52P Novel inhibitors of androgen receptor with antiproliferative potency against hormone-sensitive and hormone-resistant breast cancer cells

Abstract

The growth of most breast cancers depends on estrogens. The hormone therapy is aimed at reducing the effect of estrogens and their receptors on tumor cells and suppressing the rate of tumor growth. The androgen receptor, another steroid receptor, is a novel potential target in breast cancer cells. The work aims to develop selective androgen receptor inhibitors with proapoptotic activity. A series of 1-substituted isatine-5-sulfonamides was synthesized applying Sandmeyer’s methodology and subsequent alkylation of the heterocycle moiety by various benzyl chlorides. The hormone-dependent MCF7 breast cancer cell line was purchased from ATCC. Antiproliferative activity was assessed by the MTT test. The hormone-resistant MCF7/HT subline was obtained by long-term cultivation of MCF7 cells with the active form of tamoxifen, 4-hydroxytamoxifen (HT). Analysis of the antiproliferative activity of the prepared series of new 1-substituted isatin-5-sulfonamides revealed several compounds with low micromolar IC50 values. Compound LCTA-3344 was more active than the reference drug, well-known apoptosis activator 2 (N-(3,4-dichlorobenzyl)isatine). It was determined that isatin-5-sulfonamide LCTA-3344 at micromolar concentrations induces BCL2-dependent apoptosis in MCF7 cells. Moreover, compound LCTA-3344 significantly blocked androgen receptor signaling. Isatin-5-sulfonamide LCTA-3344 in concentrations from 1 to 50 μM caused suppression of the growth of hormone-resistant cell subline MCF7/HT, the IC50 value was 1.4 μM. Interestingly, the hormone-resistant cells did not lose their sensitivity to LCTA-3344 and were more susceptible compared to the parent MCF7 line, for which the IC50 value was 2.6 μM. Thus, a series 1-substituted isatin-5-sulfonamides with high activity against hormone-sensitive breast cancer cells was obtained. The compound LCTA-3344 exhibiting antiproliferative effects against both hormone-sensitive and hormone-resistant breast cancer cells induced apoptosis and significantly inhibited the activity of the androgen receptor. Further in-depth investigation of the anticancer properties of LCTA-3344 is in development.