Histone deacetylase inhibitors (HDIs) are promising anticancer drugs, which inhibit proliferation of a wide variety of cancer cells including breast carcinoma cells. In the present study, we investigated the influence of valproic acid (VPA) and suberoylanilide hydroxamic acid (SAHA, vorinostat), alone or in combination with cisplatin (CDDP) on proliferation, induction of apoptosis and cell cycle progression in MCF7, T47D and MDA-MB-231 human breast carcinoma cell lines. The type of interaction between HDIs and CDDP was determined by an isobolographic analysis. The isobolographic analysis is a very precise and rigorous pharmacodynamic method, to determine the presence of synergism, addition or antagonism between different drugs with using variety of fixed dose ratios. Our experiments show that the combinations of CDDP with SAHA or VPA at a fixed-ratio of 1:1 exerted additive interaction in the viability of MCF7 cells, while in T47D cells there was a tendency to synergy. In contrast, sub-additive (antagonistic) interaction was observed for the combination of CDDP with VPA in MDA-MB-231 “triple-negative” (i.e. estrogen receptor negative, progesterone receptor negative, and HER-2 negative) human breast cancer cells, whereas combination of CDDP with SAHA in the same MDA-MB-231 cell line yielded additive interaction. Additionally, combined HDIs/CDDP treatment resulted in increase in apoptosis and cell cycle arrest in all tested breast cancer cell lines in comparison with a single therapy. In conclusion, the additive interaction of CDDP with SAHA or VPA suggests that HDIs could be combined with CDDP in order to optimize treatment regimen in some human breast cancers.

Summary: Purpose:The study investigated the types of interactions between lamotrigine (LTG) and first-generation antiepileptic drugs (AEDs) or topiramate (TPM) with isobolographic analysis.Methods: Anticonvulsant and adverse-effect profiles of combinations of LTG with other AEDs, at fixed ratios of 1:3, 1:1, and 3:1, were evaluated in the maximal electroshock (MES)-induced seizures and the chimney test (motor performance) in mice, which allowed the determination of benefit indices (BIs) for individual combinations.Results: Combinations of LTG with TPM or valproate (VPA), at fixed ratios of 1:1, were significantly supraadditive (synergistic) in the MES test and, simultaneously, subadditive (antagonistic) in the chimney test, showing the best profile for AED combinations. In contrast, combinations between LTG and carbamazepine (CBZ), in terms of antiseizure protection against MES, were subadditive (antagonistic) and additive in the chimney test, resulting in unfavorable AED combinations. Moreover, the combination of LTG with phenobarbital (PB), at a fixed ratio of 1:1, despite synergy in the MES test, also was synergistic in the chimney test, resulting in a modest BI for AED combination. LTG combined with phenytoin was additive in both the MES and chimney tests in mice. The remaining combinations, at fixed ratios not mentioned earlier, also showed an average BI for AED combinations. Furthermore, LTG combined with all studied AEDs did not affect long-term memory in mice. None of the AEDs influenced the free plasma level of LTG, whereas LTG slightly reduced the free plasma concentration of PB.Conclusions: Interactions between LTG and TPM or LTG and VPA at a fixed ratio of 1:1 might be profitable from a preclinical point of view, displaying the most optimal BI.

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The objective of this study was to characterize the anticonvulsant and acute adverse-effect potentials of topiramate (TPM) and gabapentin (GBP)-two second-generation antiepileptic drugs administered alone and in combination in the maximal electroshock (MES)-induced seizures and chimney test in mice. The anticonvulsant and acute adverse effects of the combination of TPM with GBP at the fixed ratio of 1:1 were determined using the type I isobolographic analysis for nonparallel dose-response relationship curves (DRRCs). To ascertain any pharmacokinetic contribution to the observed interaction between TPM and GBP, total brain concentrations of both drugs were determined. The isobolographic analysis of interaction for TPM and GBP, whose DRRCs were not parallel in both MES and chimney tests, was accompanied with a presentation of all required calculations allowing the determination of lower and upper lines of additivity. The isobolographic analysis revealed that TPM combined with GBP at the fixed-ratio combination of 1:1 interacted supraadditively (synergistically) in terms of suppression of MES-induced seizures, and simultaneously, the combination produced additive interaction with respect to motor coordination impairment (adverse effects) in the chimney test. The evaluation of pharmacokinetic characteristics of interaction for the combination of TPM with GBP revealed that neither TPM nor GBP affected their total brain concentrations in experimental animals, and thus, the observed interaction in the MES test was pharmacodynamic in nature. In conclusion, the combination of TPM with GBP, because of supraadditivity in the MES test and additivity in terms of motor coordination impairment in the chimney test as well as lack of pharmacokinetic interactions between drugs, fulfilled the criterion of a favorable combination, worthy of recommendation in further clinical practice.