Research on the synergistic effect of a novel apoptosis inducer combined with AKT and HSP90 selective inhibitors on hormone-sensitive and hormone-resistant breast cancer cell lines

One of the frequent malignant tumors affecting women is breast cancer. This tumor develops and occurs due to several internal and external factors. Resistance is a key challenge in modern breast cancer therapy. Novel 1-substituted isatin-5-sulfonamides with antiproliferative effects on the basis of isatin-core-contained antitumor compounds were synthesized in three stages via alkylation with benzyl chlorides. The work aims at the synergistic effect of the obtained 1-substituted isatin-5-sulfonamides exhibiting pro-apoptotic activity and combined with heat shock protein 90 (HSP90) and protein kinase B (AKT) selective inhibitors in breast cancer cell lines, which are sensitive and resistant to antiestrogens. 4-hydroxytamoxifen (HT) was applied to create a resistant cell subline (MCF7/HT); a resistance index amounted to 2. MCF7/p53-LUC cell subline was obtained through transfection using the p53-responsive luciferase reporter plasmid. Lead compound LCTA-3344 exhibited the most significant antiproliferative effect; its half-maximal inhibitory concentration (IC50) on MCF7/HT (1.4±0.1 μМ) was less compared to that on MCF7 (2.6±0.3 μМ). Combinations of apoptosis inducer LCTA-3344 and AKT Inhibitor IV were synergistic on MCF7 and MCF7/HT, demonstrating the combination index (CI) values of 0.8 and 0.4 (a higher activity), respectively. Apoptosis inducer LCTA-3344 combined with AKT Inhibitor X and HSP90 inhibitor did not show such significant activity with a minimal CI value of 0.9. Compound LCTA-3344 did not enhance luciferase activity in MCF7/p53-LUC cell subline, while chemotherapeutic agent doxorubicin has been determined to be its potent inducer. In conclusion, apoptosis inducer LCTA-3344 was 1.9-fold more active toward MCF7/HT in comparison to the parental cell line. Compound LCTA-3344 together with AKT Inhibitor IV was the most active drug combination on the MCF7/HT subline, with a CI of 0.4. Compound LCTA-3344 induced apoptosis through a p53-independent mechanism, which holds promise as a novel therapy for hormone-resistant breast cancers. AKT Inhibitor IV caused apoptosis of MCF7 cells to a greater extent than compound LCTA-3344, and their combination resulted in a synergistic effect.