Quinacrine Based Gold Hybrid Nanoparticles Caused Apoptosis through Modulating Replication Fork in Oral Cancer Stem Cells

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.

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“…Another study from the same research group showed the effectiveness of silver and gold-based hybrid nanoparticles in downregulating cancer stem cell-specific markers by 40-60%. Loss of DNA repair activity due to downregulation of the BER mechanism was also observed due to QC NPs [108]. Quinacrine-loaded Undaria pinnatifida fucoidan nanoparticles have been shown to enhance the effect of QC by nearly 5.7-fold and induced 68% tumor reduction in xenograft models compared to 20% with liquid drug alone in pancreatic cancer cells [109].…”

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“…Led to excessive DNA damage and re-replication mediated replication stress and replication fork stalling. [ 189 ] FeAu bimetallic NPs (FeAu NPs) MMP-1 antibody Antibodies specific for MMP-1 conjugated to FeAu NPs Synergistic effect of biomarker-specific antibodies and magnetic NP-induced hyperthermia A 3.07-fold increase in uptake in HSC-3 cells compared to L929 (fibroblast) cells, which caused a 5-fold decrease in cell viability. [ 70 ] Zeolitic imidazolate framework-8 (ZIF-8) USP30 inhibitor MF-094 USP30 inhibitor MF-094 loaded in ZIF-8-PDA and polyethylene glycol-thioketal (PEGTK) to fabricate ZIF-8-PDA-PEGTK NPs Targeting inhibition of USP30 by MF-094@NPs USP30 regulated cell viability, glutamine consumption, and apoptosis of OSCC cells by regulating c-Myc deubiquitination.…”

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“…The positive apoptosis-related protein Bax increased (6.1 times) and the negative apoptosis-related protein Bcl-XL decreased (by 5 times). [ 122 ] AuNPs Chemotherapy and radiotherapy Cetuximab and cisplatin-conjugated OSCC Combination therapy improves radiotherapy sensitivity. The sensitization enhancement ratio was calculated as 1.2 and 1.9, for AuNPs and AuNP ​+ ​Cetuximab, respectively.…”

“…Tumor metastasis to local or remote recurrence caused by tumor stem cells is a major factor in tumor treatment failure. AuNPs with quinacrine can induce oral cancer stem cell apoptosis by inhibiting DNA replication [ 122 ]. In addition to delivering anti-cancer drugs, AuNPs themselves have also shown anti-tumor effects [ 124 ].…”