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Quantitative Biology

ISSN 2095-4689

ISSN 2095-4697(Online)

CN 10-1028/TM

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Quant. Biol.    2021, Vol. 9 Issue (3) : 329-340    https://doi.org/10.15302/J-QB-021-0237
RESEARCH ARTICLE
Systems analysis of the “weights” of Bcl-2 and Mcl-1 in mitochondrial apoptosis pathway establishes a predictor for best drug combination ratio
Zongwei Guo1, Fangkui Yin2, Peiran Wang2, Ting Song2(), Zhichao Zhang2()
1. School of Bioengineering, Dalian University of Technology, Dalian 116024, China
2. State Key Laboratory of Fine Chemicals, School of Chemistry, Dalian University of Technology, Dalian 116024, China
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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.
Keywords weights of Bcl-2/Mcl-1      drug-target network      Bcl-2/Mcl-1 inhibitors combination      mathematical modeling     
Corresponding Author(s): Ting Song,Zhichao Zhang   
Just Accepted Date: 30 January 2021   Online First Date: 22 March 2021    Issue Date: 29 September 2021
 Cite this article:   
Zongwei Guo,Fangkui Yin,Peiran Wang, et al. Systems analysis of the “weights” of Bcl-2 and Mcl-1 in mitochondrial apoptosis pathway establishes a predictor for best drug combination ratio[J]. Quant. Biol., 2021, 9(3): 329-340.
 URL:  
https://academic.hep.com.cn/qb/EN/10.15302/J-QB-021-0237
https://academic.hep.com.cn/qb/EN/Y2021/V9/I3/329
Fig.1  Mathematical model of Bcl-2-controlled MOMP that was formulated in terms of Bcl-2 protein interactions.
Cell lines
(30)		 Model prediceddependency Experimentally determineddependency Bcl-2
level
(nM)		 Bcl-xL
level
(nM)		 Mcl-1
level
(nM)		 Bax
level
(nM)		 Bak
level
(nM)		 Puma
level
(nM)		 Bim
level
(nM)
RS4;11 ● ● 280 300 35 312 224 8 8
MOLM-13 ● ● 351 289 42 276 285 13 6
MDA-MB-231a ● ● 225 145 125 332 301 7 11
NCI-H23 ?▲ ?▲ 14 20 145 236 520 9 15
MCF-7a ?▲ ?▲ 283 163 188 270 314 13 9
OCI-AML3b ?▲ ?▲ 213 104 226 294 280 16 7
T-47D ■ ■ 312 112 102 341 330 19 6
HCT-116a ■ ■ 247 576 31 327 655 21 13
THP-1a ■ ■ 186 98 72 286 320 18 12
Hep-G2 ■ ■ 340 354 82 254 231 11 17
SNU-423 ● ● 379 127 55 432 176 7 9
Panc 10.05 ● ● 402 252 58 358 417 15 10
U-118MG ● ● 174 388 94 258 479 16 22
AU-565 ?▲ ?▲ 24 20 93 425 328 12 13
HCC-1954 ?▲ ?▲ 41 32 105 267 422 8 19
SK-BR-3 ?▲ ?▲ 45 21 89 350 346 20 8
BT-20 ?▲ ?▲ 53 45 112 278 531 15 9
Capan-1 ?▲ ?▲ 62 25 95 356 321 10 16
COLO-679 ■ ?▲ 368 184 105 402 255 9 12
HCC-1395 ■ ?▲ 319 305 87 268 521 14 18
CFPAC-1 ?▲ ?▲ 46 36 107 325 379 11 15
DBTRG-05MG ■ ● 287 228 85 246 321 13 7
SK-MEL-5 ● ● 314 191 64 332 412 15 11
SK-MEL-28 ● ● 520 115 101 542 164 18 16
OV-90 ■ ■ 311 269 120 348 317 14 12
Panc 02.03 ■ ■ 276 264 92 259 415 10 13
SW-480 ● ● 458 217 83 452 316 8 14
Hs-766T ■ ■ 546 364 128 387 464 9 11
SW-948 ■ ■ 241 332 102 259 523 14 10
A-172 ■ ■ 641 211 130 521 357 16 9
Tab.1  Model predicted Bcl-2 and/or Mcl-1 dependency in comparison with experimental finding in literature
Fig.2  Correlation analysis of Bcl-2 protein levels, Mcl-1 protein levels, and Mcl-1 production rates with Bcl-2 or Mcl-1 dependency.
Fig.3  Statistical analysis of the best-fit parameter for the degradation rates of Mcl-1/A-1210477 and Mcl-1/compound 5.
Fig.4  The model predicted best combination ratios of ABT-737/A-1210477 and ABT-737/compound 5 in various cancers.
Fig.5  The best combination ratios of ABT-737/A-1210477 and ABT-737/compound 5 were experimentally verified in MCF-7 and MDA-MB-231.
Fig.6  Percentage change of the best drug ratio λ in response to a 5% increase or decrease of each parameter.
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