TRP Channels in Cancer: Signaling Mechanisms and Translational Approaches

Biomolecules, Journal Year: 2023, Volume and Issue: 13(10), P. 1557 - 1557

Published: Oct. 22, 2023

Ion channels play a crucial role in wide range of biological processes, including cell cycle regulation and cancer progression. In particular, the transient receptor potential (TRP) family has emerged as promising therapeutic target due to its involvement several stages development dissemination. TRP are expressed large variety cells tissues, by increasing cation intracellular concentration, they monitor mechanical, thermal, chemical stimuli under physiological pathological conditions. Some members superfamily, namely vanilloid (TRPV), canonical (TRPC), melastatin (TRPM), ankyrin (TRPA), have been investigated different types cancer, breast, prostate, lung, colorectal cancer. involved processes such proliferation, migration, invasion, angiogenesis, drug resistance, all related mechanistically associated with signaling pain. Understanding cellular molecular mechanisms which influence provides new opportunities for targeted strategies. Selective inhibitors initial scrutiny experimental animals anti-cancer agents. In-depth knowledge these their regulatory may lead strategies treatment, providing perspectives effective therapies.

Language: Английский

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Molecular and Cellular Involvement in CIPN

Biomedicines, Journal Year: 2024, Volume and Issue: 12(4), P. 751 - 751

Published: March 28, 2024

Many anti-cancer drugs, such as taxanes, platinum compounds, vinca alkaloids, and proteasome inhibitors, can cause chemotherapy-induced peripheral neuropathy (CIPN). CIPN is a frequent harmful side effect that affects the sensory, motor, autonomic nerves, leading to pain, numbness, tingling, weakness, reduced quality of life. The causes are not fully known, but they involve direct nerve damage, oxidative stress, inflammation, DNA microtubule dysfunction, altered ion channel activity. also affected by genetic, epigenetic, environmental factors modulate risk intensity damage. Currently, there no effective treatments or prevention methods for CIPN, symptom management mostly symptomatic palliative. Therefore, high demand better understanding cellular molecular mechanisms involved in well development new biomarkers therapeutic targets. This review gives an overview current knowledge challenges field focusing on biological underlying this disorder.

Language: Английский

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Impact of cannabinoids on cancer outcomes in patients receiving immune checkpoint inhibitor immunotherapy

Frontiers in Immunology, Journal Year: 2025, Volume and Issue: 16

Published: March 5, 2025

Cannabinoids relieve pain, nausea, anorexia and anxiety, improve quality of life in several cancer patients. The immunotherapy with checkpoint inhibitors (ICIs), although very successful a subset patients, is accompanied by moderate to severe immune-related adverse events (ir-AE) that often necessitate its discontinuation. Because their role symptomatic relief, cannabinoids have been used combination immune inhibitor (ICI) immunotherapy. A few studies strongly suggest the use medicinal cannabis patients attenuates many ir-AE associated ICI increase tolerability. However, no significant beneficial effects on overall survival, progression free survival or relapses were observed; rather, some noted concurrent administration clinical benefits latter. cannabinoids' well documented immunosuppressive mediated through cannabinoid recptor-2 (CB2), we propose considering this receptor as an inhibitory per se. simultaneous neutralization CB2, treatment, may lead better outcomes receiving In regard, such cannabidiol (CBD) cannabigerol (CBG), little agonism for be therapeutic choices. Additional strategies e.g., monoacylglycerol lipase (MAGL) degrade endocannabinoids lipogenesis formation lipid bilayers cells also explored. Future should take into consideration gut microbiota, CYP450 polymorphism haplotypes, cannabinoid-drug interactions genetic somatic variations occurring receptors signaling pathways personalized cannabis-based therapies ICIs. This rational knowledge-based regimens tailored individual

Language: Английский

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The Role of TRPM7 in Oncogenesis

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(2), P. 719 - 719

Published: Jan. 5, 2024

This review summarizes the current understanding of role transient receptor potential melastatin-subfamily member 7 (TRPM7) channels in pathophysiology neoplastic diseases. The TRPM family represents largest and most diverse group TRP superfamily. Its subtypes are expressed virtually all human organs playing a central (patho)physiological events. TRPM7 protein (along with TRPM2 TRPM6) is unique that it has kinase activity addition to channel function. Numerous studies demonstrate chanzyme tumorigenesis other tumor hallmarks such as proliferation, migration, invasion metastasis. Here we provide an up-to-date overview about possible TRMP7 broad range malignancies tumors nervous system, head neck cancers, malignant neoplasms upper gastrointestinal tract, colorectal carcinoma, lung cancer, urinary breast female reproductive organs, prostate cancer pathologies. Experimental data show increased expression and/or function observed types. Thus, may be promising target therapy.

Language: Английский

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Molecular determinants of TRPM8 function: key clues for a cool modulation

Frontiers in Pharmacology, Journal Year: 2023, Volume and Issue: 14

Published: June 14, 2023

Cold thermoreceptor neurons detect temperature drops with highly sensitive molecular machinery concentrated in their peripheral free nerve endings. The main entity responsible for cold transduction these is the thermo-TRP channel TRPM8. Cold, cooling compounds such as menthol, voltage, and osmolality rises activate this polymodal ion channel. Dysregulation of TRPM8 activity underlies several physiopathological conditions, including painful hypersensitivity response to axonal damage, migraine, dry-eye disease, overactive bladder, forms cancer. Although could be an attractive target treating prevalent diseases, there still a need potent specific modulators potentially suitable future clinical trials. This goal requires complete understanding determinants underlying activation by chemical physical agonists, inhibition antagonists, modulatory mechanisms behind its function guide more successful treatment strategies. review recapitulates information obtained from different mutagenesis approaches that have allowed identification amino acids cavity comprised S1-S4 TRP domains determine modulation ligands. In addition, we summarize studies revealing regions within N- C-terminus transmembrane domain contribute cold-dependent gating. We also highlight latest milestone field: cryo-electron microscopy structures TRPM8, which provided better comprehension 21 years extensive research channel, shedding light on bases modulation, promoting rational design novel drugs selectively regulate abnormal under pathophysiological conditions.

Language: Английский

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Role of TRP Channels in Cancer-Induced Bone Pain

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(3), P. 1229 - 1229

Published: Jan. 30, 2025

The burden of cancer is growing in almost every country. Bone metastases significantly affect the prognosis and lead to an increase mortality morbidity. management cancer-induced bone pain (CIBP) still shows various unmet needs. Opioid use burdened by a number possible side effects. Moreover, recent progresses treatment increased life expectancy patients, even those with metastatic disease. In this narrative review, we reported main findings regarding TRP channel function models. cation channels play key role different functions cells, including regulation their potential for metastasization, are involved pathways perception, through peripheral central Genetic deletion decreased sensitivity following tumour cell inoculation. Preclinical data suggest modulators some channels, such as TRPV1, TRPA1, TRPM7 TRPM8. Clinical results scarce; however, physiological modulating remodelling involvement preclinical models have garnered interest areas research last few years, innovative analgesic strategies that may overcome long-term effects opioids.

Language: Английский

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An adamantane‐based ligand as a novel chemical tool for thermosensory TRPM8 channel therapeutic modulation

FEBS Journal, Journal Year: 2025, Volume and Issue: unknown

Published: March 23, 2025

Transient receptor potential cation channel subfamily M member 8 (TRPM8) is a nonselective thermosensory expressed in peripheral nociceptor terminals where it transduces cold temperatures and cooling agents such as menthol. TRPM8 dysfunction has been involved disabling sensory symptoms, allodynia. In addition, its widespread expression signaled this pivotal therapeutic target for variety of diseases, from neuropathies to cancer. Thus, the design validation antagonists an important endeavor biomedicine. To address this, we used multicomponent Passerini Ugi reactions novel family modulators using scaffold adamantane ring that exhibits drug‐like qualities. These green chemistry transformations are ideal fast synthesis libraries medium complexity with minimal or no generation waste by‐products. We report identification agonists antagonists. Among them, 2‐((3S,5S,7S)‐adamantan‐1‐ylamino)‐2‐oxoethyl [1,1′‐biphenyl]‐2‐carboxylate (referred compound 23 ) potent selective antagonist reduces TRPM8‐induced neuronal firing primary cultures. Compound 10‐fold higher potency human (hTRPM8) than hTRPV1 hTRPA1 channels. Notably, local administration significantly attenuated oxaliplatin‐induced allodynia by modulating epidermal endings. α‐acyloxy carboxamide appears promising candidate topically intervene on TRPM8‐mediated neuropathies.

Language: Английский

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Novel insights into the role of ion channels in cellular DNA damage response

Mutation Research/Reviews in Mutation Research, Journal Year: 2024, Volume and Issue: 793, P. 108488 - 108488

Published: Jan. 1, 2024

The DNA damage response (DDR) is a complex and highly regulated cellular process that detects repairs damage. integrity of the molecule crucial for proper functioning survival cells, as can lead to mutations, genomic instability, various diseases, including cancer. DDR safeguards genome by coordinating series signaling events repair mechanisms maintain stability prevent propagation damaged daughter cells. study an ion channels in context promising avenue biomedical research. Lately, it has been reported movement ions through plays role physiological processes, nerve signaling, muscle contraction, cell maintaining membrane potential. Knowledge regarding involvement could support refinement our approach several pathologies, mainly cancer, perhaps innovative therapies. In this review, we focused on channel's possible DDR. We present analysis DDR, their mechanisms, outcomes. By addressing these areas, aim provide comprehensive perspective potentially guide future research field. It worth noting interplay between multifaceted. More needed fully understand underlying potential therapeutic implications interactions.

Language: Английский

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Implication of TRPM8, CD47, and CDK4 expressions in hepatocellular carcinoma progression

Journal of Immunoassay and Immunochemistry, Journal Year: 2025, Volume and Issue: unknown, P. 1 - 17

Published: Feb. 16, 2025

Participation of TRPM8 in hepatocellular carcinoma (HCC) development was not precisely declared. CD47 mediates immune escape and macrophage phagocytosis tumors. CDK4 oncogenesis. Synergistic implications TRPM8, CD47, HCC were This research aims to demonstrate the expressions CD47and declare correlations significance. Paraffin blocks from 101 hCC 82 adjacent non-tumorous liver immunostained using antibodies. showed highly significant increased than control tissue (p < 0.001) for all. significantly associated with poor prognostic criteria as high tumor grade, advanced stage, microvascular invasion, necrosis. There a association between cirrhotic non-cirrhotic regarding positive 0.02) 0.045). direct relationships each immunohistochemical antibody other two. Prolonged overall survival low = 0.019). In conclusion, may regulate synergistic functions oncogenesis accomplish unfavorable might share cirrhosis. could be therapeutic targets HCC.

Language: Английский

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Direct modulation of TRPM8 ion channels by rapamycin and analog macrolide immunosuppressants

Published: Feb. 28, 2025

Rapamycin (sirolimus), a macrolide compound isolated from the bacterium Streptomyces hygroscopicus , is widely used as oral medication for prevention of transplant rejection and treatment lymphangioleiomyomatosis. It also incorporated in coronary stent coatings to prevent restenosis topical preparations skin disorders. Rapamycin’s vivo activities are generally ascribed its binding protein FKBP12, leading potent inhibition mechanistic target rapamycin kinase (mTOR) by FKBP12-rapamycin complex. The specific rapamycin-induced interaction between domains mTOR FKBP12 frequently employed cell biological research, rapid chemically-induced dimerization strategies. Here we show that activates TRPM8, cation channel expressed sensory nerve endings serves primary cold sensor mammals. Using combination electrophysiology, Saturation Transfer Triple-Difference (STTD) NMR spectroscopy molecular docking-based targeted mutagenesis, demonstrate directly binds TRPM8. We identify rapamycin-binding site groove voltage sensor-like domain pore domain, distinct sites cooling agents known TRPM8 agonists menthol icilin. Related immunosuppressants act partial agonists, competing with same site. These findings novel provide new insights into mechanisms activation, which may assist development therapies targeting this ion channel. Moreover, our indicate caution needed when using approaches based on study regulation.

Language: Английский

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