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.