Sapitinib dosage, which is required to achieve Cmax of at least 5 g/mL, was not previously tested in clinical trials. 13 combinations of drugs and/or selective inhibitors predicted by Oncobox and 10 random combinations. Synergy scores for Oncobox predictions were significantly higher than for randomly selected drug combinations. Thus, Ncam1 the proposed approach significantly outperforms random selection of drugs and can be adopted to enhance discovery of new synergistic combinations of anticancer target drugs. inhibitor Sapitinib and Sunitinib or (ii) Sunitinib alone; (C) Temsirolimus-resistant cells treated with (i) combination of Temsirolimus and EGFR inhibitor Sapitinib or (ii) Temsirolimus alone; (D) Pazopanib-resistant cells treated with (i) combination of Pazopanib and EGFR inhibitor Sapitinib or (ii) Pazopanib alone. Dashed collection corresponds to single drug, solid linecombination. Sapitinib in SKOV-3 cells. We next tested predicted combinations of Sapitinib, inhibitor of ErbB2, ErbB3, and EGFR, in Pazopanib-, Sunitinib-, and Temsirolimus-resistant SKOV-3 cell populations. We found that these drugs could take action synergistically in case of Sunitinib or Pazopanib (Physique 6B,D), but the effect was not synergistic in case of Temsirolimus (Physique 6C). U73122 and Sapitinib in NGP-127 cells. We examined three Oncobox predictions made for NGP-127 cell lines. Around the na?ve NGP-127 cells, the combinations of Sorafenib + U73122 and Pazopanib Imrecoxib + U73122 worked additively (Determine 7A,B), and the same was observed for the combination of Pazopanib + Sapitinib around the Pazopanib-resistant cell lines (Determine 7C). Open in a separate window Physique 7 Viability of NGP-127 cells treated with different combinations of target drugs: (A) Sorafenib with Phospholipase C inhibitor U73122; (B) Pazopanib with Phospholipase C inhibitor U73122; and (C) NGP-127 cell lines adapted to Pazopanib and treated with (i) combination of Pazopanib and EGFR inhibitor Sapitinib or (ii) Pazopanib alone. Dashed collection corresponds to single drug, solid linecombination. Random drugs/inhibitors combinations. We Imrecoxib also tested 10 random drugs/inhibitors combinations, which were not predicted by our method. Of those, one combination showed synergistic effect, in five cases this effect was additive and in four cases it was antagonistic (Physique S1). However, the synergistic effect was seen in the na?ve SKOV-3 cells treated with Sorafenib and U73122, which was predicted to be effective in the Sorafenib-resistant SKOV-3 cells. Conclusion. Overall, we investigated 13 predictions of the drugs/inhibitors combinations done by the Oncobox platform. In three cases we observed a synergistic effect of the drugs and in eight cases the effect of the drug combination was additive. The antagonistic effect was seen for only two combinations. The difference between Bliss synergy scores calculated for Oncobox predicted combinations and scores for random combinations was significant according to fused oncoprotein [13,18]. However, it remained unclear whether the same method will be reproducibly effective for the other objects. It was also unexplored if this approach provides advantage compared to randomly taken combinations of drugs/inhibitors. Here, we examined five target drugs on two different cell lines for a period of up to four months. Somewhat similar experiments which focused on the discovery of synergistic drug combinations were conducted by Di Nicolantonio and coauthors . However, in that study the cell lines were grown in the presence of chemotherapeutic drugs for only six days, which is usually poorly correlated with the period of chemotherapy in clinical practice. Several other related attempts were recently published, but they experienced either a lower quantity of cell populations analyzed , or lower quantity of drugs tested , or both . Other computational methods for predicting synergistic pairs of drugs using gene expression data were also reported. He et al. explained a personalized predictor of drug combinations for leukemia patients which was successfully validated in 10 out of 24 cases . The Drug-Induced Genomic Residual Effect (DIGRE) model also showed promising results in predicting effective pairs of drugs; however it was only validated for a single combination: gefitinib and docetaxel in various concentrations . The Ranking-system of Anticancer Synergy (RACS) is usually another transcriptomic-based approach for selecting effective drug combinations . Approximately 60% of RACS-predicted combinations were shown to take action synergistically, while 13% of randomly selected pairs showed same effect. Integrative pharmacogenomic approach for predicting effective combinations was also proposed . The authors experimentally tested only one Imrecoxib combination of drugs, which appeared to act in a synergistic manner. Interestingly, the Desire consortium assessed overall performance of 32 previously reported methods for predicting synergistic combinations in B cell lymphoma and only four of them were significantly better than random guessing . However, none of the above discussed Imrecoxib studies reported synergistic effects in cells, which are already resistant to target drugs. Moreover, Oncobox provides a list of.