Pyridostatin stabilizes G-quadruplex DNA structures with a dissociation constant (Kd) of 490 nM, leading to growth arrest in human cancer cells by causing DNA damage dependent on both replication and transcription. It specifically targets the Src proto-oncogene, leading to reduced SRC protein levels and decreased SRC-dependent cell movement in human breast cancer cells[1][2].
体外研究
Pyridostatin (10 μM for 48 hours) triggers cell cycle arrest[1].
As a highly selective G-quadruplex DNA-binding molecule, Pyridostatin stabilizes the G-quadruplex structure, resulting in neurite retraction, loss of synapses, and neuronal death in a dose-dependent manner. It induces double-strand breaks (DSBs) in the DNA of cultured primary neurons. Notably, Pyridostatin treatment (1-5 μM, overnight) reduces BRCA1 protein levels at the transcriptional level, a crucial protein for the maintenance and repair of the neuronal genome[3].
Pyridostatin 细胞实验
Cell Line
Concentration
Treated Time
Description
References
Astrocytes
2 µM
Overnight
PDS downregulates Atg7 mRNA and ATG7 protein levels
Autophagy. 2020 Dec;16(12):2252-2259
Neurons
2 µM
Overnight
PDS downregulates Atg7 expression and reduces autophagy
Autophagy. 2020 Dec;16(12):2252-2259
IPAM cells
10 µM
12 hours
To evaluate the stabilizing effect of PDS on the PRRSV-G4 structure and its impact on viral replication. Results showed that PDS treatment significantly inhibited PRRSV replication.
Nucleic Acids Res. 2023 Oct 27;51(19):10752-10767
HeLa cells
20 µM
12 hours
To investigate the effect of Pyridostatin on the interaction between G3BP1 and rG4 structures, results showed that Pyridostatin could displace G3BP1 from mRNA, with the most pronounced effects observed in the 3'-untranslated regions (3'-UTR) of mRNAs.
Nucleic Acids Res. 2021 Nov 8;49(19):11323-11336
HEK293T cells
20 µM
12 hours
To investigate the effect of Pyridostatin on the interaction between G3BP1 and rG4 structures, results showed that Pyridostatin could displace G3BP1 from mRNA, with the most pronounced effects observed in the 3'-untranslated regions (3'-UTR) of mRNAs.
Nucleic Acids Res. 2021 Nov 8;49(19):11323-11336
U2OS human osteosarcoma cell line
1 µM
12 hours
Pyridostatin-α formed nuclear foci in cells, co-localizing with hPif1.
Nat Chem Biol. 2012 Feb 5;8(3):301-10
DLD1 BRCA2−/−
2 µM
16 hours
Evaluate the effect of Pyridostatin on DNA damage in BRCA2−/− cells, showing significant increase in DNA breaks, repaired after 72 hours
EMBO Mol Med. 2022 Mar 7;14(3):e14501
DLD1 BRCA2+/+
2 µM
16 hours
Evaluate the effect of Pyridostatin on DNA damage in BRCA2+/+ cells, showing no significant increase in DNA breaks
EMBO Mol Med. 2022 Mar 7;14(3):e14501
RPE-1 BRCA1−/−
10 µM
2 days
Evaluate DNA damage and immune responses induced by Pyridostatin in BRCA1-deficient cells, showing increased KAP1 Ser824 and IRF3 Ser386 phosphorylation
EMBO Mol Med. 2022 Mar 7;14(3):e14501
A549
10 µM
2 hours H2O2 treatment, 4 hours recovery
To study the effect of PDS (rG4 structure stabilizer) on FEN1 expression, results showed that PDS pretreatment upregulated FEN1 expression.
Antioxidants (Basel). 2023 Jan 26;12(2):276
HeLa cancer cells
10 µM
24 hours
Applied mass spectrometry (MS) based quantitative proteomics to profile the protein expression of HeLa cells subjected to PDS treatment. Results showed that PDS significantly downregulated 22 proteins but upregulated 16 proteins.
Nucleic Acids Res. 2022 Apr 8;50(6):3070-3082
PK-15 CD163 cells
10 µM
24 hours
To investigate the effect of PDS on PRRSV replication. Results showed that PDS treatment significantly reduced viral RNA levels and protein expression.
Nucleic Acids Res. 2023 Oct 27;51(19):10752-10767
Murine B16-F10 melanoma cells
10 µM
24 hours
To study the immune gene activation effect of PDS in murine melanoma cells, showing PDS activated STING translocation and immune gene expression in wild-type B16 cells but not in STING knockout cells.
Nucleic Acids Res. 2021 Jul 9;49(12):6673-6686
Human MRC5 normal lung cells
10 µM
24 hours
To determine the immune gene activation effect of PDS in normal cells, showing only IFNB gene was activated and secreted IFNB protein levels were much lower than in MCF-7 cells.
Nucleic Acids Res. 2021 Jul 9;49(12):6673-6686
Human MCF-7 breast cancer cells
10 µM
24 hours
To measure the cytotoxic potency of PDS, showing its IC50 is 81.6 μM. At a lower dose of 10 μM, PDS only slightly affected MCF-7 cell growth but increased the levels of G4 and γH2AX (phosphorylated S139 H2AX histone) foci.
Nucleic Acids Res. 2021 Jul 9;49(12):6673-6686
HEK293T cells
5 µM
24 hours
To evaluate the effect of the PA-PDS conjugate ligand on the regulation of gene expression in the hTERT 5-12 DNA promoter region. Results showed that the PA-PDS conjugate ligand significantly reduced Renilla luciferase activity more than PA or PDS alone.
Nucleic Acids Res. 2024 Oct 14;52(18):10775-10787
HepG2 cells
20 µM
24 hours
To investigate the effect of PDS on RNAPII-mediated long-range DNA contacts, results showed that PDS treatment significantly reduced DNA contacts involving G4 structure loci.
Nucleic Acids Res. 2023 Sep 8;51(16):8434-8446
HeLa cells
100 µM
24 hours
Assessed the effect of Pyridostatin on cell survival, showing increased sensitivity in USP50-depleted cells
Nat Commun. 2024 Sep 16;15(1):8102
SV40-transformed human MRC5 fibroblasts
2 µM
24 hours
Pyridostatin promoted growth arrest via inducing replication- and transcription-dependent DNA damage, leading to G2 phase cell cycle arrest.
Nat Chem Biol. 2012 Feb 5;8(3):301-10
H1299+shBRCA2 DOX
10 µM
3 days
Evaluate the activation of immune responses by Pyridostatin in BRCA2-deficient cells, showing increased IRF3 Ser386 phosphorylation
EMBO Mol Med. 2022 Mar 7;14(3):e14501
Human telomere DNA
100 nM
30 minutes
To evaluate the binding of Pyridostatin (PDS) to telomeric G-quadruplex and its inhibitory effect on DNA polymerase. Results showed that the dissociation constant Kd of PDS was 440 ±80 nM, and at 100 nM concentration, 18.7% of G-quadruplex was bound to PDS.
Nucleic Acids Res. 2019 Apr 23;47(7):3295-3305
Human telomeric G-quadruplex
20 nM to 2 µM
30 seconds
To determine the dissociation constant of PDS with G-quadruplex, results showed Kd of 490±80 nM
Nat Chem. 2011 Aug 28;3(10):782-7
Human telomeric G-quadruplex
0.5 µM
30 seconds
To evaluate the effect of PDS on the mechanical stability of G-quadruplex, results showed increased mechanical stability of PDS-bound G-quadruplex
Nat Chem. 2011 Aug 28;3(10):782-7
HEK293T cells
2 µM or 10 µM
4 days
To study the effect of PDS on DNA damage and cell cycle in RAD51-deficient cells
Mol Cell. 2016 Feb 4;61(3):449-460
HepG2 cells
20 µM
48 hours
To investigate the effect of PDS on HsACBP transcription, results showed that PDS significantly inhibited HsACBP transcription
To study the DNA damage response and cell cycle effects of PDS in BRCA2-deficient cells
Mol Cell. 2016 Feb 4;61(3):449-460
Various cancer cell lines
2 µM
72 hours
Pyridostatin inhibited cell proliferation and induced apoptosis in some cells.
Nat Chem Biol. 2012 Feb 5;8(3):301-10
HT1080 fibrosarcoma cells
0.89 µM (GI50)
72 hours
Evaluate the growth inhibition effect of PDS family ligands, PDSI showed the strongest growth inhibition
J Am Chem Soc. 2013 Jul 3;135(26):9640-3
Pyridostatin 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Silkworm (Bombyx mori)
Fifth instar larvae
Injection
2, 4 or 6 μl of 15 mM
Single injection, observed at 12, 24 and 36 hours post-injection
To investigate the effect of PDS on larval development and lipid metabolism, results showed that PDS treatment led to reductions in fat body mass, body size and weight, and growth and metamorphic rates
Nucleic Acids Res. 2022 Jul 8;50(12):6953-6967
CB17-SCID mice
DLD1 BRCA2−/− xenograft tumours
Intravenous injection
7.5 mg/kg/day
Five consecutive days, followed by 2-day break and five more days of treatment
Evaluate the inhibitory effect of Pyridostatin on BRCA2-deficient tumours, showing significant suppression of tumour growth
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