scholarly journals Antitumor effects of Tv1 venom peptide in liver cancer

2019 ◽  
Author(s):  
Prachi Anand ◽  
Petr Filipenko ◽  
Jeannette Huaman ◽  
Michael Lyudmer ◽  
Marouf Hossain ◽  
...  
Keyword(s):  
Liver Cancer ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Cancer Therapies ◽  
Antitumor Effects ◽  
Venom Peptides ◽  
Calcium Dependent ◽  
Venom Peptide

AbstractA strategy for treating the most common type of liver cancer, hepatocellular carcinoma (HCC) applies a targeted therapy using venom peptides that are selective for ion channels and transporters overexpressed in tumor cells. Here, we report selective anti-HCC properties of Tv1, a venom peptide from the predatory marine terebrid snail, Terebra variegata. Tv1 was applied in vitro to liver cancer cells and administered in vivo to allograft tumor mouse models. Tv1 inhibited the proliferation of murine HCC cells via calcium dependent apoptosis resulting from down-regulation of the cyclooxygenase-2 (COX-2) pathway. Additionally, tumor sizes were significantly reduced in Tv1-treated syngeneic tumor-bearing mice. Tv1’s mechanism of action involves binding to specific transient receptor potential (TRP) cation channels that are overexpressed in HCC cell models. Our findings demonstrate the unique potential of venom peptides to function as tumor specific ligands in the quest for targeted cancer therapies.

scholarly journals Selective Inhibition of Liver Cancer Cells Using Venom Peptide

Marine Drugs ◽  
2019 ◽  
Vol 17 (10) ◽  
pp. 587 ◽  
Author(s):  
Prachi Anand ◽  
Petr Filipenko ◽  
Jeannette Huaman ◽  
Michael Lyudmer ◽  
Marouf Hossain ◽  
...  
Keyword(s):  
Ion Channels ◽  
Liver Cancer ◽  
Mechanism Of Action ◽  
Transient Receptor Potential ◽  
Trp Channels ◽  
Receptor Potential ◽  
Selective Inhibition ◽  
Cancer Therapies ◽  
Venom Peptides ◽  
Venom Peptide

Increasingly cancer is being viewed as a channelopathy because the passage of ions via ion channels and transporters mediate the regulation of tumor cell survival, death, and motility. As a result, a potential targeted therapy for cancer is to use venom peptides that are selective for ion channels and transporters overexpressed in tumor cells. Here we describe the selectivity and mechanism of action of terebrid snail venom peptide, Tv1, for treating the most common type of liver cancer, hepatocellular carcinoma (HCC). Tv1 inhibited the proliferation of murine HCC cells and significantly reduced tumor size in Tv1-treated syngeneic tumor-bearing mice. Tv1’s mechanism of action involves binding to overexpressed transient receptor potential (TRP) channels leading to calcium dependent apoptosis resulting from down-regulation of cyclooxygenase-2 (COX-2). Our findings demonstrate the importance of modulating ion channels and the unique potential of venom peptides as tumor specific ligands in the quest for targeted cancer therapies.

scholarly journals Emerging Roles for Ion Channels in Ovarian Cancer: Pathomechanisms and Pharmacological Treatment

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 668
Author(s):  
Concetta Altamura ◽  
Maria Raffaella Greco ◽  
Maria Rosaria Carratù ◽  
Rosa Angela Cardone ◽  
Jean-François Desaphy
Keyword(s):  
Ovarian Cancer ◽  
Ion Channels ◽  
Transient Receptor Potential ◽  
Critical Role ◽  
Gynecologic Cancer ◽  
Receptor Potential ◽  
Transient Receptor Potential Channels ◽  
Platinum Resistance

Ovarian cancer (OC) is the deadliest gynecologic cancer, due to late diagnosis, development of platinum resistance, and inadequate alternative therapy. It has been demonstrated that membrane ion channels play important roles in cancer processes, including cell proliferation, apoptosis, motility, and invasion. Here, we review the contribution of ion channels in the development and progression of OC, evaluating their potential in clinical management. Increased expression of voltage-gated and epithelial sodium channels has been detected in OC cells and tissues and shown to be involved in cancer proliferation and invasion. Potassium and calcium channels have been found to play a critical role in the control of cell cycle and in the resistance to apoptosis, promoting tumor growth and recurrence. Overexpression of chloride and transient receptor potential channels was found both in vitro and in vivo, supporting their contribution to OC. Furthermore, ion channels have been shown to influence the sensitivity of OC cells to neoplastic drugs, suggesting a critical role in chemotherapy resistance. The study of ion channels expression and function in OC can improve our understanding of pathophysiology and pave the way for identifying ion channels as potential targets for tumor diagnosis and treatment.

scholarly journals Novel role of transient receptor potential vanilloid 2 in the regulation of cardiac performance

2014 ◽  
Vol 306 (4) ◽  
pp. H574-H584 ◽  
Author(s):  
Jack Rubinstein ◽  
Valerie M. Lasko ◽  
Sheryl E. Koch ◽  
Vivek P. Singh ◽  
Vinicius Carreira ◽  
...  
Keyword(s):  
Vascular Function ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Transient Receptor Potential Vanilloid ◽  
Wild Type ◽  
Transient Receptor ◽  
Systolic And Diastolic Function ◽  
Myocyte Contractility

Transient receptor potential cation channels have been implicated in the regulation of cardiovascular function, but only recently has our laboratory described the vanilloid-2 subtype (TRPV2) in the cardiomyocyte, though its exact mechanism of action has not yet been established. This study tests the hypothesis that TRPV2 plays an important role in regulating myocyte contractility under physiological conditions. Therefore, we measured cardiac and vascular function in wild-type and TRPV2−/− mice in vitro and in vivo and found that TRPV2 deletion resulted in a decrease in basal systolic and diastolic function without affecting loading conditions or vascular tone. TRPV2 stimulation with probenecid, a relatively selective TRPV2 agonist, caused an increase in both inotropy and lusitropy in wild-type mice that was blunted in TRPV2−/− mice. We examined the mechanism of TRPV2 inotropy/lusitropy in isolated myocytes and found that it modulates Ca2+ transients and sarcoplasmic reticulum Ca2+ loading. We show that the activity of this channel is necessary for normal cardiac function and that there is increased contractility in response to agonism of TRPV2 with probenecid.

Involvement of the vanilloid receptor 1 in the mechanisms of analgesic effect of amizonum

2014 ◽  
Vol 31 (1) ◽  
pp. 41-49
Author(s):  
Oleh Yadlovskyi ◽  
Tatiana Bukhtiarova ◽  
Lyudmila Bobkova ◽  
Irina Tatianshenko ◽  
Igor Monchak ◽  
...  
Keyword(s):  
Portal Vein ◽  
Active Site ◽  
Analgesic Effect ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Theoretical Background ◽  
Tail Flick ◽  
Intermolecular Complex

SUMMARY The study of features of pharmacodynamics of a new analgesic is an important and urgent task of modern pharmacology. These data allow us to clarify the nosology for application of an analgesic and to create a theoretical background to optimize its use. An effect mediated by the transient receptor potential cation channel, subfamily V, member 1 (TRPV1) activation can also be an effective mechanism of the analgesic action. We evaluated the possibility of TRPV1 participation in implementation of the analgesic effect with the antiviral action of amizonum during the experiment. It is known that amino acids Tyr511 and Ser512 are the main components of the active site of TRPV1. In this connection, dipeptide Tyr-Ser has been completely synthesized as a model of the active site of TRPV1. In the experiment model this was shown, using the spectrophotometric method, with the formation of the “capsaicin - Tyr- Ser” intermolecular complex at the level of the stability constant Kkor=0.998 and Kr=0.3•10-4 L/mol and the “amizonum - Tyr-Ser” weak intermolecular complex Kr=0.05•104 L/mol; Kkor= 0.995, respectively. The data verification was carried out in experiments in vitro (isolated ratportal vein) and in vivo (Tail-flick model), with the TRPV1 agonist. It was shown that the amplitude of smooth muscle (SM) contraction of the portal vein at a capsaicin concentration 0.1 μmol/L, 0.5 μmol/L capsazepine, and 1.0 μmol/L amizonum was +30.3±5.3%, -3.2± 2.7% and +7.1±3.2% from initial level, respectivelly. In a combined application of amizonum with capsaicin or capsazepine, the amplitude of contraction of the SM portal vein was 20.1± 1.3% and -3.0±1.4%, respectively. This indicates the absence of action of amizonum under combined use of capsaicinoids. The Tail-flick model showed atypical potentiation of the amizonum antinociception with the use of capsaicin. The obtained data suggest the low probability of the participation of TRPV1 in the implementation of the antinociceptive action of amizonum.

Abstract 1287: TRPV4-Deficient Mice Exhibit Impaired Endothelium-Dependent Relaxation Induced by Acetylcholine in Vitro and in Vivo

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
David Zhang ◽  
Suelhem Mendoza ◽  
Aaron Bubolz ◽  
Makoto Suzuki ◽  
David Gutterman
Keyword(s):  
Blood Pressure ◽  
Endothelial Cells ◽  
Carotid Arteries ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Transient Receptor Potential Vanilloid ◽  
Mice Model ◽  
Synthase Inhibitor

Agonist-induced Ca 2+ entry in endothelial cells is important for the synthesis and release of vasoactive factors, although mechanisms of Ca 2+ entry remain largely unknown. Emerging evidence suggests that the transient receptor potential vanilloid 4 (TRPV4) channel, a Ca 2+ -permeant TRP channel, is expressed in endothelial cells and may be involved in the regulation of vascular tone. Here we investigated the potential role of TRPV4 channels in acetylcholine-induced vasodilation in vitro and in vivo using the TRPV4 knockout (TRPV4 −/− ) mice model. Carotid arteries were isolated and preconstricted with the thromboxane A2 mimetic U46619. Concentration-dependent relaxations to acetylcholine (10 −9 –10 −5 M) were markedly reduced in carotids of TRPV4 −/− vs. wild-type (WT) mice (maximal relaxations of 31±12% vs 53±4%, respectively; n=4 mice). There was no significant change in the ED50 for Ach. In both WT and TRPV4 −/− , acetylcholine-induced relaxations were blocked and converted to constrictions by the NO synthase inhibitor L-NAME (maximal relaxations of −25±6% and −24±7%, respectively). There was no difference in papaverine-induced relaxations between WT and TRPV4 −/− mice (maximal relaxations of 93±3% vs. 90±3%, respectively). U46619 caused similar contractions in carotid arteries from those mice. We also compared in vivo vasodilator effects of acetylcholine by measuring changes in blood pressure in those animals. Intravenous administration of acetylcholine (15 ng/gm bolus) decreased blood pressure by 32±6 mmHg in WT mice (from 90±15 to 57±10 mmHg; n=6), whereas blood pressure was reduced by only 10 mmHg in TRPV4 −/− mice (from 67±6 to 56±4 mmHg; n=12). Acetylcholine caused similar reductions in heart rate in WT and TRPV4 −/− mice, with mean changes of 365±57 and 292±40 beats/min, respectively. We conclude that the endothelium-dependent vasodilator response to acetylcholine is reduced both in vitro and in vivo in TRPV4 −/− mice, and these findings may provide novel insight into the mechanisms of Ca 2+ entry evoked by chemical agonists in endothelial cells. The paradoxically lower baseline blood pressure in TRPV4 −/− mice requires further investigation.

scholarly journals Calcium and TRPV4 promote metastasis by regulating cytoskeleton through the RhoA/ROCK1 pathway in endometrial cancer

2020 ◽  
Vol 11 (11) ◽  
Author(s):  
Xingchen Li ◽  
Yuan Cheng ◽  
Zhiqi Wang ◽  
Jingyi Zhou ◽  
Yuanyuan Jia ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Cancer Progression ◽  
Transient Receptor Potential ◽  
Calcium Influx ◽  
Biological Significance ◽  
Receptor Potential ◽  
Transient Receptor Potential Vanilloid ◽  
Mechanistic Investigation

AbstractTransient receptor potential vanilloid 4 (TRPV4) is a calcium-permeable cation channel that has been associated with several types of cancer. However, its biological significance, as well as its related mechanism in endometrial cancer (EC) still remains elusive. In this study, we examined the function of calcium in EC, with a specific focus on TRPV4 and its downstream pathway. We reported here on the findings that a high level of serum ionized calcium was significantly correlated with advanced EC progression, and among all the calcium channels, TRPV4 played an essential role, with high levels of TRPV4 expression associated with cancer progression both in vitro and in vivo. Proteomic and bioinformatics analysis revealed that TRPV4 was involved in cytoskeleton regulation and Rho protein pathway, which regulated EC cell migration. Mechanistic investigation demonstrated that TRPV4 and calcium influx acted on the cytoskeleton via the RhoA/ROCK1 pathway, ending with LIMK/cofilin activation, which had an impact on F-actin and paxillin (PXN) levels. Overall, our findings indicated that ionized serum calcium level was significantly associated with poor outcomes and calcium channel TRPV4 should be targeted to improve therapeutic and preventive strategies in EC.

A role for transient receptor potential ankyrin 1 cation channel (TRPA1) in airway hyper-responsiveness?

2015 ◽  
Vol 93 (3) ◽  
pp. 171-176 ◽  
Author(s):  
Aruni Jha ◽  
Pawan Sharma ◽  
Vidyanand Anaparti ◽  
Min H. Ryu ◽  
Andrew J. Halayko
Keyword(s):  
Airway Inflammation ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Cation Channel ◽  
Chronic Obstructive ◽  
Airway Narrowing ◽  
Airway Caliber ◽  
Transient Receptor

Airway smooth muscle (ASM) contraction controls the airway caliber. Airway narrowing is exaggerated in obstructive lung diseases, such as asthma and chronic obstructive pulmonary disease (COPD). The mechanism by which ASM tone is dysregulated in disease is not clearly understood. Recent research on ion channels, particularly transient receptor potential cation channel, subfamily A, member 1 (TRPA1), is uncovering new understanding of altered airway function. TRPA1, a member of the TRP channel superfamily, is a chemo-sensitive cation channel that can be activated by a variety of external and internal stimuli, leading to the influx of Ca2+. Functional TRPA1 channels have been identified in neuronal and non-neuronal tissues of the lung, including ASM. In the airways, these channels can regulate the release of mediators that are markers of airway inflammation in asthma and COPD. For, example, TRPA1 controls cigarette-smoke-induced inflammatory mediator release and Ca2+ mobilization in vitro and in vivo, a response tied to disease pathology in COPD. Recent work has revealed that pharmacological or genetic inhibition of TRPA1 inhibits the allergen-induced airway inflammation in vitro and airway hyper-responsiveness (AHR) in vivo. Collectively, it appears that TRPA1 channels may be determinants of ASM contractility and local inflammation control, positioning them as part of novel mechanisms that control (patho)physiological function of airways and ASM.

Transient receptor potential ankyrin 1 (TRPA1) ion channel in the pathophysiology of peripheral diabetic neuropathy

2013 ◽  
Vol 4 (3) ◽  
pp. 129-136 ◽  
Author(s):  
Ari Koivisto ◽  
Antti Pertovaara
Keyword(s):  
Diabetic Neuropathy ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Axon Reflex ◽  
Pain Hypersensitivity ◽  
Peripheral Diabetic Neuropathy ◽  
Transient Receptor ◽  
Sustained Activation

AbstractBackgroundTransient receptor potential ankyrin 1 (TRPA1) is a non-selective cation channel permeable to calcium that is expressed on pain-mediating primary afferent nerve fibers. Here we review recent experimental evidence supporting the hypothesis that activation of the TRPA1 channel by reactive compounds generated in diabetes mellitus, such as 4-hydroxynonenal and methylglyoxal, exerts an important role in the pathophysiology of peripheral diabetic neuropathy (PDN). The hypothesis includes development of the early diabetic pain hypersensitivity and the later loss of cutaneous nerve endings of pain fibers and their dysfunction, which are hallmarks of peripheral diabetic neuropathy (PDN).Methods The evidence for a role of the TRPA1 channel in PDN consists of in vitro patch clamp and calcium imaging data and assessments of pain behavior, axon reflex measurements, and immunohistochemical analyses of cutaneous innervation in an experimental animal model of diabetes. The experiments were combined with blocking the TRPA1 channel with selective antagonists Chembridge-5861528 or A-967079.ResultsIn vitro studies indicate that under physiological concentration of Ca2+, methylglyoxal and 4-hydroxynonenal produce sustained activation of the TRPA1 channel and sustained inflow of calcium. In vivo studies indicate that diabetic pain hypersensitivity is maintained by the TRPA1 channel as indicated by the antihypersensitivity effect induced by acute blocking of the TRPA1 channel. Moreover, TRPA1 channel is involved in the development of diabetic hypersensitivity as indicated by prevention of the development of pain hypersensitivity in diabetic animals treated daily with Chembridge-5861528. The diabetes-induced loss of substance P-like cutaneous innervation and that of the TRPA1 channel-mediated cutaneous axon reflex function during the later phase of diabetes were also prevented or delayed by prolonged blocking of the TRPA1 channel. No motor impairment or other obvious side-effects were observed following block of the TRPA1 channel.Conclusions Together the in vitro and in vivo results indicate that reactive compounds generated in diabetes exert, through action on the TRPA1 channel, an important role in the pathophysiology of PDN. Sustained activation of the TRPA1 channel is a plausible mechanism that contributes to the early diabetic pain hypersensitivity and the later loss of cutaneous pain fiber endings and their dysfunction with prolonged diabetes.ImplicationsBlocking the TRPA1 channel with a selective antagonist provides a promising disease-modifying treatment for PDN, with only minor, if any, side-effects.

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