Abstract P6-11-13: In vitro antineoplastic evaluation of rationally designed naphtoquinone-derived drugs in triple-negative breast cancer cell line

Abstract

Abstract Background: Breast cancer (BC) comprises multiple diseases harboring different genetic alterations, which subtypes respond differently to treatment, and are associated to distinct clinical outcomes. Likewise, triple negative breast cancer (TNBCs) are a heterogeneous subgroup of BC, immunophenotypically negative for estrogen and progesterone receptor, and HER2, that account for 10–15% of all invasive BC, affecting mostly African-American and Hispanic pre-menopausal women. Considering that TNBC have poor prognosis, and cannot be effectively treated with current targeted therapies, the discovery of new treatment options is imperative. Methods: Novel naphtoquinone-derived drugs were rationally designed to act through multiple pathways aiming the avoidance of drug-resistant phenotype acquisition by tumor cells, and were synthesized following high efficiency and low cost method. Drugs antineoplastic efficacy (AE) was accessed in claudin-low TNBC cell line, MDA-MB-231, through the evaluation of cellular metabolic viability (CMV) (MTT method). Drugs structures are protected by patent. Cells were cultured in RPMI media supplemented with 10% (v/v) FBS and antibiotics until subconfluence; then, 1.5×105 cells/well were subcultured for 72h prior to treatment with drugs (10−4, 10−5, 10−6, 10−7, and 10−8 M). After 24h, CMV was assessed. Experiments in which the lineage was treated with cisplatin, doxorubicin or paclitaxel were run in parallel. The mean and standard-deviation of the absorbancies were used to calculate CMV and drugs IC50 (PrismaGraphPad version 5.1). Findings: We screened the AE of 43 novel naftoquinones-derived drugs in MDA-MB-231 lineage; seven have decreased its CMV by, at least, 50%, as: PIC1 (IC50 1.15×10−4M; CMV decrease of 50%); PIC6 (IC50 4.24×10−5M; CMV decrease of 70%); PIC10 (IC50 5.07×10−5M; CMV decrease of 70%); PIC 20 (IC50 1.38×10−5M; CMV decrease of 90%); PIC21 (IC50 5.00×10−5M; CMV decrease of 70%); S5 (IC50 7.26×10−5M; CMV decrease of 60%); M20 (IC50 7.94×10−5M; CMV decrease of 60%). Their AE was significantly higher than that of cisplatin (IC50 1.56×10−4M; CMV decrease < 10%), doxorubicin (IC50 1.76×10−4M; CMV decrease of 38%), and paclitaxel (IC50 5.05×10−7M; CMV decrease of 20%). Interpretation: Altogether, our results present potential novel antineoplastic drugs to treat TNBC from a panel of in house rationally designed naftoquinones-derived compounds, developing an innovative and economically viable project. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-11-13.