Background:Inhibitors of B-cell CLL/lymphoma 2 (Bcl-2) family proteins have shown hope as antitumor drugs.While the notion that it is efficient to coordinate,balance,and neutralize both arms of the anti-apoptotic Bcl-2 family has been validated in many cancer cells,the weights of the two arms contributing to apoptosis inhibition have not been explored.This study analyzed the best combination ratio for different Bcl-2 selective inhibitors.Methods:We used a previously established mathematical model to study the weights of Bcl-2 (representing both Bcl-2 and Bcl-xL in this study) and myeloid cell leukemia-1 (Mcl-1).Correlation and single-parameter sensitivity analysis were used to find the major molecular determinants for Bcl-2 and Mcl-1 dependency,as well as their weights.Biological experiments were used to verify the mathematical model.Results:Bcl-2 protein level and Mcl-1 protein level,production,and degradation rates were the major molecular determinants for Bcl-2 and Mcl-1 dependency.The model gained agreement with the experimental assays for ABT-737/A-1210477 and ABT-737/compound 5 combination effect in MCF-7 and MDA-MB-231.Two sets of equations composed of Bcl-2 and Mcl-1 levels were obtained to predict the best combination ratio for Bcl-2 inhibitors with Mcl-1 inhibitors that stabilize and downregulate Mcl-1,respectively.Conclusions:The two sets of equations can be used as tools to bypass time-consuming and laborious experimental screening to predict the best drug combination ratio for treatment.