Excipient of paclitaxel induces metabolic dysregulation and unfolded protein response

  • iScience. 2021 Sep 25;24(10):103170. doi: 10.1016/j.isci.2021.103170.
Qian Dai  1 ,  Xiaolin Liu  1 ,  Tao He  2 ,  Chao Yang  3 ,  Jinfeng Jiang  3 ,  Yin Fang  1 ,  Zhoukai Fu  2 ,  Yuan Yuan  3 ,  Shujun Bai  1 ,  Tong Qiu  1 ,  Rutie Yin  1 ,  Ping Ding  3  4 ,  Jie Chen  2 ,  Qintong Li  1
Affiliations
  • 1. Departments of Obstetrics & Gynecology and Pediatrics, West China Second University Hospital, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Center of Growth, Metabolism and Aging, State Key Laboratory of Biotherapy and Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu 610041, China.
  • 2. Department of Breast Surgery, Clinical Research Center for Breast Diseases, West China Hospital, Sichuan University, Chengdu 610041, China.
  • 3. Divisions of Bioinformatics & Immunology, Cunde Therapeutics, Chengdu 610093, China.
  • 4. Non-coding RNA and Drug Discovery Key Laboratory of Sichuan Province, Chengdu Medical College, Chengdu 610500, China.
PMID: 34646996 DOI: 10.1016/j.isci.2021.103170
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 Angiopoietin Like 4 (ANGPTL4), a major regulator of human blood lipid profile. Notably, premedication with dexamethasone further enhances the expression of ANGPTL4. 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.

Keywords
Biological sciences; Cancer; Cell biology; Molecular biology.
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