Uveal melanoma (UM) is the most common primary intraocular tumor in adults, which is associated with poor prognosis. Up to 50% of UM patients develop metastasis. Therapeutics that have proven effective in cutaneous melanoma have little success in treating UM, possibly due to its low mutational burden. Therefore, new drug therapies are highly desired for UM. Our in vitro studies showed that Elaiophylin, a late-stage autophagy inhibitor, exhibited an outstanding anticancer activity in human UM cell lines and human UM primary cells through suppressing mitophagy, inducing oxidative stress and leading to autophagic cell death. Our mechanistic study revealed that Elaiophylin exerted its effect by down-regulating SIRT1 and thus influencing deacetylation and mitochondrial localization of FoxO3a. In our confirmatory experiments, SRT1720, a SIRT1 specific activator, could attenuate Elaiophylin-induced inhibition of mitophagy and elevation of oxidative stress, and such effects was partly reversed by FoxO3a knockdown. Our further in vivo studies showed that Elaiophylin dramatically inhibited tumor growth in the human UM xenograft mouse model, which was accompanied with a decreased SIRT1 expression. Thus, the current study is the first to demonstrate that Elaiophylin has a potent anti-cancer effect against UM, which activity is possibly mediated through regulating SIRT1-FoxO3a signaling axis. And Elaiophylin may be a new and promising drug candidate to treat human UM.
Background
Ultrasound-targeted microbubble destruction (UTMD) technology is a new drug and gene delivery strategy. This study investigates novel ultrasound (US) sensitive siRNA-loaded nanobubbles (siRNA-NBs) to explore the relationship between PDLIM5 mediated autophagy and drug resistance development using epidermal growth factor tyrosine kinase inhibitors (EGFR-TKIs) in the treatment of non-small cell lung cancer (NSCLC).
Methods
US sensitive siRNA-NBs were designed to inhibit the expression of PDLIM5 in gefitinib-resistant human NSCLC PC9GR cells in vitro. The expression of autophagy-related proteins (P62 and LC3-II/I) and autophagosomes in PC9GR cells after PDLIM5 gene silencing were explored.
Results
US-sensitive PDLIM5-targeted siRNA-NBs were effectively delivered into PC9GR cells, inhibiting PDLIM5 expression, increasing LC3-II/I and p62 expressions and increasing autophagosomes in PC9GR cells in vitro.
Conclusions
Using UTMD, US-sensitive siRNA-NBs have the potential as an ideal delivery vector to mediate highly effective RNA interference for NSCLC cells. Furthermore, PDLIM5 plays a role in the autophagy-mediated resistance in gefitinib-resistant PC9GR cells.
Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) is a first-line targeted drug for the treatment of advanced non-small cell lung cancer (NSCLC) in clinical practice, but EGFR-TKI-acquired resistance limits...
Lung adenocarcinoma (LADC) is the most prevalent lung cancer sub-type, and targeted therapy developed in recent years has made progress in its treatment. Erdafitinib, a potent and selective pan-FGFR tyrosine kinase inhibitor, has been confirmed to be effective for the treatment of LADC; however, the molecular mechanism responsible for this effect is unclear. The in vitro study showed that erdafitinib exhibited an outstanding anti-cancer activity in human LADC cell line A549 by inducing S-phase cell-cycle arrest and cell apoptosis. The mechanistic study based on the transcriptomic data revealed that erdafitinib exerted its anti-cancer effect by affecting the cell cycle-related pathway, and CDK2 was the regulatory target of this drug. In addition, CDK2 overexpression significantly attenuated the anti-cancer effect of erdafitinib by affecting the transcriptional activity and expression of E2F1, as well as the expression of CDK1. The in vivo study showed that erdafitinib presented an obvious anti-cancer effect in the A549 xenograft mice model, which was accompanied by the reduced expression of CDK2. Thus, this study demonstrates the anti-cancer effect of erdafitinib against LADC for the first time based on in vitro and in vivo models, whose activity is achieved by targeting CDK2 and regulating downstream E2F1-CDK1 signaling. This study may be helpful for expanding the clinical application of erdafitinib in treating LADC.
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