Excipient of paclitaxel induces metabolic dysregulation and unfolded protein response

Abstract

Summary 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.

Cytarabine induces cachexia with lipid malabsorption via zippering the junctions of lacteal in murine small intestine

“…In previous studies, it has been reported that chemotherapeutic agents, such as paclitaxel and platinum-based drugs, disrupt lipid homeostasis both in human and mice ( 62 , 70 ). Our study is the first to highlight the role of lacteal junction in lipid malabsorption in a chemotherapy-induced cachexia mouse model.…”

A Novel Pyroptosis-Related Prognostic Signature for Cervical Squamous Cell Carcinoma

“… 36 Moreover, ANGPTL4 is upregulated due to Cremophor EL, which promotes aerobic glycolysis and triggers proinflammatory gene expression and caspase/gasdermin E-dependent pyroptosis. 37 …”

Massive hypertriglyceridemia associated with paclitaxel; a case report

“…Dai et al have reported that paclitaxel induces aerobic glycolysis and hypertriglyceridemia ( Dai et al, 2021 ). These metabolic effects are proposed to be linked with the excipient CrEL, which is unique to paclitaxel as compared with other taxane-containing chemotherapies.…”

“…Paclitaxel, which is hydrophobic, is formulated with CrEL, which enhances drug solubility ( Scripture et al, 2005 ). Dai et al demonstrated patients with breast cancer developed higher triglyceride levels in the group that received paclitaxel with CrEL, compared to abraxane (nanoparticle albumin-bound paclitaxel), docetaxel and non-taxanes ( Dai et al, 2021 ). There was a triglyceride increase in all four groups, however in the paclitaxel with CrEL group, 8% developed triglyceride concentrations above 131 mg/dL (3.4 mmol/L ) and 44% demonstrated a 70% rise in triglycerides after this therapy.…”