Successful treatment of excessive dose of carbamazepine

Metastatic breast cancer is linked to an undesired prognosis. One early and crucial metastatic step is the interaction of cancer emboli with adjacent stroma or endothelial cells, and understanding the mechanisms of this interaction provides the basis to define new targets as well as drugs for therapy and disease management. A three-dimensional (3D) co-culture model allowing the examination of lymphogenic dissemination of breast cancer cells was recently developed which facilitates not only the study of metastatic processes but also the testing of therapeutic concepts. This 3D setting consists of MCF-7 breast cancer cell spheroids (representing a ductal and hormone-dependent subtype) and of hTERT-immortalised lymph endothelial cell (LEC; derived from foreskin) monolayers. Tumour spheroids repel the continuous LEC layer, thereby generating "circular chemorepellent-induced defects" (CCIDs) that are reminiscent to the entry gates through which tumour emboli intravasate lymphatics. We found that the ion channel blocker carbamazepine (which is clinically used to treat epilepsy, schizophrenia and other neurological disorders) inhibited CCID formation significantly. This effect correlated with the inhibition of the activities of NF-κB, which contributes to cell motility, and with the inactivation of the mobility proteins MLC2, MYPT1 and FAK which are necessary for LEC migration. NF-κB activity and cell movement are prerequisites of CCID formation. On the other hand, the expression of the motility protein paxillin and of the NF-κB-dependent adhesion mediator ICAM-1 was unchanged. Also the activity of ALOX12 was unaffected. ALOX12 is the main enzyme synthesising 12(S)-HETE, which then triggers CCID formation. The relevance of the inhibition of CYP1A1, which is also involved in the generation of mid-chain HETEs such as 12(S)-HETE, by carbamazepine remains to be established, because the constitutive level of 12(S)-HETE did not change upon carbamazepine treatment. Nevertheless, the effect of carbamazepine on the inhibition of CCID formation as an early step of breast cancer metastasis was significant and substantial (~30 %) and achieved at concentrations that are found in the plasma of carbamazepine-treated adults (40-60 μM). The fact that carbamazepine is a drug approved by the US Food and Drug Administration facilitates a "from-bench-to-bedside" perspective. Therefore, the here presented data should undergo scrutiny in vivo.

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Inhibition of tumour spheroid-induced prometastatic intravasation gates in the lymph endothelial cell barrier by carbamazepine: drug testing in a 3D model

Teichmann

Kretschy

Köpf

et al. 2013

Arch Toxicol

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Nano optical and electrochemical sensors and biosensors for detection of narrow therapeutic index drugs

et al. 2021

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Overdose of carbamazepine before hanging by a child: a case report of a complex suicide

Vadysinghe

Thilakarathne

2018

Egypt J Forensic Sci

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Background: Compared to death by hanging, fatal cases due to carbamazapine intake is hardly seen. We are reporting a rare case where the victim had used this combination to terminate life as a complex suicide. Case presentation: The deceased was a 16-year-old school girl, who had been on carbamazepine for 10 years for epilepsy. Following a heated argument with her family members, who had disapproved of her love affair, the victim was found hanging from a rafter in her bedroom, with a plume of froth coming from both nostrils and mouth. A complete death investigation, including scene investigation and complete autopsy examination, was carried out. Her stomach contained pieces of tablets which were later confirmed to be carbamazepine, which was also seen in fatal levels in the blood. The cause of death was confirmed as hanging, in a patient who had ingested a massive dose of carbamazepine. The manner of death was suicide and more towards planned complex type. Conclusion: The value of toxicological analysis should not be underestimated even in cases of hanging. This case further highlights the responsibility cast upon the guardians of children diagnosed with chronic diseases like epilepsy, where stressful situations need to be handled in a tactful manner, to avoid catastrophic consequences.

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Successful treatment of excessive dose of carbamazepine

Cited by 8 publications

References 9 publications

Inhibition of tumour spheroid-induced prometastatic intravasation gates in the lymph endothelial cell barrier by carbamazepine: drug testing in a 3D model

Inhibition of tumour spheroid-induced prometastatic intravasation gates in the lymph endothelial cell barrier by carbamazepine: drug testing in a 3D model

Nano optical and electrochemical sensors and biosensors for detection of narrow therapeutic index drugs

Overdose of carbamazepine before hanging by a child: a case report of a complex suicide

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