Assessment of the TRPM8 inhibitor AMTB in breast cancer cells and its identification as an inhibitor of voltage gated sodium channels

Yapa, Kunsala T. D. S.; Deuis, Jennifer R.; Peters, Amelia A.; Kenny, Paraic A.; Roberts‐Thomson, Sarah J.; Vetter, Irina; Monteith, Gregory R.

doi:10.1016/j.lfs.2018.02.030

Cited by 28 publications

(28 citation statements)

References 68 publications

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“…To the best of our knowledge, there are no data on expression levels in A549, HT29 and PSN1 tumor cell lines, while for MDA-MB-231 the results described so far are contradictory. Thus, while the TRPM8 antagonist AMTB decreases viable cells in MDA-MB-231 breast cancer cells and TRPM8 levels are high in basal breast cancers, the TRPM8 expression does not seem very high in this and other breast cancer cell lines 53 . On the contrary, a work by Liu and coworkers identified high levels of channel expression in different breast cancer cell lines, including MDA-MB-231 54 .…”

Section: Growth Inhibitory Activity In Tumor Cells a Number Of Recenmentioning

confidence: 70%

Highly functionalized β-lactams and 2-ketopiperazines as TRPM8 antagonists with antiallodynic activity

Bonache

Martín-Escura

Martínez

et al. 2020

Sci Rep

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The cool sensor transient receptor potential melastatin channel 8 (TRPM8) is highly expressed in trigeminal and dorsal root ganglia, playing a key role in cold hypersensitivity associated to different peripheral neuropathies. Moreover, these channels are aberrantly expressed in different cancers, and seem to participate in tumor progression, survival and invasion. Accordingly, the search for potent and selective TRPM8 modulators attracted great interest in recent years. We describe new heterocyclic TRPM8 antagonist chemotypes derived from N-cloroalkyl phenylalaninol-Phe conjugates. The cyclization of these conjugates afforded highly substituted β-lactams and/or 2-ketopiperazine (KP) derivatives, with regioselectivity depending on the N-chloroalkyl group and the configuration. These derivatives behave as TRPM8 antagonists in the Ca 2+ microfluorometry assay, and confirmed electrophysiologically for the best enantiopure β-lactams 24a and 29a (IC 50 , 1.4 and 0.8 µM). Two putative binding sites by the pore zone, different from those found for typical agonists and antagonists, were identified by in silico studies for both β-lactams and KPs. β-Lactams 24a and 29a display antitumor activity in different human tumor cell lines (micromolar potencies, A549, HT29, PSN1), but correlation with TRPM8 expression could not be established. Additionally, compound 24a significantly reduced cold allodynia in a mice model of oxaliplatin-induced peripheral neuropathy.

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Section: Growth Inhibitory Activity In Tumor Cells a Number Of Recenmentioning

confidence: 70%

Highly functionalized β-lactams and 2-ketopiperazines as TRPM8 antagonists with antiallodynic activity

Bonache

Martín-Escura

Martínez

et al. 2020

Sci Rep

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“…As shown in Figure 8F , a partial reversible calcium response could be observed in comparison to the irreversible calcium response shown in Figure 8B of the same experiment. Since icilin activates both TRPM8 and TRPA1 ( 78 , 79 ), AMTB (10 μM), a highly selective TRPM8 blocker, was used to probe for TRPM8 ( 21 , 80 ). Specifically, icilin reversibly increased the fluorescence ratio from 0.2045 ± 0.0019 to 0.2477 ± 0.0165 after 400 s ( n = 16; p < 0.001; Figure 8F ), which AMTB blocked (10 μM; 0.2021 ± 0.0020; n = 16; p < 0.001; Figures 8G,H ).…”

Section: Resultsmentioning

confidence: 99%

Vascular Endothelial Growth Factor (VEGF) Induced Downstream Responses to Transient Receptor Potential Vanilloid 1 (TRPV1) and 3-Iodothyronamine (3-T1AM) in Human Corneal Keratocytes

et al. 2018

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This study was undertaken to determine if crosstalk among the transient receptor potential (TRP) melastatin 8 (TRPM8), TRP vanilloid 1 (TRPV1), and vascular endothelial growth factor (VEGF) receptor triad modulates VEGF-induced Ca2+ signaling in human corneal keratocytes. Using RT-PCR, qPCR and immunohistochemistry, we determined TRPV1 and TRPM8 gene and protein coexpression in a human corneal keratocyte cell line (HCK) and human corneal cross sections. Fluorescence Ca2+ imaging using both a photomultiplier and a single cell digital imaging system as well as planar patch-clamping measured relative intracellular Ca2+ levels and underlying whole-cell currents. The TRPV1 agonist capsaicin increased both intracellular Ca2+ levels and whole-cell currents, while the antagonist capsazepine (CPZ) inhibited them. VEGF-induced Ca2+ transients and rises in whole-cell currents were suppressed by CPZ, whereas a selective TRPM8 antagonist, AMTB, increased VEGF signaling. In contrast, an endogenous thyroid hormone-derived metabolite 3-Iodothyronamine (3-T1AM) suppressed increases in the VEGF-induced current. The TRPM8 agonist menthol increased the currents, while AMTB suppressed this response. The VEGF-induced increases in Ca2+ influx and their underlying ionic currents stem from crosstalk between VEGFR and TRPV1, which can be impeded by 3-T1AM-induced TRPM8 activation. Such suppression in turn blocks VEGF-induced TRPV1 activation. Therefore, crosstalk between TRPM8 and TRPV1 inhibits VEGFR-induced activation of TRPV1.

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“…In contrast with our conclusion, the previous report was concluded that icilin can modulate glutamatergic neurons in the brain through a TRP-independent pathway, regardless of whether the neurons are stimulated intracellularly or by hyperactive microcircuitry (Pezzoli et al, 2014). Moreover, it was reported that AMTB inhibited voltage gated sodium channels (Yapa et al, 2018). However, we revealed that the suppressive effect of high concentrated icilin on EDs was antagonized when AMTB, a TRPM8 inhibitor, was administered just before icilin injection ( Figure 2E–H ).…”

Section: Discussionmentioning

confidence: 99%

Suppressive Effects of Cooling Compounds Icilin on Penicillin G-Induced Epileptiform Discharges in Anesthetized Rats

et al. 2019

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More than 30% of patients with epilepsy are refractory and have inadequate seizure control. Focal cortical cooling (FCC) suppresses epileptiform discharges (EDs) in patients with refractory focal cortical epilepsy. However, little is known about the mechanism by which FCC inhibits seizures at 15°C, and FCC treatment is highly invasive. Therefore, new antiepileptic drugs are needed that produce the same effects as FCC but with different mechanisms of action. To address this need, we focused on transient receptor potential melastatin 8 (TRPM8), an ion channel that detects cold, which is activated at 15°C. We examined whether TRPM8 activation suppresses penicillin G (PG)-induced EDs in anesthetized rats. Icilin, a TRPM8 and TRP Ankyrin 1 agonist, was administered after PG injection, and a focal electrocorticogram (ECoG) and cortical temperature were recorded for 4 h. We measured spike amplitude, duration, firing rate, and power density in each band to evaluate the effects of icilin. PG-induced EDs and increased delta, theta, alpha, and beta power spectra were observed in the ECoG. Icilin suppressed EDs while maintaining cortical temperature. In particular, 3.0-mM icilin significantly suppressed PG-induced spike amplitude, duration, and firing rate and improved the increased power density of each band in the EDs to the level of basal activity in the ECoG. These suppressive effects of 3.0-mM icilin on EDs were antagonized by administering N-(3-aminopropyl)-2-[(3-methylphenyl) methoxy]-N-(2-thienylmethyl)-benzamide hydrochloride (AMTB), a selective TRPM8 inhibitor. Our results suggest that TRPM8 activation in epileptic brain regions may be a new therapeutic approach for patients with epilepsy.

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Assessment of the TRPM8 inhibitor AMTB in breast cancer cells and its identification as an inhibitor of voltage gated sodium channels

Abstract: TRPM8 levels may be elevated in basal breast cancers, however, TRPM8 expression appears to be lost in many breast cancer cell lines. Some of the effects of AMTB attributed to TRPM8 may be due to effects on Na channels.

Cited by 28 publications

References 68 publications

Highly functionalized β-lactams and 2-ketopiperazines as TRPM8 antagonists with antiallodynic activity

Highly functionalized β-lactams and 2-ketopiperazines as TRPM8 antagonists with antiallodynic activity

Vascular Endothelial Growth Factor (VEGF) Induced Downstream Responses to Transient Receptor Potential Vanilloid 1 (TRPV1) and 3-Iodothyronamine (3-T1AM) in Human Corneal Keratocytes

Suppressive Effects of Cooling Compounds Icilin on Penicillin G-Induced Epileptiform Discharges in Anesthetized Rats

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