Epigenetics Involvement in Oxaliplatin-Induced Potassium Channel Transcriptional Downregulation and Hypersensitivity

Pereira, Vanessa; Lamoine, Sylvain; Cuménal, Mélissa; Lolignier, Stéphane; Aissouni, Youssef; Pizzoccaro, Anne; Prival, Laetitia; Balayssac, David; Eschalier, Alain; Bourinet, Emmanuel; Busserolles, Jérôme

doi:10.1007/s12035-021-02361-6

Cited by 12 publications

(15 citation statements)

References 77 publications

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“…Given that TREK channels are known to participate in acute nociception it is possible that the inhibition of TREK channels by treprostinil is responsible for the subcutaneous site pain experienced by PAH patients. This is similar to the acute pain induced by oxaliplatin when used in cancer therapy (Poupon et al, 2018) which is attributable to a down regulation of TREK and TRAAK channels (Pereira et al, 2021). The mean plasma concentration of treprostinil in patients is around 10-20 ng/ml (25-50 nM) which is in the range of the IC 50 s seen here for block of TREK-1 and TREK-2 channels.…”

Section: Attenuation Of Treprostinil Inhibition Of Trek Channelssupporting

confidence: 72%

The Prostacyclin Analogue, Treprostinil, Used in the Treatment of Pulmonary Arterial Hypertension, is a Potent Antagonist of TREK-1 and TREK-2 Potassium Channels

2021

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Pulmonary arterial hypertension (PAH) is an aggressive vascular remodeling disease that carries a high morbidity and mortality rate. Treprostinil (Remodulin) is a stable prostacyclin analogue with potent vasodilatory and anti-proliferative activity, approved by the FDA and WHO as a treatment for PAH. A limitation of this therapy is the severe subcutaneous site pain and other forms of pain experienced by some patients, which can lead to significant non-compliance. TWIK-related potassium channels (TREK-1 and TREK-2) are highly expressed in sensory neurons, where they play a role in regulating sensory neuron excitability. Downregulation, inhibition or mutation of these channels leads to enhanced pain sensitivity. Using whole-cell patch-clamp electrophysiological recordings, we show, for the first time, that treprostinil is a potent antagonist of human TREK-1 and TREK-2 channels but not of TASK-1 channels. An increase in TASK-1 channel current was observed with prolonged incubation, consistent with its therapeutic role in PAH. To investigate treprostinil-induced inhibition of TREK, site-directed mutagenesis of a number of amino acids, identified as important for the action of other regulatory compounds, was carried out. We found that a gain of function mutation of TREK-1 (Y284A) attenuated treprostinil inhibition, while a selective activator of TREK channels, BL-1249, overcame the inhibitory effect of treprostinil. Our data suggests that subcutaneous site pain experienced during treprostinil therapy may result from inhibition of TREK channels near the injection site and that pre-activation of these channels prior to treatment has the potential to alleviate this nociceptive activity.

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Section: Attenuation Of Treprostinil Inhibition Of Trek Channelssupporting

confidence: 72%

The Prostacyclin Analogue, Treprostinil, Used in the Treatment of Pulmonary Arterial Hypertension, is a Potent Antagonist of TREK-1 and TREK-2 Potassium Channels

2021

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“…Of note, while acute OIPN is known as a channelopathy, including transcriptional variation of a variety of ion channels involved in cold and pain perception, only a discrete number of ion channels (GIRK1 and Kv3.3) showed distinct mRNA levels in DRG neurons between OIPN and sham animals at day 21. We previously showed an increase in HDAC3 expression in DRG neurons from mice administered with a single dose of oxaliplatin [ 17 ]. However, in the present work, we failed to observe any transcriptional differences of class I HDACs (HDAC1, HDAC2, and HDAC3) in mice treated with repeated dose of vehicle or oxaliplatin.…”

Section: Resultsmentioning

confidence: 99%

“…Most dysregulated genes encode for ion channels involved in cold and mechanical perception, including members of the transient receptor potential (TRP), the two-pore potassium channels (K2P) and the voltage-dependent potassium (Kv) families. We recently demonstrated that oxaliplatin-mediated downregulation of K + channels of the K2P and Kv families involves a transcription factor known as the neuron-restrictive silencer factor (NRSF), and its epigenetic corepressors, class I histone deacetylases (HDACs) [ 17 ]. Furthermore, the class I HDAC inhibitor, MS-275, exerted a preventive effect against both neuropathy and K + channels downregulation after a single-dose of administered oxaliplatin [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

“…We recently demonstrated that oxaliplatin-mediated downregulation of K + channels of the K2P and Kv families involves a transcription factor known as the neuron-restrictive silencer factor (NRSF), and its epigenetic corepressors, class I histone deacetylases (HDACs) [ 17 ]. Furthermore, the class I HDAC inhibitor, MS-275, exerted a preventive effect against both neuropathy and K + channels downregulation after a single-dose of administered oxaliplatin [ 17 ]. Whether sustained peripheral epigenetic events are involved in OIPN chronicization is not known.…”

Section: Introductionmentioning

confidence: 99%

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The Class I HDAC Inhibitor, MS-275, Prevents Oxaliplatin-Induced Chronic Neuropathy and Potentiates Its Antiproliferative Activity in Mice

Lamoine

Cuménal

Barrière

et al. 2021

IJMS

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Oxaliplatin, the first-line chemotherapeutic agent against colorectal cancer (CRC), induces peripheral neuropathies, which can lead to dose limitation and treatment discontinuation. Downregulation of potassium channels, which involves histone deacetylase (HDAC) activity, has been identified as an important tuner of acute oxaliplatin-induced hypersensitivity. MS-275, a class I histone deacetylase inhibitor (HDACi), prevents acute oxaliplatin-induced peripheral neuropathy (OIPN). Moreover, MS-275 exerts anti-tumor activity in several types of cancers, including CRC. We thus hypothesized that MS-275 could exert both a preventive effect against OIPN and potentially a synergistic effect combined with oxaliplatin against CRC development. We first used RNAseq to assess transcriptional changes occurring in DRG neurons from mice treated by repeated injection of oxaliplatin. Moreover, we assessed the effects of MS-275 on chronic oxaliplatin-induced peripheral neuropathy development in vivo on APCMin/+ mice and on cancer progression when combined with oxaliplatin, both in vivo on APCMin/+ mice and in a mouse model of an orthotopic allograft of the CT26 cell line as well as in vitro in T84 and HT29 human CRC cell lines. We found 741 differentially expressed genes (DEGs) between oxaliplatin- and vehicle-treated animals. While acute OIPN is known as a channelopathy involving HDAC activity, chronic OIPN exerts weak ion channel transcriptional changes and no HDAC expression changes in peripheral neurons from OIPN mice. However, MS-275 prevents the development of sensory neuropathic symptoms induced by repeated oxaliplatin administration in APCMin/+ mice. Moreover, combined with oxaliplatin, MS-275 also exerts synergistic antiproliferative and increased survival effects in CT26-bearing mice. Consistently, combined drug associations exert synergic apoptotic and cell death effects in both T84 and HT29 human CRC cell lines. Our results strongly suggest combining oxaliplatin and MS-275 administration in CRC patients in order to potentiate the antiproliferative action of chemotherapy, while preventing its neurotoxic effect.

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“…Among them, studies suggested that OXP induces a hyperexcitability of primary sensory neurons related to a dysregulation or variation of the expression of ion channels involved in mechanical and cold sensitivity ( Grolleau et al, 2001 ; Park et al, 2009 ; Park et al, 2011 ; Kawashiri et al, 2012 ). More particularly, others recently reported that OIAS was associated with a downregulation of K + channels in the DRG, following a single dose of OXP ( Pereira et al, 2021 ). Another mechanism of OIAS is the generation of oxidative stress at the spinal level.…”

Section: Discussionmentioning

confidence: 99%

Ramipril Alleviates Oxaliplatin-Induced Acute Pain Syndrome in Mice

et al. 2021

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Oxaliplatin is a key drug for colorectal cancer that causes OXP-induced peripheral neuropathy, a dose-limiting effect characterized by cold and tactile hyperesthesia. The relationship between the sensory nervous system and modulation of the renin-angiotensin system has been described, focusing on pain and neurodegeneration in several animal models. We assessed the effect of the RAS modulator, ramipril, an angiotensin converting-enzyme inhibitor in a mouse model of OXP-induced acute pain syndrome. OXP was administered in Swiss mice at a cumulative dose of 15 mg/kg (3 x 5 mg/kg/3 days, i.p.). RAM was administered i.p. every day from 24 h before the first OXP injection until the end of the experiments. We evaluated OIAS development and treatment effects by sensorimotor tests, intraepidermal nerve fiber and dorsal root ganglia-neuron immunohistochemical analyses, and sciatic nerve ultrastructural analysis. OXP-treated mice showed tactile allodynia and cold hypersensitivity, without motor impairment and evidence of nerve degeneration. RAM prevented cold sensitivity and improved recovery of normal tactile sensitivity in OXP-treated mice. Our finding that RAM alleviates OXP-induced pain is a step towards evaluating its therapeutic potential in patients receiving OXP treatment.

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Epigenetics Involvement in Oxaliplatin-Induced Potassium Channel Transcriptional Downregulation and Hypersensitivity

Cited by 12 publications

References 77 publications

The Prostacyclin Analogue, Treprostinil, Used in the Treatment of Pulmonary Arterial Hypertension, is a Potent Antagonist of TREK-1 and TREK-2 Potassium Channels

The Prostacyclin Analogue, Treprostinil, Used in the Treatment of Pulmonary Arterial Hypertension, is a Potent Antagonist of TREK-1 and TREK-2 Potassium Channels

The Class I HDAC Inhibitor, MS-275, Prevents Oxaliplatin-Induced Chronic Neuropathy and Potentiates Its Antiproliferative Activity in Mice

Ramipril Alleviates Oxaliplatin-Induced Acute Pain Syndrome in Mice

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