Exosome inhibition improves response to first‐line therapy in small cell lung cancer

Exosomes are recognized as important mediators of cell‐to‐cell communication, facilitating carcinogenesis. Although there have been significant advancements in exosome research in recent decades, no drugs that target the inhibition of sEV secretion have been approved for human use. For this study, w...

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Bibliographic Details
Published in:Journal of cellular and molecular medicine 2024-02, Vol.28 (4), p.e18138-n/a
Main Authors: Irep, Nesrin, Inci, Kubilay, Tokgun, Pervin Elvan, Tokgun, Onur
Format: Article
Language:English
Subjects:
Aniline Compounds
Apoptosis
BAX protein
Bcl-2 protein
Benzylidene Compounds
Biosynthesis
Cancer therapies
Carcinogenesis
Caspase-3
Caspase-9
CD63 antigen
CD9 antigen
Cell growth
Cell interactions
Cell proliferation
Chemotherapy
Cisplatin
combination therapy
Cytotoxicity
Etoposide
exosome
Exosomes
Exosomes - metabolism
Humans
Lung cancer
Lung Neoplasms - drug therapy
Lung Neoplasms - metabolism
nsMase2
Original
p53 Protein
Proteins
RAB27A
Reagents
SCLC
Small cell lung carcinoma
Small Cell Lung Carcinoma - drug therapy
Small Cell Lung Carcinoma - metabolism
Transmission electron microscopy
Tumor cell lines
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Summary:Exosomes are recognized as important mediators of cell‐to‐cell communication, facilitating carcinogenesis. Although there have been significant advancements in exosome research in recent decades, no drugs that target the inhibition of sEV secretion have been approved for human use. For this study, we employed GW4869 and Nexinhib20 as inhibitors of exosome synthesis and trafficking combined. First, we found that Nexinhib20 and GW4869 effectively inhibited RAB27A and neutral sphingomyelinase 2 (nSMase2) nsMase2. Interestingly, the inhibition of nsMase2 and RAB27A decreased expression of CD9, CD63 and Tsg101, both at RNA and protein levels. We used a combination treatment strategy of cisplatin/etoposide plus GW4869 or Nexinhib20 on small cell lung cancer (SCLC) cell lines. The combination treatment of GW4869 or Nexinhib20 effectively enhanced the inhibitory effects of first‐line chemotherapy on the SCLC cells. Furthermore, we demonstrated that reducing exosome release through GW4869 and Nexinhib20 treatment effectively reduced cellular proliferation and significantly induced apoptosis in SCLC cells. Also, we showed that combining exosome inhibition with chemotherapy has a significant synergistic effect on cellular proliferation. We also found increased p53 and p21 expressions with western blot and significantly changing Bax, BCL2, caspase‐3 and caspase‐9 expressions. Inhibiting the exosome pathway offers opportunities for developing novel, effective treatment strategies for SCLC.
ISSN:1582-1838
1582-4934
1582-4934
DOI:10.1111/jcmm.18138