hERG1 (i) is aberrantly expressed in human gastric cancer since its early stages; (ii) drives an intracellular pathway leading to VEGF-A secretion; (iii) can be exploited to identify a gastric cancer patients' group where a combined treatment with antiangiogenic drugs and noncardiotoxic hERG1 inhibitors could be proposed. Clin Cancer Res; 20(6); 1502–12. ©2014 AACR.

In the present study we showed that the α-adrenoceptor antagonists phentolamine, yohimbine, prazosin, corynanthine and idazoxan, when cumulatively applied in high concentrations (1-100 μmol/l), can increase spontaneous myogenic activity in the rat portal vein. 5-Methyl-urapidil and rauwolscine were ineffective in this respect. Pretreatment with phenoxybenzamine in a concentration of 1 μmol/l (20 min), which results in alkylation of all functional α-adrenoceptors in the rat portal vein, was unable to antagonize the increase in spontaneous myogenic activity elicited by phentolamine. Antazoline (1-100 μmol/l), a H1antagonist and 2-substituted imidazoline which is devoid of α-adrenoceptor blocking properties, exhibited similar effects on spontaneous myogenic activity as its structurally closely related analogue phentolamine. Since phentolamine is reported to interact with ATP-sensitive K+channels we investigated the role of K+channels in more detail. The K+channel openers cromakalim and diazoxide elicited a decrease in spontaneous myogenic activity. Glibenclamide (0.3-3 μmol/l), a selective blocker of ATP-sensitive K+channels in cardiac and pancreatic tissues, and phentolamine (1-10 μmol/l) shifted the concentration-response curves of cromakalim and diazoxide concentration dependently to the right. Yohimbine showed only a modest effect in the highest concentration (100 μmol/l) applied. E-4031 (0.01-0.3 μmol/l), a sotalol derivative and one of the most selective blockers of the delayed rectifier current (I(k)) in cardiac tissue, was a potent contractile agent when added to the rat portal vein in the same way as the α-adrenoceptor antagonists. All other α-adrenoceptor antagonists as well as E-4031, when tested in concentrations which maximally stimulated spontaneous myogenic activity, failed to influence the relaxations induced by cromakalim and diazoxide. The results of the present study cannot be explained on the basis of α-adrenoceptor blockade. Phentolamine, in contrast to the other α-adrenoceptor antagonists, can block glibenclamide-sensitive K+channels in the rat portal vein. However, it seems unlikely that this property can explain its potent effects on spontaneous myogenic activity, since glibenclamide itself was inactive.

In the present study we showed that the α-adrenoceptor antagonists phentolamine, yohimbine, prazosin, corynanthine and idazoxan, when cumulatively applied in high concentrations (1-100 μmol/l), can increase spontaneous myogenic activity in the rat portal vein. 5-Methyl-urapidil and rauwolscine were ineffective in this respect. Pretreatment with phenoxybenzamine in a concentration of 1 μmol/l (20 min), which results in alkylation of all functional α-adrenoceptors in the rat portal vein, was unable to antagonize the increase in spontaneous myogenic activity elicited by phentolamine. Antazoline (1-100 μmol/l), a H1antagonist and 2-substituted imidazoline which is devoid of α-adrenoceptor blocking properties, exhibited similar effects on spontaneous myogenic activity as its structurally closely related analogue phentolamine. Since phentolamine is reported to interact with ATP-sensitive K+channels we investigated the role of K+channels in more detail. The K+channel openers cromakalim and diazoxide elicited a decrease in spontaneous myogenic activity. Glibenclamide (0.3-3 μmol/l), a selective blocker of ATP-sensitive K+channels in cardiac and pancreatic tissues, and phentolamine (1-10 μmol/l) shifted the concentration-response curves of cromakalim and diazoxide concentration dependently to the right. Yohimbine showed only a modest effect in the highest concentration (100 μmol/l) applied. E-4031 (0.01-0.3 μmol/l), a sotalol derivative and one of the most selective blockers of the delayed rectifier current (I(k)) in cardiac tissue, was a potent contractile agent when added to the rat portal vein in the same way as the α-adrenoceptor antagonists. All other α-adrenoceptor antagonists as well as E-4031, when tested in concentrations which maximally stimulated spontaneous myogenic activity, failed to influence the relaxations induced by cromakalim and diazoxide. The results of the present study cannot be explained on the basis of α-adrenoceptor blockade. Phentolamine, in contrast to the other α-adrenoceptor antagonists, can block glibenclamide-sensitive K+channels in the rat portal vein. However, it seems unlikely that this property can explain its potent effects on spontaneous myogenic activity, since glibenclamide itself was inactive.