Role of gamma radiation on functional expression of the voltage-gated potassium channel Kv10.1 and its importance in the radiobiological response

Luis, Enoch; Figueroa, César Oliver Lara; Pastén, María Luisa Durán; Vega, Erika Patricia Azorín

doi:10.1016/j.apradiso.2022.110331

Cited by 4 publications

(5 citation statements)

References 25 publications

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“…As shown in this translational clinical trial, 177 Lu-iPSMA and 177 Lu-DOTATOC significantly reduce cancer pain. Thus, modern radiobiology suggests that the mechanism that drives pain relief is the reduction on ionic flux through the functional expression of voltage-gated ion channels, generating a radiation-induced nerve rearrangement [ 28 ].…”

Section: Discussionmentioning

confidence: 99%

Improving Overall Survival and Quality of Life in Patients with Prostate Cancer and Neuroendocrine Tumors Using 177Lu-iPSMA and 177Lu-DOTATOC: Experience after 905 Treatment Doses

et al. 2023

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177Lu-iPSMA is a novel radioligand developed at ININ-Mexico with a high affinity for the PSMA protein heavily expressed in cancer cells of approximately 95% of patients with metastatic castration-resistant prostate cancer (mCRPC). 177Lu-DOTATOC is a patent-free radioligand, molecularly recognized by somatostatin receptors (SSTR-2) overexpressed in cancer cells of about 80% of patients with metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NET). This translational research aimed to determine the efficacy and safety of 177Lu-iPSMA and 177Lu-DOTATOC developed as GMP pharmaceutical formulations for treating progressive and advanced mCRPC and NET. One hundred and forty-five patients with mCRPC and one hundred and eighty-seven subjects with progressive NET (83% GEP-NET and 17% other NET), treated with 177Lu-iPSMA and 177Lu-DOTATOC, respectively, were evaluated. Patients received a mean dose of 7.4 GBq per administration of 177Lu-iPSMA (range 1–5 administrations; 394 treatment doses) or 177Lu-DOTATOC (range 2–8 administrations; 511 treatment doses) at intervals of 1.5–2.5 months. Efficacy was assessed by SPECT/CT or PET/CT. Results were stratified by primary tumor origin and number of doses administered. Patients with mCRPC showed overall survival (OS) of 21.7 months with decreased radiotracer tumor uptake (SUV) and PSA level in 80% and 73% of patients, respectively. In addition, a significant reduction in pain (numerical scale from 10–7 to 3–1) was observed in 88% of patients with bone metastases between one and two weeks after the second injection. In the GEP-NET population, the median progression-free survival was 34.7 months, with an OS of >44.2 months. The treatments were well tolerated. Only ten patients experienced grade ≥ 3 myelosuppression (3% of all patients). The observed safety profiles and favorable therapeutic responses demonstrated the potential of 177Lu-iPSMA and 177Lu-DOTATOC to improve overall survival and quality of life in patients with progressive and advanced mCRPC and NET.

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Section: Discussionmentioning

confidence: 99%

Improving Overall Survival and Quality of Life in Patients with Prostate Cancer and Neuroendocrine Tumors Using 177Lu-iPSMA and 177Lu-DOTATOC: Experience after 905 Treatment Doses

et al. 2023

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“…In glioblastoma, down-regulation of miR-296-3p increased Kv10.1expression [ 54 ]; interestingly, miRNA’s expression could be associated with multi-drug resistance, probably through regulating Kv10.1 [ 54 ]. Similarly, it has been observed that Kv10.1 expression seems to confer a radioresistant phenotype [ 55 ].…”

Section: The Voltage-gated Potassium Channel Kv101mentioning

confidence: 93%

“…Survival curves showed HEK-Kv10.1 cells remained unchanged after irradiation. In contrast, the survival curve of HEK-WT cells dramatically decreased with a 4 Gy radiation, suggesting that the expression of Kv10.1 confers to cells a radioresistant phenotype [ 55 ].…”

Section: The Voltage-gated Potassium Channel Kv101mentioning

confidence: 99%

“…As we have seen, Kv10.1 transcription is regulated by factors implicated in cell cycle progression (most of them converging in E2F1); moreover, Kv10.1-pharmacological inhibition reduces cell proliferation rate in cells where it is overexpressed, suggesting Kv10.1 is temporally regulated. The first indication of this phenomenon was that Kv10.1-permeability and -expression level depends on the cell cycle [ 55 ]. Recently, it was demonstrated that E2F1, which controls Kv10.1, would be expressed just during a short period in the cell cycle and not constitutively as had been thought for many years.…”

Section: Hallmarks Of Cancer and Kv101 Expressionmentioning

confidence: 99%

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The Kv10.1 Channel: A Promising Target in Cancer

Luis

Anaya-Hernández

León-Sánchez

et al. 2022

IJMS

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Carcinogenesis is a multistage process involving the dysregulation of multiple genes, proteins, and pathways that make any normal cell acquire a cancer cell phenotype. Therefore, it is no surprise that numerous ion channels could be involved in this process. Since their discovery and subsequent cloning, ion channels have been established as therapeutic targets in excitable cell pathologies (e.g., cardiac arrhythmias or epilepsy); however, their involvement in non-excitable cell pathologies is relatively recent. Among all ion channels, the voltage-gated potassium channels Kv10.1 have been established as a promising target in cancer treatment due to their high expression in tumoral tissues compared to low levels in healthy tissues.

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“…Diverse authors have shown an overexpression of Kv10.1 in cancer samples, contrasting with a low expression in healthy tissues ( Farias et al, 2004 ; Hemmerlein et al, 2006 ; Ortiz et al, 2011 ; Martínez et al, 2015 ; Luis et al, 2022a ). Also, it has been described that Kv10.1 overexpression is associated with increased cell proliferation, angiogenesis, and chemo- and radio-resistance phenotype ( Pardo et al, 1999 ; Downie et al, 2008 ; Bai et al, 2013 ; Luis et al, 2022b ). Notably, Kv10.1 knock-out mice show no behavioral abnormalities, suggesting that side effects due to the Kv10.1-blocking can be insignificant.…”

Section: Introductionmentioning

confidence: 99%

Fluorescent membrane potential assay for drug screening on Kv10.1 channel: identification of BL-1249 as a channel activator

Gómez-Herrera,

Patlán,

Estrada-Garrido

et al. 2023

Front. Pharmacol.

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Resting membrane potential is a bioelectric property of all cells. Multiple players govern this property, the ion channels being the most important. Ion channel dysfunction can affect cells’ resting membrane potential and could be associated with numerous diseases. Therefore, the drug discovery focus on ion channels has increased yearly. In addition to patch-clamp, cell-based fluorescent assays have shown a rapid and reliable method for searching new ion channel modulators. Here, we used a cell-based membrane potential assay to search for new blockers of the Kv10.1, a potassium channel strongly associated with cancer progression and a promising target in anticancer therapy. We found that fluoxetine and miconazole can inhibit the Kv10.1 channel in the micromolar range. In contrast, BL-1249 potentiates Kv10.1 currents in a dose-dependent manner, becoming the first molecule described as an activator of the channel. These results demonstrate that cell-based membrane potential assay can accelerate the discovery of new Kv10.1 modulators.

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Role of gamma radiation on functional expression of the voltage-gated potassium channel Kv10.1 and its importance in the radiobiological response

Cited by 4 publications

References 25 publications

Improving Overall Survival and Quality of Life in Patients with Prostate Cancer and Neuroendocrine Tumors Using 177Lu-iPSMA and 177Lu-DOTATOC: Experience after 905 Treatment Doses

Improving Overall Survival and Quality of Life in Patients with Prostate Cancer and Neuroendocrine Tumors Using 177Lu-iPSMA and 177Lu-DOTATOC: Experience after 905 Treatment Doses

The Kv10.1 Channel: A Promising Target in Cancer

Fluorescent membrane potential assay for drug screening on Kv10.1 channel: identification of BL-1249 as a channel activator

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