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TRPM8 Ion Channels Differentially Modulate Proliferation and Cell Cycle Distribution of Normal and Cancer Prostate Cells  [PDF]
María Ll. Valero, Fernanda Mello de Queiroz, Walter Stühmer, Félix Viana, Luis A. Pardo
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0051825
Abstract: Overexpression of the cation-permeable channel TRPM8 in prostate cancers might represent a novel opportunity for their treatment. Inhibitors of TRPM8 reduce the growth of prostate cancer cells. We have used two recently described and highly specific blockers, AMTB and JNJ41876666, and RNAi to determine the relevance of TRPM8 expression in the proliferation of non-tumor and tumor cells. Inhibition of the expression or function of the channel reduces proliferation rates and proliferative fraction in all tumor cells tested, but not of non-tumor prostate cells. We observed no consistent acceleration of growth after stimulation of the channel with menthol or icilin, indicating that basal TRPM8 expression is enough to sustain growth of prostate cancer cells.
Transient Receptor Potential Vanilloid 1 is essential for cisplatin-induced heat hyperalgesia in mice
Lauren E Ta, Allan J Bieber, Susan M Carlton, Charles L Loprinzi, Philip A Low, Anthony J Windebank
Molecular Pain , 2010, DOI: 10.1186/1744-8069-6-15
Abstract: In this study, using real-time, reverse transcriptase, polymerase chain reaction (RT-PCR), we analyzed the expression of TRPV1, TRPM8, and TRPA1 induced by cisplatin or oxaliplatin in vitro and in vivo. For in vitro studies, cultured E15 rat dorsal root ganglion (DRG) neurons were treated for up to 48 hours with cisplatin or oxaliplatin. For in vivo studies, trigeminal ganglia (TG) were isolated from mice treated with platinum drugs for three weeks. We show that cisplatin and oxaliplatin-treated DRG neurons had significantly increased in TRPV1, TRPA1, and TRPM8 mRNA expression. TG neurons from cisplatin treated mice had significant increases in TRPV1 and TRPA1 mRNA expression while oxaliplatin strongly induced only TRPA1. Furthermore, compared to the cisplatin-treated wild-type mice, cisplatin-treated TRPV1-null mice developed mechanical allodynia but did not exhibit enhancement of noxious heat- evoked pain responses. Immunohistochemistry studies showed that cisplatin-treated mice had no change in the proportion of the TRPV1 immunopositive TG neurons.These results indicate that TRPV1 and TRPA1 could contribute to the development of thermal hyperalgesia and mechanical allodynia following cisplatin-induced painful neuropathy but that TRPV1 has a crucial role in cisplatin-induced thermal hyperalgesia in vivo.Painful peripheral neuropathy is the principle dose-limiting factor requiring discontinuation of chemotherapy with platinum-based drugs such as cisplatin and oxaliplatin [1]. Cisplatin is widely used for treatment of solid tumors especially against testicular, ovarian, and bladder cancers [2,3]. Oxaliplatin is a third generation platinum analogue which is highly effective for metastatic colorectal cancer [4-6]. Platinum-based drugs presumably exert their antitumor activity by binding to DNA and distorting the helical structure in a way that inhibits transcription [7] and induces apoptotic cell death through DNA damage recognition pathways [8,9]. Up to thirty to for
Role of TRPM8 in dorsal root ganglion in nerve injury-induced chronic pain
Lin Su, Chao Wang, Yong-hao Yu, Yong-ying Ren, Ke-liang Xie, Guo-lin Wang
BMC Neuroscience , 2011, DOI: 10.1186/1471-2202-12-120
Abstract: Mechanical allodynia, cold and thermal hyperalgesia of CCI rats began on the 4th day following surgery and maintained at the peak during the period from the 10th to 14th day after operation. The level of TRPM8 protein in L5 dorsal root ganglion (DRG) ipsilateral to nerve injury was significantly increased on the 4th day after CCI, and reached the peak on the 10th day, and remained elevated on the 14th day following CCI. This time course of the alteration of TRPM8 expression was consistent with that of CCI-induced hyperalgesic response of the operated hind paw. Besides, activation of cold receptor TRPM8 of CCI rats by intrathecal application of menthol resulted in the inhibition of mechanical allodynia and thermal hyperalgesia and the enhancement of cold hyperalgesia. In contrast, downregulation of TRPM8 protein in ipsilateral L5 DRG of CCI rats by intrathecal TRPM8 antisense oligonucleotide attenuated cold hyperalgesia, but it had no effect on CCI-induced mechanical allodynia and thermal hyperalgesia.TRPM8 may play different roles in mechanical allodynia, cold and thermal hyperalgesia that develop after nerve injury, and it is a very promising research direction for the development of new therapies for chronic neuroapthic pain.Chronic neuropathic pain is a refractory pain characterized by its complex mechanisms and diverse clinical manifestations [1]. Traditional therapies usually bring about many side effects [2]. Moderate cold stimuli can relieve pain [3], which provides an inspiration for developing new treatments of chronic pain. Recently, transient receptor potential (TRP) channel family has been proposed to play an important role in thermosensation in mammals. Six thermosensitive ion channels of this family have been discovered, including TRPV1, TRPV2, TRPV3, TRPV4, TRPM8 and TRPA1. Among them, TRPM8 and TRPA1 are responsive to cold stimuli [4]. TRPM8 is a ligand-gated non-selective cation channel involved in detection of sensations such as coolness. It is per
Pharmacological Blockade of TRPM8 Ion Channels Alters Cold and Cold Pain Responses in Mice  [PDF]
Wendy M. Knowlton,Richard L. Daniels,Radhika Palkar,Daniel D. McCoy,David D. McKemy
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0025894
Abstract: TRPM8 (Transient Receptor Potential Melastatin-8) is a cold- and menthol-gated ion channel necessary for the detection of cold temperatures in the mammalian peripheral nervous system. Functioning TRPM8 channels are required for behavioral responses to innocuous cool, noxious cold, injury-evoked cold hypersensitivity, cooling-mediated analgesia, and thermoregulation. Because of these various roles, the ability to pharmacologically manipulate TRPM8 function to alter the excitability of cold-sensing neurons may have broad impact clinically. Here we examined a novel compound, PBMC (1-phenylethyl-4-(benzyloxy)-3-methoxybe?nzyl(2-aminoethyl)carbamate)which robustly and selectively inhibited TRPM8 channels in vitro with sub-nanomolar affinity, as determined by calcium microfluorimetry and electrophysiology. The actions of PBMC were selective for TRPM8, with no functional effects observed for the sensory ion channels TRPV1 and TRPA1. PBMC altered TRPM8 gating by shifting the voltage-dependence of menthol-evoked currents towards positive membrane potentials. When administered systemically to mice, PBMC treatment produced a dose-dependent hypothermia in wildtype animals while TRPM8-knockout mice remained unaffected. This hypothermic response was reduced at lower doses, whereas responses to evaporative cooling were still significantly attenuated. Lastly, systemic PBMC also diminished cold hypersensitivity in inflammatory and nerve-injury pain models, but was ineffective against oxaliplatin-induced neuropathic cold hypersensitivity, despite our findings that TRPM8 is required for the cold-related symptoms of this pathology. Thus PBMC is an attractive compound that serves as a template for the formulation of highly specific and potent TRPM8 antagonists that will have utility both in vitro and in vivo.
Sensitization of capsaicin and icilin responses in oxaliplatin treated adult rat DRG neurons
Uma Anand, William R Otto, Praveen Anand
Molecular Pain , 2010, DOI: 10.1186/1744-8069-6-82
Abstract: 48 hour exposure to oxaliplatin resulted in dose related reduction in neurite length, density, and number of neurons compared to vehicle treated controls, using Gap43 immunostaining. Neurons treated acutely with 20 μg/ml oxaliplatin showed significantly higher signal intensity for cyclic AMP immunofluorescence (160.5 ± 13 a.u., n = 3, P < 0.05), compared to controls (120.3 ± 4 a.u.). Calcium imaging showed significantly enhanced capsaicin (TRPV1 agonist), responses after acute 20 μg/ml oxaliplatin treatment where the second of paired capsaicin responses increased from 80.7 ± 0.6% without oxaliplatin, to 171.26 ± 29% with oxaliplatin, (n = 6 paired t test, P < 0.05); this was reduced to 81.42 ± 8.1% (P < 0.05), by pretretreatment with the cannabinoid CB2 receptor agonist GW 833972. Chronic oxaliplatin treatment also resulted in dose related increases in capsaicin responses. Similarly, second responses to icilin (TRPA1/TRPM8 agonist), were enhanced after acute (143.85 ± 7%, P = 0.004, unpaired t test, n = 3), and chronic (119.7 ± 11.8%, P < 0.05, n = 3) oxaliplatin treatment, compared to control (85.3 ± 1.7%). Responses to the selective TRPM8 agonist WS-12 were not affected.Oxaliplatin treatment induces TRP sensitization mediated by increased intracellular cAMP, which may cause neuronal damage. These effects may be mitigated by co-treatment with adenylyl cyclase inhibitors, like CB2 agonists, to alleviate the neurotoxic effects of oxaliplatin.Though advances in cancer detection and therapy have significantly advanced life expectancy in cancer patients, quality of life may be severely compromised due to the development of painful neuropathy [1-4]. Chemotherapy-induced peripheral neuropathy is a common, rapidly induced effect observed soon after administration of anti-cancer agents [5-7] resulting in numbness, tingling and pain distributed in a distal stocking-and-glove pattern [8,9]. Oxaliplatin is a highly active antineoplastic agent, licensed for treating colorectal
Acute cold hypersensitivity characteristically induced by oxaliplatin is caused by the enhanced responsiveness of TRPA1 in mice  [cached]
Zhao Meng,Isami Kouichi,Nakamura Saki,Shirakawa Hisashi
Molecular Pain , 2012, DOI: 10.1186/1744-8069-8-55
Abstract: Background Oxaliplatin, a platinum-based chemotherapeutic agent, causes an unusual acute peripheral neuropathy. Oxaliplatin-induced acute peripheral neuropathy appears in almost all patients rapidly after infusion, and is triggered or exacerbated by cold, while its mechanisms are poorly understood. In this study, the involvement of thermosensitive transient receptor potential channels (TRPA1, TRPM8 and TRPV1) in oxaliplatin-induced acute hypersensitivity was investigated in mice. Results A single intraperitoneal administration of oxaliplatin (1–10 mg/kg) induced cold but not mechanical hypersensitivity within 2 h in a dose-dependent manner. Infusion of the oxaliplatin metabolite, oxalate (1.7 mg/kg), also induced acute cold hypersensitivity, while another platinum-based chemotherapeutic agent, cisplatin (5 mg/kg), or the non-platinum-containing chemotherapeutic agent, paclitaxel (6 mg/kg) failed to induce mechanical or cold hypersensitivity. The oxaliplatin-induced acute cold hypersensitivity was abolished by the TRPA1 antagonist HC-030031 (100 mg/kg) and by TRPA1 deficiency. The nocifensive behaviors evoked by intraplantar injections of allyl-isothiocyanate (AITC; TRPA1 agonist) were significantly enhanced in mice treated for 2 h with oxaliplatin (1–10 mg/kg) in a dose-dependent manner, while capsaicin (TRPV1 agonist)-evoked nocifensive behaviors were not affected. Menthol (TRPM8/TRPA1 agonist)-evoked nocifensive-like behaviors were also enhanced by oxaliplatin pretreatment, which were inhibited by TRPA1 deficiency. Similarly, oxalate enhanced, but neither cisplatin nor paclitaxel affected AITC-evoked nocifensive behaviors. Pretreatment of cultured mouse dorsal root ganglia (DRG) neurons with oxaliplatin (30–300 μM) for 1, 2, or 4 h significantly increased the number of AITC-sensitive neurons in a concentration-dependent manner whereas there was no change in the number of menthol- or capsaicin-sensitive neurons. Conclusions Taken together, these results suggest that a brief treatment with oxaliplatin or its metabolite oxalate is sufficient to enhance the responsiveness of TRPA1 but not that of TRPM8 and TRPV1 expressed by DRG neurons, which may contribute to the characteristic acute peripheral neuropathy induced by oxaliplatin.
On Visibility and Blockers  [cached]
Attila Pór,David R. Wood
Journal of Computational Geometry , 2010,
Abstract: This expository paper discusses some conjectures related to visibility and blockers for sets of points in the plane.
On Visibility and Blockers  [PDF]
Attila Pór,David R. Wood
Mathematics , 2009,
Abstract: This expository paper discusses some conjectures related to visibility and blockers for sets of points in the plane.
Adsorption of Oxaliplatin by Hydroxyapatite
Betsiou M.,Sikalidis C.,Papageorgiou A.
Bioautomation , 2007,
Abstract: Hydroxyapatite (HAP) is the main inorganic component of human skeleton. The last years a lot of interest is focused on its use as drug carrier. In this work the in vitro adsorption of the anti-cancer drug oxaliplatin, by HAP, from its aqueous solution was studied. Various initial concentrations of oxaliplatin aqueous solutions were used in order to determine the maximum adsorption capacity of HAP. Oxaliplatin's concentrations were determined through Pt determinations by atomic absorption spectrometry with flame technique, in the equilibrated solutions after shaking for 48 hours and filtering the HAP-oxaliplatin slurries. The maximum adsorption capacity was found to be 49.1 mg oxaliplatin/g HAP. In order to determine the time needed for the maximum adsorption to be achieved, six oxaliplatin - HAP slurries were prepared. The slurries had initial oxaliplatin concentrations the one that corresponds to the maximum adsorption capacity of the HAP added. The oxaliplatin determination was carried out after 0, 10, 20, 30, 40 and 48 hours in each different slurry. The maximum adsorption capacity was achieved after 20 hours. The adsorption of oxaliplatin by HAP was found to follow the Freundlich equation.
Inorganic Polyphosphate Modulates TRPM8 Channels  [PDF]
Eleonora Zakharian, Baskaran Thyagarajan, Robert J. French, Evgeny Pavlov, Tibor Rohacs
PLOS ONE , 2009, DOI: 10.1371/journal.pone.0005404
Abstract: Polyphosphate (polyP) is an inorganic polymer built of tens to hundreds of phosphates, linked by high-energy phosphoanhydride bonds. PolyP forms complexes and modulates activities of many proteins including ion channels. Here we investigated the role of polyP in the function of the transient receptor potential melastatin 8 (TRPM8) channel. Using whole-cell patch-clamp and fluorescent calcium measurements we demonstrate that enzymatic breakdown of polyP by exopolyphosphatase (scPPX1) inhibits channel activity in human embryonic kidney and F-11 neuronal cells expressing TRPM8. We demonstrate that the TRPM8 channel protein is associated with polyP. Furthermore, addition of scPPX1 altered the voltage-dependence and blocked the activity of the purified TRPM8 channels reconstituted into planar lipid bilayers, where the activity of the channel was initiated by cold and menthol in the presence of phosphatidylinositol 4,5-biphosphate (PtdIns(4,5)P2). The biochemical analysis of the TRPM8 protein also uncovered the presence of poly-(R)-3-hydroxybutyrate (PHB), which is frequently associated with polyP. We conclude that the TRPM8 protein forms a stable complex with polyP and its presence is essential for normal channel activity.
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