Related Experiment Video
Updated: Dec 21, 2025
Preparation and Photoacoustic Analysis of Cellular Vehicles Containing Gold Nanorods
Published on: May 2, 2016
Quinacrine Based Gold Hybrid Nanoparticles Caused Apoptosis through Modulating Replication Fork in Oral Cancer Stem
Krushna Chandra Hembram1, Somya Ranjan Dash1, Biswajit Das1
1Cancer Biology Division, School of Biotechnology, Kalinga Institute of Industrial Technology, Campus-11, Patia, Bhubaneswar, Odisha 751024, India.
Abstract:
The presence of cancer stem cells (CSCs) in the tumor microenvironment is responsible for the development of chemoresistance and recurrence of cancer. Our previous investigation revealed the anticancer mechanism of quinacrine-based silver and gold hybrid nanoparticles (QAgNP and QAuNP) in oral cancer cells, but to avoid cancer recurrence, it is important to study the effect of these nanoparticles (NPs) on CSCs. Here, we developed an in vitro CSCs model using SCC-9 oral cancer cells and validated via FACS analysis. Then, 40-60% of cells were found to be CD44+/CD133+ and CD24-. QAuNP showed excellent anti-CSC growth potential against SCC-9-cancer stem like cells (IC50 = 0.4 μg/mL) with the down-regulation of representative CSC markers. Prolonged exposure of QAuNP induced the S-phase arrest and caused re-replication shown by the extended G2/M population and apoptosis to SCC-9-CSC like cells. Up-regulation of BAX, PARP cleavage, and simultaneous down-regulation of Bcl-xL in prolonged treatment to CSCs suggested that the majority of the cells have undergone apoptosis. QAuNP treatment also caused a loss in DNA repair in CSCs. Mostly, the base excision repair (BER) components (Fen-1, DNA ligase-1, Pol-β, RPA, etc.) were significantly down-regulated after QAuNP treatment, which suggested its action against DNA repair machinery. The replication fork maintenance-related proteins, RAD 51 and BRCA-2, were also deregulated. Very surprisingly, depletion of WRN (an interacting partner for Pre-RC and Fen-1) and a significant increase in expression of fork-degrading nuclease MRE-11 in 96 h treated NPs were observed. Results suggest QAuNP treatment caused excessive DNA damage and re-replication mediated replication stress (RS) and stalling of the replication fork. Inhibition of BER components hinders the flap clearance activity of Fen-1, and it further caused RS and stopped DNA synthesis. Overall, QAuNP treatment led to irreparable replication fork movement, and the stalled replication fork might have degraded by MRE-11, which ultimately results in apoptosis and the death of the CSCs.
Insights
Quinacrine-based gold nanoparticles (QAuNP) effectively target cancer stem cells (CSCs) by inducing DNA damage and apoptosis. This novel approach inhibits DNA repair, offering a promising strategy against chemoresistance and cancer recurrence.
Area of Science:
- Nanotechnology in Oncology
- Cancer Stem Cell Biology
- Molecular Mechanisms of Drug Resistance
Background:
- Cancer stem cells (CSCs) drive chemoresistance and recurrence in oral cancer.
- Previous studies showed quinacrine-based nanoparticles (QAgNP, QAuNP) have anticancer effects.
- Targeting CSCs is crucial to prevent cancer relapse.
Purpose of the Study:
- To investigate the anti-CSC effects of QAuNP in oral cancer.
- To elucidate the molecular mechanisms underlying QAuNP's action on CSCs.
- To evaluate QAuNP's potential in overcoming chemoresistance.
Main Methods:
- Development of an in vitro CSC model using SCC-9 oral cancer cells.
- Validation of CSC markers (CD44+/CD133+, CD24-) via FACS analysis.
- Assessment of QAuNP's impact on CSC proliferation, cell cycle, apoptosis, and DNA repair pathways.
Main Results:
- QAuNP demonstrated significant anti-CSC growth potential (IC50 = 0.4 μg/mL) and down-regulated CSC markers.
- QAuNP induced S-phase arrest, re-replication, apoptosis (up-regulated BAX, cleaved PARP; down-regulated Bcl-xL), and DNA repair inhibition (down-regulated BER components).
- QAuNP treatment led to replication stress, stalled replication forks, and degradation by MRE-11, resulting in CSC apoptosis.
Conclusions:
- QAuNP effectively targets and eliminates oral cancer stem cells.
- QAuNP induces DNA damage and replication stress, overwhelming CSC repair mechanisms.
- QAuNP presents a promising therapeutic strategy against chemoresistant oral cancers.
