Lacosamide at therapeutic concentrations induces histone hyperacetylation in vitro

Granit, Avital; Tetro, Nino; Shmuel, Miri; Peretz, Tamar; Eyal, Sara

doi:10.1002/epi4.12269

Cited by 8 publications

(6 citation statements)

References 18 publications

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“…Levetiracetam does not have intrinsic histone deacetylase inhibitor (HDACI) activity; its major metabolite 2-pyrrolidinone-n-butyric acid (PBA) does, though to a lesser degree than valproic acid [ 40 ]. Lacosamide induces histone hyperacetylation in vitro though it is not a direct inhibitor of HDAC1 [ 41 ]. While HDACIs may have the potential to cause reactivation of chromosomally integrated HHV-6, it seems unlikely that our patient’s antiepileptic medications precipitated such a reactivation [ 42 ].…”

Section: Discussionmentioning

confidence: 99%

Persistent viremia in an immunocompetent patient with inherited chromosomally integrated HHV-6B

Obeid

Gakhal

McDonald

2021

Access Microbiology

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Human herpesvirus-6 (HHV-6), the virus which causes roseola, has traditionally been associated with benign and self-limited childhood illness. However, HHV-6 establishes lifelong latency and can reactivate in immunocompromised adult patients. In about 1% of cases, it integrates into the human genome as inherited chromosomally integrated HHV-6 (iciHHV-6). We report the case of a 70-year-old man presenting with altered mental status and agitation. His infectious workup revealed a cerebrospinal fluid sample positive for HHV-6 with virus detectable in the blood as well. He was subsequently treated with ganciclovir. HHV-6 viremia (DNAemia) persisted, and the antiviral medications were switched to foscarnet under the assumption of treatment failure due to drug resistance. After several admissions to the hospital for the same complaint, and after noticing that DNAemia persisted despite adequate treatment for HHV-6, infectious disease specialists ordered testing for chromosomally integrated virus. Test results confirmed the presence of iciHHV-6, explaining his consistently elevated serum viral load. Primary HHV-6 infection in adults causes a transient increase in viral load with resolution and clearance after a few weeks while iciHHV-6 is characterized by persistent detection of viral DNA at a high copy number. Individuals with iciHHV-6 can develop HHV-6 disease and are at increased risk for active viral replication when treated with immunosuppressive medications, but only mRNA testing, which is not widely available can differentiate between latent and active infection. This makes the decision to treat challenging in this patient population. When faced with a positive HHV-6 DNA result in the setting of equivocal symptoms, clinicians should consider the possibility of chromosomally integrated virus rather than drug-resistant virus in order to reduce exposure to potentially toxic antiviral medications.

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Section: Discussionmentioning

confidence: 99%

Persistent viremia in an immunocompetent patient with inherited chromosomally integrated HHV-6B

Obeid

Gakhal

McDonald

2021

Access Microbiology

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“…For treatment, 10 6 cells were seeded in 10 cm plates, 5 replicate plates per treatment. After 24 h, cells were treated with 10 μM cisplatin alone [the IC50 of cisplatin in MDA-MB-231 cell viability assay was 12 μM ( Wawruszak et al, 2015 )], with 1 mM VPA [the concentration used for inhibition of HDAC and proliferation in MDA-MB-231 cells ( Granit et al, 2018 )], or with their combination for 72 h.…”

Section: Methodsmentioning

confidence: 99%

Metabolomic profiling of triple negative breast cancer cells suggests that valproic acid can enhance the anticancer effect of cisplatin

Granit

Mishra²,

Barasch³

et al. 2022

Front. Cell Dev. Biol.

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Cisplatin is an effective chemotherapeutic agent for treating triple negative breast cancer (TNBC). Nevertheless, cisplatin-resistance might develop during the course of treatment, allegedly by metabolic reprograming, which might influence epigenetic regulation. We hypothesized that the histone deacetylase inhibitor (HDACi) valproic acid (VPA) can counter the cisplatin-induced metabolic changes leading to its resistance. We performed targeted metabolomic and real time PCR analyses on MDA-MB-231 TNBC cells treated with cisplatin, VPA or their combination. 22 (88%) out of the 25 metabolites most significantly modified by the treatments, were acylcarnitines (AC) and three (12%) were phosphatidylcholines (PCs). The most discernible effects were up-modulation of AC by cisplatin and, contrarily, their down-modulation by VPA, which was partial in the VPA-cisplatin combination. Furthermore, the VPA-cisplatin combination increased PCs, sphingomyelins (SM) and hexose levels, as compared to the other treatments. These changes predicted modulation of different metabolic pathways, notably fatty acid degradation, by VPA. Lastly, we also show that the VPA-cisplatin combination increased mRNA levels of the fatty acid oxidation (FAO) promoting enzymes acyl-CoA synthetase long chain family member 1 (ACSL1) and decreased mRNA levels of fatty acid synthase (FASN), which is the rate limiting enzyme of long-chain fatty acid synthesis. In conclusion, VPA supplementation altered lipid metabolism, especially fatty acid oxidation and lipid synthesis, in cisplatin-treated MDA-MB-231 TNBC cells. This metabolic reprogramming might reduce cisplatin resistance. This finding may lead to the discovery of new therapeutic targets, which might reduce side effects and counter drug tolerance in TNBC patients.

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“…4,5 However, the effects of valproate and lacosamide on histone acetylation are mediated by distinct mechanisms. [6][7][8] In a series of in vitro, ex vivo, and in vivo studies, we have consistently demonstrated that the placenta is an important target of antiseizure medications (ASMs). [8][9][10][11][12][13] Specifically, several ASMs are capable of interfering with the expression of placental uptake carriers that mediate the transfer of essential compounds from maternal blood to fetal circulation and of efflux carriers that restrict the distribution of noxious compounds to the fetus.…”

Section: Introductionmentioning

confidence: 99%

“…Lacosamide shares with valproate the ability to induce histone hyperacetylation, which has been suggested as a mechanism of valproate teratogenicity 4,5 . However, the effects of valproate and lacosamide on histone acetylation are mediated by distinct mechanisms 6–8 …”

Section: Introductionmentioning

confidence: 99%

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Lacosamide effects on placental carriers of essential compounds in comparison with valproate: Studies in perfused human placentas

et al. 2022

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Objective Lacosamide is increasingly being prescribed to pregnant women, although its effects on the developing fetus have not been fully clarified yet. Previously, we have shown that several antiseizure medications, particularly valproate, can affect the expression of carriers of essential compounds in placental cells. Here, our aim was to assess the effect of short ex vivo exposure of human placentas to lacosamide on the expression of carriers of essential nutrients required by the human fetus. Methods Placentas were obtained from cesarean deliveries of women with no known epilepsy. Cotyledons were cannulated and perfused over 180 min in the presence of lacosamide at 2.5 μg/ml (10 μmol·L−1, n = 7) or 10 μg/ml (40 μmol·L−1, n = 6), representing low and high therapeutic concentrations, respectively, in the maternal perfusate. Valproate (83 μg/ml, 500 μmol·L−1, n = 6) and the perfusion solution (n = 6) were used as the respective positive and negative controls. A customized gene panel array was used to analyze the expression of carrier genes in the perfused cotyledons. Results Following a 3‐h perfusion, the mRNA expression of SLC19A1 (encoding the reduced folate carrier 1) was downregulated in placentas treated with 10 μg/ml lacosamide (50%) as compared with the vehicle (p < .05). Across all groups, a significant difference was observed in the expression of SLC19A3 (thiamine transporter 2; 52%, 20%, and 9% decrease by 10 μg/ml lacosamide, 83 μg/ml valproate, and 2.5 μg/ml lacosamide, respectively; p < .05). Significance Lacosamide at high therapeutic concentrations exerted pharmacological effects on the human placenta. Our findings, if manifested in vivo, suggest that lacosamide could potentially affect folate supply to the fetus and support therapeutic monitoring and careful adjustment of lacosamide plasma concentrations during pregnancy.

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Lacosamide at therapeutic concentrations induces histone hyperacetylation in vitro

Cited by 8 publications

References 18 publications

Persistent viremia in an immunocompetent patient with inherited chromosomally integrated HHV-6B

Persistent viremia in an immunocompetent patient with inherited chromosomally integrated HHV-6B

Metabolomic profiling of triple negative breast cancer cells suggests that valproic acid can enhance the anticancer effect of cisplatin

Lacosamide effects on placental carriers of essential compounds in comparison with valproate: Studies in perfused human placentas

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