Background: Cancer development has been associated with alterations in polyamine biosynthesis and metabolism, which induce cell proliferation, angiogenesis, expression of genes related to tumor invasion and metastasis; whereas inhibit apoptosis. Based on the strong rational to develop novel polyamine depleting molecules, and adding the strategy to have substances that can control cancer through different cellular pathways aiming to bypass the acquisition of drug resistant phenotype by cancer cells; this work aimed to screen, in an ovarian cancer (OVCA) line, 40 novel rationally developed potential anti-cancer compounds, following rapid, high efficient, and low cost synthetic methodologies, then confirmed by spectroscopic techniques. OVCA is the most lethal gynecological malignancy, with high rates of chemoresistance and disease relapse; therefore, supporting the urge to generate novel anti-OVCA agents. Methods: Novel naphthoquinone-derived compounds were rationally designed to act through multiple cellular pathways aiming the avoidance of drug resistant phenotype acquisition by cancer cells, and were synthesized by rapid, efficient and low cost synthetic method. Drugs antineoplastic efficacy (AE) was accessed in OVCAR3, 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, antibiotics and antifungics, in 5% CO2, until subconfluence; then, 1.5x105 cells/well were subcultured for 72h prior to treatment with drugs in different concentrations (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 have screened the AE of 40 novel naphtoquinone-derived drugs in OVCAR3; five have decreased its CMV by, at least, 70%, namely: M8 (IC50 1.64x10−5M; CMV decrease of 90%); M10 (IC50 1.37x10−5M; CMV decrease of 96%); M14 (IC50 1.45x10−5M; CMV decrease of 85%); PIC10 (IC50 9.13x10−6M; CMV decrease of 95%); PIC20 (IC50 5.31x10−5M; CMV decrease of 70%). The IC50 for cisplatin, the gold therapy against OVCA was 3.87x10−5M and CMV decrease was 85%. Interpretation: We herein present novel drugs to treat OVCA; whereas PIC 10 is more potent that cisplatin, M8, M10, M14, PIC10 and PIC20 seem to have similar or higher antineoplastic efficacy in treating cisplatin-resistant OVCA. We strongly believe that the present pre-clinical research project is innovative, as it introduces novel anti-OVCA drugs, economically viable and socially important, as it might bring hope to put OVCA treatment in a perspective in which the disease control is a real possibility. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 924. doi:1538-7445.AM2012-924

Background Ovarian cancer (OVCA) is the second cause of gynecological-cancer deaths in Brazil, being frequently associated to chemotherapy resistance, a characteristic usually associated to PI3K/Akt/mTOR. We herein present data concerning the role of mTORC2 in cisplatin-resistant phenotype acquisition by OVCA cells. Methods Antineoplastic efficacy of cisplatin, doxorubicin, paclitaxel, and rapamycin was accessed, in different combinations, in the OVCA lineage OVCAR3 (cisplatin-resistant, advanced serous OVCA), through cellular metabolic viability (CMV) (MTT method). Cells were cultured in RPMI media supplemented with 10% (v/v) FBS and antibiotics until subconfluence. To characterize the role of mTORC1 or mTORC2 in OVCAR3 MCV, 1.5x105 cells/well were treated according to: EA1) Inhibition of mTORC1: Drugs at IC50 for 24h; EA2) Inhibition of mTORC1 and mTORC2: Rapamycin 100nM for 72h, followed by drugs at IC50 for 24h. Modulation of MTOR expression by PKA, PKC, and PI3K was investigated by real time RT-PCR. Statistical analysis was performed using PrismaGraphPad version 5.1. Findings OVCAR3 CMV was not significantly changed by cisplatin (IC50 0,08mM) nor paclitaxel (IC50 0,06nM) or rapamycin (IC50 0,02nM) (CMV 95%, 100%, 100%, respectively), but by doxorubicin (IC50 0,02nM) (CMV 60%), especially in combination with cisplatin (CMV 31%), following EA1. Considering the irreversible doxorubicin-induced cardiotoxicity, we pursued with EA2. Intriguingly, OVCAR3 cisplatin sensitivity was, at least partially, recovered (CMV 65%). No addictive effect was observed with cisplatin/doxorubicin following EA2 (CMV 60%), suggesting that OVCA-resistant patient might benefit from less toxic rapamycin-based chemotherapy, leaving doxorubicin for palliative final-staged disease management. Finally, neither PKA nor PI3K modulate MTOR expression; however, PKC suppresses its transcription by 4.42-fold. Interpretation Altogether, our data suggest that mTORC2, but not mTORC1, might influence cisplatin sensitivity in OVCA. Moreover, PKC inhibits the expression of MTORC in cisplatin-resistant OVCA. We propose that the inhibition of mTORC2 followed by cisplatin treatment might lead to a conjunction of autophagic cell death and apoptosis in OVCA. Of remarkable clinical interest, we point to the urge of better design clinical trials, in which not only novel drugs are tested, but also the chronological order of drugs administration to the patient is seen as crucial for treatment efficacy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 161. doi:1538-7445.AM2012-161