New TRPM8 blockers exert anticancer activity over castration-resistant prostate cancer models

Sarno, Veronica Di; Giovannelli, Pia; Medina-Peris, Alicia; Ciaglia, Tania; Donato, Marzia Di; Musella, Simona; Lauro, Gianluigi; Vestuto, Vincenzo; Smaldone, Gerardina; Matteo, Francesca Di; Bifulco, Giuseppe; Castoria, Gabriella; Migliaccio, Antimo; Fernández-Carvajal, Asia; Campiglia, Pietro; Gómez-Monterrey, Isabel; Ostacolo, Carmine; Bertamino, Alessia

doi:10.1016/j.ejmech.2022.114435

Cited by 12 publications

(9 citation statements)

References 48 publications

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“…The chemical synthesis of compounds CPK1 , 4 , 6 , 9 , 11 – 17 , 19 , and 20 has been previously described, − as also reported in Table S1. The remaining compounds have been synthesized as reported below.…”

Section: Results and Discussionmentioning

confidence: 99%

In Silico Assisted Identification, Synthesis, and In Vitro Pharmacological Characterization of Potent and Selective Blockers of the Epilepsy-Associated KCNT1 Channel

Iraci,

Carotenuto,

Ciaglia

et al. 2024

J. Med. Chem.

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Gain-of-function (GoF) variants in KCNT1 channels cause severe, drug-resistant forms of epilepsy. Quinidine is a known KCNT1 blocker, but its clinical use is limited due to severe drawbacks. To identify novel KCNT1 blockers, a homology model of human KCNT1 was built and used to screen an in-house library of compounds. Among the 20 molecules selected, five (CPK4, 13, 16, 18, and 20) showed strong KCNT1-blocking ability in an in vitro fluorescence-based assay. Patch-clamp experiments confirmed a higher KCNT1-blocking potency of these compounds when compared to quinidine, and their selectivity for KCNT1 over hERG and Kv7.2 channels. Among identified molecules, CPK20 displayed the highest metabolic stability; this compound also blocked KCNT2 currents, although with a lower potency, and counteracted GoF effects prompted by 2 recurrent epilepsy-causing KCNT1 variants (G288S and A934T). The present results provide solid rational basis for future design of novel compounds to counteract KCNT1-related neurological disorders.

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Section: Results and Discussionmentioning

confidence: 99%

In Silico Assisted Identification, Synthesis, and In Vitro Pharmacological Characterization of Potent and Selective Blockers of the Epilepsy-Associated KCNT1 Channel

Iraci,

Carotenuto,

Ciaglia

et al. 2024

J. Med. Chem.

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“…A proof-of-concept for future precision was recently demonstrated in some studies, where the teams used a Transient Receptor Potential Melastatin 8 channel (TRPM8) agonist, an ion channel in the plasma membrane, encapsulated into a Lipid NanoCapsule in order to inhibit PCa cell migration. The use of TRPM8 has a great impact in castration-resistant prostate cancer, which is considered to be the most aggressive form of PCa, because it is usually resistant to androgen deprivation therapy [ 11 , 12 ]. However, it is clear that over time a high index of body mass will influence our general physical well-being, along with age and other factors, and can lead to negative results in cases of pathologies, such as cancers.…”

Section: Discussionmentioning

confidence: 99%

Associations between Body Mass Index and Prostate Cancer: The Impact on Progression-Free Survival

et al. 2023

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Background and objectives: This study aimed to evaluate the impact of body mass index on PCa outcomes in our institution and also to find if there are statistically significant differences between the variables. Materials and Methods: A retrospective chart review was performed to extract information about all male patients with prostate cancer between 1 February 2015, and 25 October 2022, and with information about age, weight, height, follow-up, and PSA. We identified a group of 728 patients, of which a total of 219 patients resulted after the inclusion and exclusion criteria were applied. The primary endpoint was progression-free survival, which was defined as the length of time that the patient lives with the disease, but no relapses occur, and this group included 105 patients. In this case, 114 patients had a biological, local or metastatic relapse and were included in the progression group. Results: Our study suggests that prostate cancer incidence rises with age (72 ± 7.81 years) in men with a normal BMI, but the diagnostic age tends to drop in those with higher BMIs, i.e., overweight, and obese in the age range of 69.47 ± 6.31 years, respectively, 69.1 ± 7.51 years. A statistically significant difference was observed in the progression group of de novo metastases versus the absent metastases group at diagnostic (p = 0.04). The progression group with metastases present (n = 70) at diagnostic had a shorter time to progression, compared to the absent metastases group (n = 44), 18.04 ± 11.37 months, respectively, 23.95 ± 16.39 months. Also, PSA levels tend to diminish with increasing BMI classification, but no statistically significant difference was observed. Conclusions: The median diagnostic age decreases with increasing BMI category. Overweight and obese patients are more likely to have an advanced or metastatic prostate cancer at diagnosis. The progression group with metastatic disease at diagnostic had a shorter time to progression, compared to the absent metastases group. Regarding prostate serum antigen, the levels tend to become lower in the higher BMI groups, possibly leading to a late diagnosis.

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“…This model is usually resistant to deprivation of androgen therapy (ADT) and is considered the most aggressive form of PCa. No effects were detected in PCa cells devoid of the AR receptor ( 202 , 203 ). These TRPM8 antagonists interfere with AR/TRPM8 crosstalk by a non-genomic mechanism abolishing the AR/TRPM8 complex assembly, and counteracting the increase in intracellular Ca 2+ levels.…”

Section: Trpm Channels: Characteristics and Functionsmentioning

confidence: 97%

On the modulation of TRPM channels: Current perspectives and anticancer therapeutic implications

et al. 2023

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The transient melastatin receptor potential (TRPM) ion channel subfamily functions as cellular sensors and transducers of critical biological signal pathways by regulating ion homeostasis. Some members of TRPM have been cloned from cancerous tissues, and their abnormal expressions in various solid malignancies have been correlated with cancer cell growth, survival, or death. Recent evidence also highlights the mechanisms underlying the role of TRPMs in tumor epithelial-mesenchymal transition (EMT), autophagy, and cancer metabolic reprogramming. These implications support TRPM channels as potential molecular targets and their modulation as an innovative therapeutic approach against cancer. Here, we discuss the general characteristics of the different TRPMs, focusing on current knowledge about the connection between TRPM channels and critical features of cancer. We also cover TRPM modulators used as pharmaceutical tools in biological trials and an indication of the only clinical trial with a TRPM modulator about cancer. To conclude, the authors describe the prospects for TRPM channels in oncology.

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New TRPM8 blockers exert anticancer activity over castration-resistant prostate cancer models

Cited by 12 publications

References 48 publications

In Silico Assisted Identification, Synthesis, and In Vitro Pharmacological Characterization of Potent and Selective Blockers of the Epilepsy-Associated KCNT1 Channel

In Silico Assisted Identification, Synthesis, and In Vitro Pharmacological Characterization of Potent and Selective Blockers of the Epilepsy-Associated KCNT1 Channel

Associations between Body Mass Index and Prostate Cancer: The Impact on Progression-Free Survival

On the modulation of TRPM channels: Current perspectives and anticancer therapeutic implications

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