Cell- and Tissue-Based Proteome Profiling and Dual Imaging of Apoptosis Markers with Probes Derived from Venetoclax and Idasanutlin

Dongsheng Zhu; Haijun Guo; Yu Chang; Yun Ni; Lin Li; Zhi-Min Zhang; Piliang Hao; Yong Xu; Ke Ding; Zhengqiu Li

doi:10.1002/anie.201802003

Cell- and Tissue-Based Proteome Profiling and Dual Imaging of Apoptosis Markers with Probes Derived from Venetoclax and Idasanutlin

Angew Chem Int Ed Engl. 2018 Jul 20;57(30):9284-9289. doi: 10.1002/anie.201802003. Epub 2018 Jun 25.

Authors

Dongsheng Zhu^{1

2}, Haijun Guo³, Yu Chang³, Yun Ni⁴, Lin Li⁴, Zhi-Min Zhang³, Piliang Hao⁵, Yong Xu^{1

2}, Ke Ding³, Zhengqiu Li³

Affiliations

¹ Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Science Park, Guangzhou, 510530, China.
² University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing, 100049, China.
³ School of Pharmacy, Jinan University, Guangzhou City Key, Laboratory of Precision Chemical Drug Development, International Cooperative Laboratory of Traditional Chinese, Medicine Modernization and Innovative Drug Development, Ministry of Education (MOE) of People's Republic of China, 601 Huangpu Avenue West, Guangzhou, 510632, China.
⁴ Institute of Advanced Materials (IAM), Nanjing Tech University, China.
⁵ School of Life Science and Technology, ShanghaiTech University, China.

PMID: 29768700
DOI: 10.1002/anie.201802003

Abstract

Venetoclax (ABT-199) and idasanutlin (RG7388) are efficient anticancer drugs targeting two essential apoptosis markers, Bcl-2 and MDM2, respectively. Recent studies have shown that the combination of these two drugs leads to remarkable enhancement of anticancer efficacy, both in vitro and in vivo. In an attempt to disclose the relationships of their protein targets, competitive affinity-based proteome profiling coupled with bioimaging was employed to characterize their protein targets in the same cancer cell line and tumor tissue. A series of protein hits, including ITPR1, GSR, RER1, PDIA3, Apoa1, and Tnfrsf17 were simultaneously identified by pull-down/LC-MS/MS with the two sets of affinity-based probes. Dual imaging was successfully carried out, with the simultaneous detection of Bcl-2 and MDM2 expression in various cancer cells. This could facilitate the novel diagnostic and therapeutic strategies of dual targeting of Bcl-2/MDM2.

Keywords: affinity-based probes; antitumor agents; apoptosis biomarkers; combination drugs; target identification.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / chemistry*
Antineoplastic Agents / pharmacology
Apoptosis
Biomarkers, Tumor / analysis*
Breast Neoplasms / drug therapy*
Breast Neoplasms / metabolism
Breast Neoplasms / pathology
Bridged Bicyclo Compounds, Heterocyclic / chemistry*
Bridged Bicyclo Compounds, Heterocyclic / pharmacology
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Fluorescent Dyes / chemistry*
Humans
MCF-7 Cells
Models, Molecular
Molecular Structure
Optical Imaging
Proteome / analysis*
Proteome / antagonists & inhibitors
Proteome / genetics
Proto-Oncogene Proteins c-bcl-2 / analysis
Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors
Proto-Oncogene Proteins c-bcl-2 / genetics
Proto-Oncogene Proteins c-mdm2 / analysis
Proto-Oncogene Proteins c-mdm2 / antagonists & inhibitors
Proto-Oncogene Proteins c-mdm2 / genetics
Pyrrolidines / chemistry*
Pyrrolidines / pharmacology
Structure-Activity Relationship
Sulfonamides / chemistry*
Sulfonamides / pharmacology
para-Aminobenzoates / chemistry*
para-Aminobenzoates / pharmacology

Substances

Antineoplastic Agents
Biomarkers, Tumor
Bridged Bicyclo Compounds, Heterocyclic
Fluorescent Dyes
Proteome
Proto-Oncogene Proteins c-bcl-2
Pyrrolidines
RG7388
Sulfonamides
para-Aminobenzoates
Proto-Oncogene Proteins c-mdm2
venetoclax