Administering CBL0137 hydrochloride eliminates viable cells at dosages surpassing 2.5 μM. This compound notably diminishes the number of colonies formed, impacting not just MiaPaCa-2 cells but also those resistant to gemcitabine, such as PANC-1 cells. In human pancreatic cancer cell treatments, CBL0137 hydrochloride leads to a concentration-dependent decrease in the protein and mRNA levels of RRM1 and RRM2[1].
体内研究
Observations from the CBL0137 hydrochloride solo treatment group and the group receiving a combination of CBL0137 hydrochloride and gemcitabine reveal extensive necrotic areas, a high number of apoptotic bodies, and a significant reduction in tumor cells. Lower doses of CBL0137 hydrochloride, between 50 to 60 mg/kg, enhance the anticancer efficacy of gemcitabine similarly to the maximum tolerated dose (MTD) of 90 mg/kg, underscoring no meaningful difference among the combination treatments. The mechanism of CBL0137 hydrochloride's action involves the inhibition of FACT by depleting the active FACT pool necessary for transcription elongation[1].
Furthermore, CBL0137 hydrochloride, when orally administered at a safe dosage of 30 mg/kg daily, following a 5 days on/2 days off regimen, effectively curtails tumor growth in xenograft models derived from colon (DLD-1), renal cell carcinoma (Caki-1), melanoma (Mel-7) cell lines, and surgical samples from pancreatic ductal adenocarcinoma patients[2].
体外研究
Administering CBL0137 hydrochloride eliminates viable cells at dosages surpassing 2.5 μM. This compound notably diminishes the number of colonies formed, impacting not just MiaPaCa-2 cells but also those resistant to gemcitabine, such as PANC-1 cells. In human pancreatic cancer cell treatments, CBL0137 hydrochloride leads to a concentration-dependent decrease in the protein and mRNA levels of RRM1 and RRM2[1].
CBL0137 HCl 细胞实验
Cell Line
Concentration
Treated Time
Description
References
HeLa
0.6 μM
48 hours
Assess cytotoxicity of CBL0137, showing IC50 of 0.1 μM
Cancer Res. 2018 Mar 15;78(6):1431-1443.
Human Fibroblasts (HS68)
5 μM
36 hours
CBL0137 induces ZBP1-dependent cell death in hIFNβ-pretreated HS68 cells.
Nature. 2022 Jun;606(7914):594-602.
Murine Embryonic Fibroblasts (MEFs)
5 μM
24 hours
CBL0137 activates ZBP1-dependent cell death, including necroptosis and apoptosis, by inducing Z-DNA formation.
Nature. 2022 Jun;606(7914):594-602.
NK-92 cells
500 nM
24 hours
CBL0137 treatment upregulated the expression of IFNs and ISGs, and enhanced NK cell-mediated killing of virus-infected cells.
Nucleic Acids Res. 2022 Aug 26;50(15):8700-8718.
HeLa cells
100, 200, 500 nM
24 hours
CBL0137 treatment upregulated the expression of IFNs and ISGs, and inhibited infections of ZIKV, influenza A, and SARS-CoV-2.
Nucleic Acids Res. 2022 Aug 26;50(15):8700-8718.
HEK293T cells
100, 200, 500 nM
24 hours
CBL0137 treatment upregulated the expression of IFNs and ISGs, and inhibited infections of ZIKV, influenza A, and SARS-CoV-2.
Nucleic Acids Res. 2022 Aug 26;50(15):8700-8718.
BJ fibroblasts
1 μM
3 hours
Induced degradation of POLR2A but no degradation of POLR1A was observed.
Nucleic Acids Res. 2024 May 8;52(8):4151-4166.
U2OS cells
1 μM
3 hours
Induced degradation of POLR2A and simultaneously enabled the trapping of Topoisomerases TOP2A and TOP2B on the chromatin.
Nucleic Acids Res. 2024 May 8;52(8):4151-4166.
NDF cells
1 μM
24 hours
To evaluate the toxicity of CBL0137 on normal fibroblasts and p53 activation. Results showed that CBL0137 caused growth arrest at 0.5-1 μM but did not induce senescence markers.
Nucleic Acids Res. 2023 Nov 27;51(21):11836-11855.
HT1080 cells
1 μM
24 hours
To evaluate the toxicity of CBL0137 on HT1080 cells and p53 activation. Results showed that CBL0137 caused growth arrest at 0.5-1 μM but did not induce senescence markers.
Nucleic Acids Res. 2023 Nov 27;51(21):11836-11855.
A1207
0.6 or 2.0 µM
1 or 16 hours
Evaluate the effect of CBL0137 on FACT, p53, and NF-ĸB. Results showed that CBL0137 caused loss of FACT subunits from the soluble protein fraction, significantly increased p53 expression, and inhibited NF-ĸB-dependent transcription.
Neuro Oncol. 2017 Feb 1;19(2):186-196.
U87MG
0.6 or 2.0 µM
1 or 16 hours
Evaluate the effect of CBL0137 on FACT, p53, and NF-ĸB. Results showed that CBL0137 caused loss of FACT subunits from the soluble protein fraction, significantly increased p53 expression, and inhibited NF-ĸB-dependent transcription.
Neuro Oncol. 2017 Feb 1;19(2):186-196.
B16 NF-κB-Luc reporter cells
5 or 10 μM
15 minutes
To assess the effect of CBL0137 on NF-κB pathway activity, results showed that CBL0137 dose-dependently suppressed NF-κB pathway activity.
Cancer Res. 2016 Nov 15;76(22):6620-6630.
B16 melanoma cells
0.7, 1.4, 2.8, or 5.6 μM
15 or 30 minutes
To evaluate the cytotoxic effects of CBL0137 on B16 melanoma cells, results showed that CBL0137 significantly reduced cell viability after 15 and 30 minutes of treatment.
Cancer Res. 2016 Nov 15;76(22):6620-6630.
BE(2)C cells
100 nM
22 hours
Evaluate the effect of CBL0137 on DNA double-strand break repair
Sci Transl Med. 2015 Nov 4;7(312):312ra176.
Non-stem tumor cells (CD133-)
100–600 nM
72 hours
Evaluate the inhibitory effect of CBL0137 on non-stem tumor cells, results showed that CBL0137 effectively inhibited the proliferation of non-stem tumor cells.
Cancer Res. 2016 Apr 15;76(8):2432-42.
GBM stem cells (CD133+)
100–600 nM
72 hours
Evaluate the inhibitory effect of CBL0137 on GBM stem cells, results showed that CBL0137 effectively inhibited the proliferation of GBM stem cells.
Cancer Res. 2016 Apr 15;76(8):2432-42.
HT1080
3 μM
1.5 hours
Study the effect of CBL0137 on FACT chromatin binding via ChIP-seq analysis
Cancer Res. 2018 Mar 15;78(6):1431-1443.
HT1080 cells
3 μM
Investigate the effect of CBL0137 on FACT distribution in transcribed genes, showing that CBL0137 treatment leads to redistribution of FACT from transcribed chromatin regions to other genomic loci.
Sci Adv. 2018 Nov 7;4(11):eaav2131.
CBL0137 HCl 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Nude mice
U87MG and A1207 orthotopic glioblastoma models
Oral or intravenous
25 mg/kg orally or 70 mg/kg intravenously
Daily oral for 8 days or weekly intravenous twice
Evaluate the antitumor effect of CBL0137 in vivo. Results showed that intravenous administration of CBL0137 significantly increased survival and accumulated more in tumor tissue than in normal brain tissue.
Neuro Oncol. 2017 Feb 1;19(2):186-196.
Mice
TH-MYCN+/+ mice
Intravenous
60 mg/kg
Every 4 days for 8 doses
Evaluate the therapeutic effect of CBL0137 on established neuroblastoma
Sci Transl Med. 2015 Nov 4;7(312):312ra176.
Mice (C57BL/6J)
B16-F10 melanoma model
Intratumoral injection
20 μM (intratumoral injection)
Every two days for a total of 4 doses
CBL0137 significantly enhances the therapeutic effect of anti-PD-1 antibody by inducing ZBP1-dependent necroptosis in fibroblasts of the tumor microenvironment (TME).
Nature. 2022 Jun;606(7914):594-602.
Nude mice
Breast cancer model
Oral gavage
30 mg/kg
Five days a week for six weeks
CBL0137 inhibited the growth of TMD-436 cells-derived tumors but TMD-231 cell-derived tumors were resistant to the treatment
Cancer Res. 2023 Apr 14;83(8):1345-1360
C57BL/6 mice
B16 melanoma model
Isolated limb perfusion (ILP) or intra-arterial infusion (IAI)
0.044, 0.111, 0.222, and 0.444 mg/mL (15-minute perfusion) or 0.022, 0.055, 0.111 and 0.222 mg/mL (30-minute perfusion)
Single 15 or 30-minute perfusion
To evaluate the antitumor efficacy of CBL0137 in vivo against melanoma, results showed that CBL0137 administered via ILP or IAI significantly suppressed tumor growth and was more effective than systemic administration.
Cancer Res. 2016 Nov 15;76(22):6620-6630.
NSG mice
Orthotopic GBM model
Oral administration
0.5 mg/mL
Replaced every 7 days, continuous treatment
Evaluate the therapeutic effect of CBL0137 on orthotopic GBM model, results showed that CBL0137 significantly prolonged the survival of mice.
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