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Tumor Discovery Sorafenib induces MVPs in NSCLC

A B

C
D

Figure 4. Effect of an aSMase inhibitor on sorafenib cytotoxicity. A549 cells (A, B) and H1299 cells (C, D) were pre-treated with imipramine (an
aSMase inhibitor, 20 µM for 1 h) followed by treatment with or without sorafenib (4 µM). After 24 and 48 h, cell viability was assessed through
sulforhodamine-B assay. Data are presented as mean ± scanning electron microscope of three independent biological replicates. Statistically significant
differences were observed between control and imipramine or sorafenib alone, as well as sorafenib and sorafenib with imipramine co-treatment.
Notes: **p<0.01, ***p<0.001 compared with control; p<0.05 compared with SF; p<0.001 compared with SF.
β
γ
Abbreviations: aSMase: Acid sphingomyelinase; IMI: Imipramine; SF: Sorafenib.
oncogenic proteins, or even chemotherapeutic agents, to drive MVP release across various cancers, including
MVP can attenuate the intracellular accumulation of NSCLC. 9,14,18 Similarly, aSMase catalyzes the hydrolysis
drugs and facilitate communications within the tumor of sphingomyelin to ceramide, a lipid known to promote
microenvironment that favor cancer cell survival. 23,24 Our membrane budding and MVP formation. 27,28,33 Our data
findings indicate that sorafenib treatment increases MVP confirm that pharmacological blockade of PAFR (via
release in NSCLC cell lines, aligning with prior work WEB2086) or inhibition of aSMase (via imipramine)
demonstrating that other anticancer agents also elevate substantially diminishes sorafenib-induced MVP release
MVP shedding. 14,19 This phenomenon may represent in NSCLC cell lines. These results underscore a therapeutic
an adaptive mechanism by which cancer cells reduce opportunity, indicating that targeting the MVP production
intracellular drug toxicity and exchange signals conducive pathways may enhance the efficacy of established anticancer
to tumor growth. drugs by reducing the vesicular export of survival signals
Notably, PAFR signaling and aSMase activity both and other resistance factors.
emerged as critical players in mediating MVP generation. Importantly, imipramine, a tricyclic antidepressant,
In line with previous reports, PAFR activation appears has garnered attention for its potent aSMase-inhibiting

Volume 4 Issue 3 (2025) 86 doi: 10.36922/TD025110019