Sorafenib generates microvesicle particles in non-small cell lung cancer

TL;DR

Sorafenib, a cancer drug, increases microvesicle release in lung cancer cells, and blocking this process could improve treatment effectiveness.

Contribution

This study reveals that the PAFR and aSMase pathways are involved in sorafenib-induced microvesicle formation in NSCLC.

Findings

Sorafenib reduces NSCLC cell viability in a dose- and time-dependent manner.

Sorafenib treatment enhances microvesicle particle (MVP) formation in NSCLC cells.

Inhibiting PAFR or aSMase reduces MVP release and increases sorafenib's cytotoxic effects.

Abstract

Despite the improved clinical outcomes resulting from the use of sorafenib, the development of resistance mechanisms continues to undermine its treatment efficacy. Recent studies have implicated the role of a phospholipid mediator, platelet-activating factor receptor (PAFR) pathway, and extracellular vesicles known as microvesicle particles (MVP) in influencing cellular behavior and the efficacy of therapeutic agents. In this study, we determined the impact of the PAFR pathway and the acid sphingomyelinase (aSMase), which is required for the biogenesis of MVP, on sorafenib-induced effects on lung cancer growth and MVP release. Using A549 and H1299 non-small cell lung cancer (NSCLC) cell lines, we showed that sorafenib treatment reduced cell viability in a dose and time-dependent manner. Notably, sorafenib also enhanced MVP formation in both NSCLC cell lines. This MVP release was significantly attenuated by pharmacologic inhibition of the PAFR pathway through the WEB2086 compound and the aSMase inhibitor, imipramine, indicating the involvement of the PAFR and aSMase in sorafenib-induced MVP biogenesis. Moreover, co-treatment with imipramine enhanced the cytotoxic effects of sorafenib, suggesting that targeting MVP-associated pathways may improve sorafenib response. Collectively, these findings offer mechanistic insight into how sorafenib modulates MVP release and supports the therapeutic potential of combining tyrosine kinase inhibitors with agents that disrupt MVP biogenesis in NSCLC.

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