Related Experiment Videos
Cardenolide-induced lysosomal membrane permeabilization demonstrates therapeutic benefits in experimental human
Tatjana Mijatovic1, Véronique Mathieu, Jean-François Gaussin
1Laboratory of Toxicology, Institute of Pharmacy, Free University of Brussels, Brussels, Belgium.
Abstract:
Non-small cell lung cancers (NSCLCs) are the leading cause of cancer deaths in most developed countries. Targeting heat shock protein 70 (Hsp70) expression and function, together with the induction of lysosomal membrane permeabilization (LMP), could overcome the multiple anti-cell death mechanisms evidenced in NSCLCs that are responsible for the failure of currently used chemotherapeutic drugs. Because cardenolides bind to the sodium pump, they affect multiple signaling pathways and thus have a number of marked effects on tumor cell behavior. The aim of the present study was to characterize in vitro and in vivo the antitumor effects of a new cardenolide (UNBS1450) on experimental human NSCLCs. UNBS1450 is a potent source of in vivo antitumor activity in the case of paclitaxel-and oxaliplatin-resistant subcutaneous human NCI-H727 and orthotopic A549 xenografts in nude mice. In vitro UNBS1450-mediated antitumor activity results from the induction of nonapoptotic cell death. UNBS1450 mediates the decrease of Hsp70 at both mRNA and protein levels, and this is at least partly due to UNBS1450-induced downregulation of NFAT5/TonEBP (a factor responsible for the transcriptional control of Hsp70). These effects were paralleled by the induction of LMP, as evidenced by acridine orange staining and immunofluorescence analysis for cathepsin B accumulation.
Insights
A novel cardenolide, UNBS1450, effectively combats non-small cell lung cancer (NSCLC) by inducing non-apoptotic cell death. It targets heat shock protein 70 (Hsp70) and lysosomal membrane permeabilization (LMP), overcoming drug resistance.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Non-small cell lung cancer (NSCLC) is a leading cause of cancer mortality globally.
- Existing chemotherapeutics often fail due to NSCLC's robust anti-cell death mechanisms.
- Targeting heat shock protein 70 (Hsp70) and inducing lysosomal membrane permeabilization (LMP) show promise for overcoming resistance.
Purpose of the Study:
- To investigate the in vitro and in vivo antitumor effects of a new cardenolide, UNBS1450, against experimental human NSCLCs.
- To elucidate the mechanisms underlying UNBS1450's anti-cancer activity.
- To assess UNBS1450's efficacy in drug-resistant NSCLC models.
Main Methods:
- In vitro and in vivo studies using human NSCLC xenografts (NCI-H727 and A549) in nude mice.
- Assessment of cell death pathways, including non-apoptotic cell death.
- Analysis of Hsp70 expression at mRNA and protein levels.
- Investigation of NFAT5/TonEBP involvement in Hsp70 regulation.
- Evaluation of lysosomal membrane permeabilization (LMP) using acridine orange staining and cathepsin B immunofluorescence.
Main Results:
- UNBS1450 demonstrated potent in vivo antitumor activity against paclitaxel- and oxaliplatin-resistant NSCLC xenografts.
- In vitro, UNBS1450 induced non-apoptotic cell death.
- UNBS1450 significantly decreased Hsp70 expression by downregulating NFAT5/TonEBP.
- These effects were accompanied by the induction of LMP.
Conclusions:
- UNBS1450 exhibits significant antitumor potential against NSCLC, including drug-resistant forms.
- The mechanism involves Hsp70 downregulation and LMP induction, leading to non-apoptotic cell death.
- UNBS1450 represents a promising therapeutic candidate for NSCLC treatment.
