Dendrimer-based selective proteostasis-inhibition strategy to control NSCLC growth and progression

Kyla Walworth, Manish Bodas, Ryan John Campbell, Doug Swanson, Ajit Sharma, Neeraj Vij

Research output: Contribution to journalArticle

Abstract

Elevated valosin containing protein (VCP/p97) levels promote the progression of non-small cell lung carcinoma (NSCLC). Although many VCP inhibitors are available, most of these therapeutic compounds have low specificity for targeted tumor cell delivery. Hence, the primary aim of this study was to evaluate the in vitro efficacy of dendrimer-encapsulated potent VCP-inhibitor drug in controlling non-small cell lung carcinoma (NSCLC) progression. The VCP inhibitor(s) (either in their pure form or encapsulated in generation-4 PAMAM-dendrimer with hydroxyl surface) were tested for their in vitro efficacy in modulating H1299 (NSCLC cells) proliferation, migration, invasion, apoptosis and cell cycle progression. Our results show that VCP inhibition by DBeQ was significantly more potent than NMS-873 as evident by decreased cell proliferation (pDBeQ) treatment increased ubiquitinated-protein accumulation in soluble protein-fraction (immunoblotting) of H1299 cells as compared to DDN-control, implying the effectiveness of DBeQ in proteostasis-inhibition. We verified by immunostaining that DDNDBeQ treatment increases accumulation of ubiquitinated-proteins that co-localizes with an ER-marker, KDEL. We observed that proteostasis-inhibition with DDNDBeQ, significantly decreased cell migration rate (scratch-assay and transwell-invasion) as compared to the control-DDN treatment (pDBeQ treatment showed a significant decrease in cell proliferation (pDBeQ treatment as compared to control-DDN. Moreover, we confirmed by clonogenic-assay that DDNDBeQ treatment significantly (p

Original languageEnglish (US)
Article numbere0158507
JournalPLoS One
Volume11
Issue number7
DOIs
StatePublished - Jul 1 2016

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ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Walworth, K., Bodas, M., Campbell, R. J., Swanson, D., Sharma, A., & Vij, N. (2016). Dendrimer-based selective proteostasis-inhibition strategy to control NSCLC growth and progression. PLoS One, 11(7), [e0158507]. https://doi.org/10.1371/journal.pone.0158507