期刊
EXPERIMENTAL AND MOLECULAR PATHOLOGY
卷 101, 期 1, 页码 12-21出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.yexmp.2016.05.013
关键词
Celastrol; Milk-derived exosomes; Drug delivery; Lung cancer
类别
资金
- Agnes Brown Duggan Endowment
- Helmsley Trust Funds
- Kentucky Lung Cancer Research Program
Celastrol (CEL), a plant-derived triterpenoid, is a known inhibitor of Hsp90 and NF-kappa B activation pathways and has recently been suggested to be of therapeutic importance in various cancers. However, the molecular mechanisms of celastrol-mediated effects in lung cancer are not systematically studied. Moreover, it suffers from poor bioavailability and off-site toxicity issues. This study aims to study the effect of celastrol loaded into exosomes against two non-small cell-lung carcinoma (NSCLC) cell lines and explore the molecular mechanisms to determine the proteins governing the cellular responses. We observed that celastrol inhibited the proliferation of A549 and H1299 NSCLC cells in a time- and concentration-dependent manner as indexed by MIT assay. Mechanistically, CEL pre-treatment of H1299 cells completely abrogated TNF alpha-induced NF-kappa B activation and upregulated the expression of ER-stress chaperones Grp 94, Grp78, and pPERK. These changes in ER-stress mediators were paralleled by an increase in apoptotic response as evidenced by higher annexin-V/PI positive cells evaluated by FACS and immunoblotting which showed upregulation of the ER stress specific pro-apoptotic transcription factor, GADD153/CHOP and alteration of Bax/Bcl2 levels. Exosomes loaded with CEL exhibited enhanced antitumor efficacy as compared to free CEL against lung cancer cell xenograft CEL did not exhibit any gross or systemic toxicity in wild-type C57BL6 mice as determined by hematological and liver and kidney function test. Together, our data demonstrate the chemotherapeutic potential of CEL in lung cancer and that exosomal formulation enhances its efficacy and reduces dose related toxicity. (C) 2016 Elsevier Inc. All rights reserved.
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