The Involvement of the RhoA/ROCK Signaling Pathway in Hypersensitivity Reactions Induced by Paclitaxel Injection

Abstract

A high incidence of hypersensitivity reactions (HSRs) largely limits the use of paclitaxel injection. Currently, these reactions are considered to be mediated by histamine release and complement activation. However, the evidence is insufficient and the molecular mechanism involved in paclitaxel injection-induced HSRs is still incompletely understood. In this study, a mice model mimicking vascular hyperpermeability was applied. The vascular leakage induced merely by excipients (polyoxyl 35 castor oil) was equivalent to the reactions evoked by paclitaxel injection under the same conditions. Treatment with paclitaxel injection could cause rapid histamine release. The vascular exudation was dramatically inhibited by pretreatment with a histamine antagonist. No significant change in paclitaxel injection-induced HSRs was observed in complement-deficient and complement-depleted mice. The RhoA/ROCK signaling pathway was activated by paclitaxel injection. Moreover, the ROCK inhibitor showed a protective effect on vascular leakage in the ears and on inflammation in the lungs. In conclusion, this study provided a suitable mice model for investigating the HSRs characterized by vascular hyperpermeability and confirmed the main sensitization of excipients in paclitaxel injection. Histamine release and RhoA/ROCK pathway activation, rather than complement activation, played an important role in paclitaxel injection-induced HSRs. Furthermore, the ROCK inhibitor may provide a potential preventive approach for paclitaxel injection side effects.

Penilloic acid is the chief culprit involved in non-IgE mediated, immediate penicillin-induced hypersensitivity reactions in mice

“…A score from 1 to 6 was given by one researcher blinded to treatment of penicillin, where “1” denoted no visible blue area, and “2 to 6” represented visible blue areas of <12.5%, 12.5%–25%, 25%–50%, 50%–75%, and >75%, respectively. The ears of each mouse were preserved in 2 ml of formamide for EB extraction ( Han et al, 2018 ; Pan et al, 2019b ).…”

Hypersensitivity reactions to small molecule drugs

“…In recent years, some small molecule drugs have been found to directly trigger aggressive vascular hyperpermeability and NADHRs (123,124). Currently, hypersensitivity reactions caused by various traditional Chinese medicine injections (125)(126)(127)(128), penicillin (123), and paclitaxel (124) are reported to be related to their adverse effects on vessels. So far, this opinion has been mainly proven by animal experiments, and the reactions occur in a dose-dependent manner.…”

“…So far, this opinion has been mainly proven by animal experiments, and the reactions occur in a dose-dependent manner. The RhoA/ROCK signaling pathway, which plays an essential role in regulating the cytoskeleton and endothelial barrier, is considered to be an important factor influencing these reactions ( 123 , 124 , 129 ).…”

The utility of H2 receptor antagonists in preventing infusion‐related reactions to paclitaxel chemotherapy

“…Early in the development of paclitaxel, it was noted to cause a high incidence of infusion-related reactions (IRR) 1 that are thought to be due in part to direct histamine release from the Cremophor vehicle. 2 As a result, it is recommended to give paclitaxel with an empiric premedication regimen including corticosteroids, H 1 -receptor antagonists (H1RA; diphenhydramine), and H 2receptor antagonists (H2RA; ranitidine, famotidine). 3 Because this premedication regimen has never been evaluated in a prospective clinical trial, there have been efforts to modify and deescalate premedications before paclitaxel to reduce toxicity for patients and remove waste in the health care system.…”