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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.

The distribution and structure of heparan sulfate and heparin are briefly reviewed. Heparan sulfate is a ubiquitous compound of animal cells whose structure has been maintained throughout evolution, showing an enormous variability regarding the relative amounts of its disaccharide units. Heparin, on the other hand, is present only in a few tissues and species of the animal kingdom and in the form of granules inside organelles in the cytoplasm of special cells. Thus, the distribution as well as the main structural features of the molecule, including its main disaccharide unit, have been maintained through evolution. These and other studies led to the proposal that heparan sulfate may be involved in the cell-cell recognition phenomena and control of cell growth, whereas heparin may be involved in defense mechanisms against bacteria and other foreign materials. All indications obtained thus far suggest that these molecules perform the same functions in vertebrates and invertebrates. Universidade Federal de São Paulo (UNIFESP) A02 Universidade Federal do Rio Grande do Norte Universidade de Mogi das Cruzes UNIFESP, EPM SciELO