{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,9,26]],"date-time":"2025-09-26T13:25:58Z","timestamp":1758893158009,"version":"3.32.0"},"reference-count":48,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2021,9,1]],"date-time":"2021-09-01T00:00:00Z","timestamp":1630454400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81430083","81903462"],"award-info":[{"award-number":["81430083","81903462"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002858","name":"China Postdoctoral Science Foundation","doi-asserted-by":"publisher","award":["2018M641694"],"award-info":[{"award-number":["2018M641694"]}],"id":[{"id":"10.13039\/501100002858","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012226","name":"Fundamental Research Funds for the Central Universities","doi-asserted-by":"publisher","award":["DUT20LK28","DUT20YG133"],"award-info":[{"award-number":["DUT20LK28","DUT20YG133"]}],"id":[{"id":"10.13039\/501100012226","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Quant. Biol."],"published-print":{"date-parts":[[2021,9]]},"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Inhibitors of B\u2010cell CLL\/lymphoma 2 (Bcl\u20102) 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\u2010apoptotic Bcl\u20102 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\u20102 selective inhibitors.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We used a previously established mathematical model to study the weights of Bcl\u20102 (representing both Bcl\u20102 and Bcl\u2010xL in this study) and myeloid cell leukemia\u20101 (Mcl\u20101). Correlation and single\u2010parameter sensitivity analysis were used to find the major molecular determinants for Bcl\u20102 and Mcl\u20101 dependency, as well as their weights. Biological experiments were used to verify the mathematical model.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Bcl\u20102 protein level and Mcl\u20101 protein level, production, and degradation rates were the major molecular determinants for Bcl\u20102 and Mcl\u20101 dependency. The model gained agreement with the experimental assays for ABT\u2010737\/A\u20101210477 and ABT\u2010737\/compound 5 combination effect in MCF\u20107 and MDA\u2010MB\u2010231. Two sets of equations composed of Bcl\u20102 and Mcl\u20101 levels were obtained to predict the best combination ratio for Bcl\u20102\u00a0inhibitors with Mcl\u20101\u00a0inhibitors that stabilize and downregulate Mcl\u20101, respectively.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>The two sets of equations can be used as tools to bypass time\u2010consuming and laborious experimental screening to predict the best drug combination ratio for treatment.<\/jats:p><\/jats:sec>","DOI":"10.15302\/j-qb-021-0237","type":"journal-article","created":{"date-parts":[[2021,2,5]],"date-time":"2021-02-05T10:43:01Z","timestamp":1612521781000},"page":"329-340","source":"Crossref","is-referenced-by-count":1,"title":["Systems analysis of the \u201cweights\u201d of Bcl\u20102 and Mcl\u20101\u00a0in mitochondrial apoptosis pathway establishes a predictor for best drug combination ratio"],"prefix":"10.1002","volume":"9","author":[{"given":"Zongwei","family":"Guo","sequence":"first","affiliation":[{"name":"<!--1--> School of Bioengineering Dalian University of Technology Dalian 116024 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fangkui","family":"Yin","sequence":"additional","affiliation":[{"name":"<!--2--> State Key Laboratory of Fine Chemicals School of Chemistry Dalian University of Technology Dalian 116024 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peiran","family":"Wang","sequence":"additional","affiliation":[{"name":"<!--2--> State Key Laboratory of Fine Chemicals School of Chemistry Dalian University of Technology Dalian 116024 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ting","family":"Song","sequence":"additional","affiliation":[{"name":"<!--2--> State Key Laboratory of Fine Chemicals School of Chemistry Dalian University of Technology Dalian 116024 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhichao","family":"Zhang","sequence":"additional","affiliation":[{"name":"<!--2--> State Key Laboratory of Fine Chemicals School of Chemistry Dalian University of Technology Dalian 116024 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