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Anti-Cancer Agents in Medicinal Chemistry


ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

Research Article

Proteomic Level Changes on Treatment in MCF-7/DDP Breast Cancer Drug- Resistant Cells

Author(s): Gongshen Jin*, Kangwei Wang, Yonghong Liu, Xianhu Liu, Xiaojing Zhang and Hao Zhang

Volume 20, Issue 6, 2020

Page: [687 - 699] Pages: 13

DOI: 10.2174/1871520620666200213102849

open access plus


Background: LCL161, a SMAC’S small molecule mimetic, can bind to a variety of IAPs and activate Caspases. We found that on its own, LCL161induces apoptosis of drug-resistant breast cancer cells by binding to a variety of IAPs and activating Caspases. However, when LCL161 is used in combination with Caspase Inhibitors (CI), its capacity to induce apoptosis of breast cancer cells is enhanced.

Objective: To carry out proteomic and bioinformatics analysis of LCL161 in combination with CI. We aim to identify the key proteins and mechanisms of breast cancer drug-resistant apoptosis, thereby aiding in the breast cancer drug resistance treatment and identification of drug targeting markers.

Methods: Cell culture experiments were carried out to explore the effect of LCL161 combined with CI on the proliferation of breast cancer drug-resistant cells. Proteomic analysis was carried out to determine the protein expression differences between breast cancer drug-resistant cells and LCL161 combined with CI treated cells. Bioinformatics analysis was carried out to determine its mechanism of action. Validation of proteomics results was done using Parallel Reaction Monitoring (PRM).

Results: Cell culture experiments showed that LCL161 in combination with CI can significantly promote the apoptosis of breast cancer drug-resistant cells. Up-regulation of 92 proteins and down-regulation of 114 proteins protein were noted, of which 4 were selected for further validation.

Conclusion: Our results show that LCL161 combined with CI can promote the apoptosis of drug-resistant breast cancer cells by down-regulation of RRM2, CDK4, and ITGB1 expression through Cancer pathways, p53 or PI3K-AKT signaling pathway. In addition, the expression of CDK4, RRM2, and CDC20 can be down-regulated by the nuclear receptor pathway to affect DNA transcription and replication, thereby promoting apoptosis of breast cancer drug-resistant cells.

Keywords: Breast cancer, proteomics, smac mimetics, Caspase Inhibitors (CI), p53, PI3k-AKT.

Graphical Abstract
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