Aconitine-Containing Agent Enhances Antitumor Activity of Dichloroacetate Against Ehrlich Carcinoma

Abstract

Significant variability of anticancer efficacy of dichloroacetate (DCA) stimulated an active search for the agents capable to enhance it antitumor action. Therefore, the aim of this work is the study of capability of aconitine-containing antiangiogenic agent BC1 to enhance anticancer activity of DCA against Ehrlich carcinoma. Materials and Methods: DCA (total dose was 1.3 g/kg of b.w.) and BC1 (total dose was 0.9 mg/kg of b.w.) were administered per os starting from the 2nd and 3rd days, respectively (8 admini strations for each agent). Antitumor efficacy of agents was estimated. Lactate level, LDH activity and the state of mitochondrial electron transport chain in tumor cells as well as phagocytic activity and reactive oxygen species (ROS) production of tumor-associated macrophages (TAM) were studied. Results: Combined administration of DCA and ВС1 resulted in 89.8% tumor growth inhibition (p < 0.001), what is by 22.5% (p < 0.05) higher that that of DCA alone. This combined treatment was accompanied with a decrease of lactate level in tumor tissue by 30% (p < 0.05) and significant elevation of LDH activity by 70% (p < 0.01). Increased level of NO-Fe-S clusters and 2-fold reduction of Fe-S cluster content were revealed in tumor tissue of mice after DCA and BC1 administration. It was shown that combined therapy did not effect TAM quantity and their phagocytic activity but stimulated ROS production by TAMs by 78% (p < 0.05) compared to this index in control animals. Conclusion: Antiangiogenic agent ВС1 in combination with DCA considerably enhances antitumor activity of DCA via significant decrease of Fe-S-containing protein level resulted from substantial elevation of nitrosylation of these proteins.

Fe‐S Clusters Emerging as Targets of Therapeutic Drugs

“…Consequently, the Fe-S center of NADH dehydrogenase 3 from respiratory complex I is degraded, leading to significant suppression of mitochondrial respiration, which is at least partially responsible for PEITC anticancer activity. Also, combined treatment by dichloroacetate and aconitine-containing antiangiogenic agent BC1 proved significant antitumor activity against Ehrlich carcinoma [ 49 ]. Using this combination, substantial nitrosylation of Fe-S proteins was obtained.…”

A Comprehensive In Silico Method to Study the QSTR of the Aconitine Alkaloids for Designing Novel Drugs

“…Its application to disease conditions proved to exhibit an activity that slowed down cancer tumor growth and to cure serious cases of dermatosis. It was also found to have an effect on postoperative analgesia [ 9 , 10 , 11 , 12 ]. However, a previous safety study has revealed that aconitine toxicity is responsible for its restriction in clinical settings.…”

“…A combined network analysis and in silico study was once performed to obtain insight on the relationship between aconitine alkaloid toxicity and the aconitine structure, and it was found that the cardiotoxicity of aconitine is the primary cause of patient death. The aconitine poison is similar to the poison created by some pivotal proteins such as the ryanodine receptor (RYR1 and RYR2), the Gap junction α-1 protein (GJA1), and the sodium–calcium exchanger (SLC8A1) [ 9 , 10 , 11 , 12 ]. However, among all existing studies about the aconitine medicinal, no one has reported detail of its specific binding target protein linked to toxicity.…”