Excipient of Paclitaxel Induces Metabolic Dysregulation and Unfolded Protein Response

Overview

Journal iScience

Publisher Cell Press

Date 2021 Oct 14

PMID 34646996

Citations 5

Authors

Qian Dai

Xiaolin Liu

Tao He

Chao Yang

Jinfeng Jiang

Yin Fang

Zhoukai Fu

Yuan Yuan

Shujun Bai

Tong Qiu

Rutie Yin

Ping Ding

Jie Chen

Qintong Li

Affiliations

Soon will be listed here.

Abstract

Taxane-based reagents, such as Taxol, Taxotere, and Abraxane, are popular anti-cancer drugs that can differ in their clinical efficacy. This difference is generally attributed to their active pharmaceutical ingredients. Here, we report a serendipitous discovery that Taxol induces metabolic dysregulation and unfolded protein response. Surprisingly, these effects of Taxol are entirely dependent on its excipient, Cremophor EL (CrEL). We show that CrEL promotes aerobic glycolysis and in turn results in drastic upregulation of (), a major regulator of human blood lipid profile. Notably, premedication with dexamethasone further enhances the expression of . Consistently, we find that the amplitude and frequency of increase in triglycerides is more prominent in Taxol-treated patients with breast cancer. In addition, we find that CrEL activates the unfolded protein response pathway to trigger proinflammatory gene expression and caspase/gasdermin E-dependent pyroptosis. Finally, we discuss the implications of these results in anti-cancer therapies.

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