Systems analysis of the “weights” of Bcl-2 and Mcl-1 in mitochondrial apoptosis pathway establishes a predictor for best drug combination ratio

Abstract

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.

Author summary

We used a mathematical model combined with experimental verification to quantitatively examine the contribution of the two arms of anti-apoptotic Bcl-2 proteins to apoptosis by weight. The correlation analysis and single-parameter sensitivity analysis showed that Bcl-2 protein level and Mcl-1 protein level, production, and degradation rates were the major molecular determinants. We gained two sets of equations as tools to bypass the time-consuming and laborious experimental screening to predict the best drug combination ratio for treatment. Biological experiments have verified the efficiency of the tools in MCF-7, MDA-MB-231, OCI-AML3, and HCT-116 cells.

Graphical abstract

Keywords

weights of Bcl-2/Mcl-1 / drug-target network / Bcl-2/Mcl-1 inhibitors combination / mathematical modeling

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SUPPLEMENTARY MATERIALS

The supplementary materials can be found online with this article at https://doi.org/ 10.15302/J-QB-021-0237.

ACKNOWLEDGEMENTS

This research was supported by the National Natural Science Foundation of China (81430083 and 81903462), the China Postdoctoral Science Foundation (2018M641694), and the Fundamental Research Funds for the Central Universities (DUT20LK28 and DUT20YG133).

COMPLIANCE WITH ETHICS GUIDELINES

The authors Zongwei Guo, Fangkui Yin, Peiran Wang, Ting Song and Zhichao Zhang declare that they have no conflict of interests.

This article does not contain any studies with human or animal subjects performed by any of the authors.

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2021 The Author(s) 2021. Published by Higher Education Press