CBL0137 is a suppressor of the histone chaperone FACT, which is crucial for chromatin transcription. By downregulating NF-kappaB and activating p53, CBL0137 effectively reinstates acetylation and trimethylation of histone H3. Its role as an anticancer agent is further underscored by its ability to trigger apoptosis in cancer cells[2].
体内研究
Further evidence of CBL0137’s antitumor efficacy is observed in preclinical models. Monotherapy or combination therapy with gemcitabine showcases significant antitumor effects, evidenced by extensive necrotic areas, a multitude of apoptotic bodies, and a marked decrease in tumor cell viability. Interestingly, doses ranging between 50 to 60 mg/kg of CBL0137 augment gemcitabine's antitumor action comparably to the maximum tolerated dose (MTD) of 90 mg/kg, indicating no significant differences among these combination therapies. This potent activity stems from CBL0137’s ability to impair FACT functionality by diminishing the active FACT pool necessary for transcription elongation[2].
Moreover, CBL0137, administered orally at a safe dosage of 30 mg/kg per day following a 5 days on/2 days off regimen, effectively inhibits tumor growth in xenograft models of colon (DLD-1), renal cell carcinoma (Caki-1), melanoma (Mel-7), and transplanted patient-derived pancreatic ductal adenocarcinoma samples[3]. Such widespread anticancer efficacy exemplifies CBL0137’s potential as a highly versatile and potent therapeutic option in the treatment of cancer.
体外研究
CBL0137's capability to entirely eliminate viable cells at dosages exceeding 2.5 μM has been documented. When used alongside gemcitabine, it notably lowers the colony formation of MiaPaCa-2 cells and even those of gemcitabine-resistant PANC-1 cells. By reducing the levels of RRM1 and RRM2 proteins and mRNA in a concentration-dependent manner, CBL0137 enhances the efficacy of gemcitabine, specifically by obstructing the drug-induced upregulation of these critical enzymes for DNA replication and repair[2].
CBL0137 细胞实验
Cell Line
Concentration
Treated Time
Description
References
D425 cells
1 µM
24 hours
Inhibited cell proliferation and induced apoptosis
Cell Death Dis. 2020 Dec 2;11(12):1029.
ONS-76 cells
2 µM
1 hour
Enhanced sensitivity to cisplatin and radiation, reduced cell viability
Cancer Lett. 2021 Nov 1;520:201-212.
HD-MB03 cells
2 µM
1 hour
Enhanced sensitivity to cisplatin and radiation, reduced cell viability
Cancer Lett. 2021 Nov 1;520:201-212.
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 downregulated 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 downregulated NF-ĸB-dependent transcription.
Neuro Oncol. 2017 Feb 1;19(2):186-196.
HT1080 cells
1-2.5 µM
15 minutes
To evaluate the effect of CBL0137 on enhancer-promoter communication (EPC), results showed that CBL0137 significantly decreased transcript yield on both chromatinized and histone-free DNA templates.
Nat Commun. 2019 Mar 29;10(1):1441.
B16 NF-κB-Luc reporter cells
5 or 10 µM
15 minutes
To evaluate the inhibitory 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.
KELLY cells
25 µM
15 minutes
Evaluate the effect of CBL0137 and PNB on chromatin condensation
Clin Cancer Res. 2021 Aug 1;27(15):4338-4352.
RCC45
2 µM
24 hours
Evaluate the effect of CBL0137 on the cell cycle of RCC45 cells
Sci Transl Med. 2011 Aug 10;3(95):95ra74.
HDMB03 cells
1 µM
24 hours
Inhibited cell proliferation and induced apoptosis
Cell Death Dis. 2020 Dec 2;11(12):1029.
D458 cells
1 µM
24 hours
Inhibited cell proliferation and induced apoptosis
Cell Death Dis. 2020 Dec 2;11(12):1029.
B16 melanoma cells
0.7, 1.4, 2.8, or 5.6 µM
15 or 30 minutes
To evaluate the in vitro cytotoxic effects of CBL0137 on B16 melanoma cells. Results showed that CBL0137 significantly reduced tumor cell viability at both 15 and 30 minutes of treatment in a dose-dependent manner.
Cancer Res. 2016 Nov 15;76(22):6620-6630.
BE(2)-C cells
100 nM, 200 nM
20 hours
Evaluate the effect of CBL0137 on PNB-induced DNA damage repair
Clin Cancer Res. 2021 Aug 1;27(15):4338-4352.
Murine Embryonic Fibroblasts (MEFs)
5 µM
24 hours
CBL0137 induced ZBP1-dependent cell death by triggering Z-DNA formation and activating ZBP1-mediated necroptosis.
Nature. 2022 Jun;606(7914):594-602.
NK-92 cells
500 nM
24 hours
To investigate the effect of CBL0137 on NK cell activation, results showed that CBL0137 significantly enhanced NK cell-mediated killing function.
Nucleic Acids Res. 2022 Aug 26;50(15):8700-8718.
HeLa cells
500 nM
24 hours
To investigate the inhibitory effect of CBL0137 on ZIKV and influenza A virus infection, results showed that CBL0137 effectively inhibited viral infection.
Nucleic Acids Res. 2022 Aug 26;50(15):8700-8718.
HEK293T cells
100, 200, 500 nM
24 hours
To investigate the induction of IFN signaling by CBL0137, results showed that CBL0137 significantly increased the expression of IFNs and ISGs.
Nucleic Acids Res. 2022 Aug 26;50(15):8700-8718.
NDFs
0.5 µM
24 hours
To evaluate the effect of CBL0137 on the transcriptome of normal dermal fibroblasts. Results showed that CBL0137 at 0.5 μM induced widespread transcriptional changes, which were similar in p53-positive and negative cells.
Nucleic Acids Res. 2023 Nov 27;51(21):11836-11855.
HT1080
0.5 µM
24 hours
To evaluate the effect of CBL0137 on the transcriptome of HT1080 cells. Results showed that CBL0137 at 0.5 μM induced widespread transcriptional changes, which were similar in p53-positive and negative cells.
Nucleic Acids Res. 2023 Nov 27;51(21):11836-11855.
NDFs
1 µM
24 hours
To evaluate the toxicity of CBL0137 on normal dermal fibroblasts and its effect on p53 activation. Results showed that CBL0137 induced p53 protein accumulation at concentrations of 0.5-1 μM and caused cell death at higher concentrations.
Nucleic Acids Res. 2023 Nov 27;51(21):11836-11855.
HT1080
1 µM
24 hours
To evaluate the toxicity of CBL0137 on HT1080 cells and its effect on p53 activation. Results showed that CBL0137 induced p53 protein accumulation at concentrations of 0.5-1 μM and caused cell death at higher concentrations.
Nucleic Acids Res. 2023 Nov 27;51(21):11836-11855.
Jeko-1
0.5-2.0 µM
24 hours
To evaluate the inhibitory effect of CBL0137 on B-NHL cell proliferation, results showed that CBL0137 significantly inhibited B-NHL cell proliferation in a concentration and time-dependent manner.
Cell Commun Signal. 2023 Jan 23;21(1):16.
Raji
0.5-2.0 µM
24 hours
To evaluate the inhibitory effect of CBL0137 on B-NHL cell proliferation, results showed that CBL0137 significantly inhibited B-NHL cell proliferation in a concentration and time-dependent manner.
Cell Commun Signal. 2023 Jan 23;21(1):16.
Farage
0.5-2.0 µM
24 hours
To evaluate the inhibitory effect of CBL0137 on B-NHL cell proliferation, results showed that CBL0137 significantly inhibited B-NHL cell proliferation in a concentration and time-dependent manner.
Cell Commun Signal. 2023 Jan 23;21(1):16.
SU-DHL-4
0.5-2.0 µM
24 hours
To evaluate the inhibitory effect of CBL0137 on B-NHL cell proliferation, results showed that CBL0137 significantly inhibited B-NHL cell proliferation in a concentration and time-dependent manner.
Cell Commun Signal. 2023 Jan 23;21(1):16.
BJ fibroblasts
1 µM
3 hours
Induced degradation of POLR2A without affecting POLR1A degradation
Nucleic Acids Res. 2024 May 8;52(8):4151-4166.
U2OS cells
1 µM
3 hours
Induced degradation of POLR2A, with a progressive consumption of form IIa and reduction in Ser5 and Ser2 phosphorylation of POLR2A
Nucleic Acids Res. 2024 May 8;52(8):4151-4166.
Human Fibroblasts (HS68)
5 µM
36 hours
CBL0137 induced Z-DNA formation and ZBP1-dependent cell death in HS68 cells.
Nature. 2022 Jun;606(7914):594-602.
MB52
300 nM
48 hours
To evaluate the effect of CBL0137 on apoptosis and cell cycle in DPM cells, results showed that CBL0137 induced apoptosis and G2-M phase cell cycle arrest.
J Exp Clin Cancer Res. 2023 Nov 16;42(1):304.
H2373
300 nM
48 hours
To evaluate the effect of CBL0137 on NF-κB and p53, results showed that CBL0137 inhibited NF-κB and activated p53.
J Exp Clin Cancer Res. 2023 Nov 16;42(1):304.
T. brucei Lister 427
0.038 µM
48 hours
Evaluate the inhibitory activity of CBL0137 against T. brucei, with an EC50 of 0.038 μM.
Evaluate the growth inhibitory activity of CBL0137 on patient-derived tumor cells, showing significant anti-growth activity against SSRP1-high tumor cells with IC50 values of 0.3–1.3 μM.
Evaluate the growth inhibitory activity of CBL0137 on HGSC cell lines, showing significant anti-growth activity against SSRP1-high HGSC cell lines with IC50 values of 0.2–0.6 μM.
J Exp Clin Cancer Res. 2022 Dec 21;41(1):355.
HeLa
2 µM
6 hours
Evaluate the effect of CBL0137 on DNA damage in HeLa cells
Sci Transl Med. 2011 Aug 10;3(95):95ra74.
MM1.S cells
0.3-3 µM
6 hours
To analyze the effect of CBL0137 on gene expression profiles, results showed that CBL0137 strongly inhibited transcription regulated by enhancers or super-enhancers.
Nat Commun. 2019 Mar 29;10(1):1441.
GBM 08-387
150 nM
6 hours
Evaluate the effect of CBL0137 combined with radiotherapy on cell growth, results showed that combination treatment significantly reduced cell growth
Cancer Lett. 2021 Feb 28;499:232-242.
GBM 3691
150 nM
6 hours
Evaluate the effect of CBL0137 combined with radiotherapy on cell growth, results showed that combination treatment significantly reduced cell growth
Cancer Lett. 2021 Feb 28;499:232-242.
GBM 1016
150 nM
6 hours
Evaluate the effect of CBL0137 combined with radiotherapy on cell growth, results showed that combination treatment reduced cell growth but did not reach statistical significance
Cancer Lett. 2021 Feb 28;499:232-242.
GBM NU757
150 nM
6 hours
Evaluate the effect of CBL0137 combined with radiotherapy on cell growth, results showed that combination treatment significantly reduced cell growth
Cancer Lett. 2021 Feb 28;499:232-242.
Non-stem tumor cells (NSTCs)
100-600 nM
72 hours
To evaluate the cytotoxic effect of CBL0137 on NSTCs, results showed NSTCs were also sensitive to CBL0137 but less so than GSCs.
Cancer Res. 2016 Apr 15;76(8):2432-42.
GBM stem cells (GSCs)
100-600 nM
72 hours
To evaluate the cytotoxic effect of CBL0137 on GSCs, results showed GSCs were highly sensitive to CBL0137.
Cancer Res. 2016 Apr 15;76(8):2432-42.
H2052
200-380 nM
72 hours
To evaluate the killing effect of CBL0137 on DPM cells, results showed that CBL0137 effectively killed DPM cells at low concentrations.
J Exp Clin Cancer Res. 2023 Nov 16;42(1):304.
H526 non-TICs
250 nM
72 hours
Evaluate the effect of CBL0137 combined with Rova-T on cell survival of H526 non-TICs, results showed no additional effect on non-TICs
Br J Cancer. 2021 Mar;124(5):893-895.
H82 non-TICs
250 nM
72 hours
Evaluate the effect of CBL0137 combined with Rova-T on cell survival of H82 non-TICs, results showed no additional effect on non-TICs
Br J Cancer. 2021 Mar;124(5):893-895.
HT1080
0.8 µM
8 hours
Evaluate the p53 activation effect of CBL0137 on HT1080 cells
Sci Transl Med. 2011 Aug 10;3(95):95ra74.
H526 TICs
250 nM
72 hours
Evaluate the effect of CBL0137 combined with Rova-T on cell survival of H526 TICs, results showed significant reduction in cell survival
Br J Cancer. 2021 Mar;124(5):893-895.
H82 TICs
250 nM
72 hours
Evaluate the effect of CBL0137 combined with Rova-T on cell survival of H82 TICs, results showed significant reduction in cell survival
Br J Cancer. 2021 Mar;124(5):893-895.
HCT116-p53 null
1 µM
8 hours
Evaluate the activation effect of CBL0137 on p53 mutants in HCT116-p53 null cells
Single 15 or 30 minutes (ILP); Single or once weekly for up to 4 weeks (i.v.)
To evaluate the antitumor efficacy and toxicity of CBL0137 via different administration routes in a B16 melanoma model. Results showed that CBL0137 delivered by ILP exhibited antitumor activity comparable to melphalan at doses corresponding to only a fraction of the systemic MTD, with lower toxicity. Intra-arterial infusion (IAI) of CBL0137 also demonstrated significant antitumor efficacy and safety.
Cancer Res. 2016 Nov 15;76(22):6620-6630.
NSG mice
Orthotopic GBM model
Oral
0.5 mg/mL
Replaced every 7 days, continuous treatment
To evaluate the therapeutic effect of CBL0137 on GBM mouse models, results showed CBL0137 significantly prolonged survival.
Daily for 7 days (subcutaneous); once a week for four weeks (orthotopic)
Evaluate the effect of CBL0137 combined with radiotherapy on survival and cancer stem cell frequency, results showed that combination treatment significantly prolonged survival and reduced cancer stem cell frequency
Cancer Lett. 2021 Feb 28;499:232-242.
NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ (NSG) mice
Subcutaneous xenograft model
Oral gavage
20 mg/kg
Twice a week for 3 weeks
To evaluate the anti-tumor effect of CBL0137 in vivo, results showed that CBL0137 significantly suppressed tumor growth and prolonged survival.
J Exp Clin Cancer Res. 2023 Nov 16;42(1):304.
C57BL/6J mice
B16-F10 melanoma model
Intratumoral injection
20 μM
Every two days for a total of 4 doses
CBL0137 significantly reversed immune checkpoint blockade (ICB) unresponsiveness by inducing ZBP1-dependent necroptosis in fibroblasts of the tumor microenvironment (TME).
Nature. 2022 Jun;606(7914):594-602.
Nude mice
Orthotopic U87MG and A1207 glioblastoma models
Oral or intravenous
25 mg/kg orally, 70 or 90 mg/kg intravenously
Various regimens: oral daily, intravenous every 4 days or once weekly for 4 weeks
Evaluate the therapeutic effect of CBL0137 on glioblastoma. Results showed that intravenous administration of CBL0137 significantly prolonged survival, increased tumor cell apoptosis, and suppressed proliferation. Oral administration showed limited efficacy.
Neuro Oncol. 2017 Feb 1;19(2):186-196.
Mice
Human tumor xenograft model
Oral gavage
30 mg/kg
5 days on/2 days off schedule for up to 4 weeks
Evaluate the antitumor effect of CBL0137 in mouse xenograft models
Sci Transl Med. 2011 Aug 10;3(95):95ra74.
Nude mice
Mammary fat pad injection model
Oral gavage
30 mg/kg
Five days a week for six weeks
Evaluate the inhibitory effect of CBL0137 on TONSL-amplified breast cancer cell lines in vivo
Cancer Res. 2023 Apr 14;83(8):1345-1360
Nude mice
Subcutaneous tumor xenograft model
Intraperitoneal injection
30 mg/kg CBL0137 and 2 mg/kg cisplatin
Every other day for four weeks
Significantly suppressed MB tumor growth
Cancer Lett. 2021 Nov 1;520:201-212.
Mice (C57BL/6, NRG, NSG)
ID8 (p53−/− BRCA1−/−) HGSC model and HGSC PDX models (DF86, DF149, LP28)
Intravenous (IV) or intraperitoneal (IP)
30-60 mg/kg
Once per week for 2 weeks
Evaluate the anti-tumor activity of CBL0137 monotherapy in HGSC models, showing significant reduction in ascitic fluid volume and tumor nodules, and prolonged survival of mice.
J Exp Clin Cancer Res. 2022 Dec 21;41(1):355.
Mice
TH-MYCN+/+ mouse model
Intravenous injection
60 mg/kg
Every 4 days for 8 doses
Evaluate the inhibitory effect of CBL0137 on neuroblastoma growth
Sci Transl Med. 2015 Nov 4;7(312):312ra176.
NOD scid IL-2 receptor gamma knockout (NSG) mice
SCLC PDX model
Intraperitoneal (Rova-T), intravenous (CBL0137)
60 mg/kg (CBL0137), 1.8 mg/kg (Rova-T)
Once weekly (CBL0137), until tumor volume reached ~1200 mm³
Evaluate the anti-tumor efficacy of CBL0137 combined with Rova-T in SCLC PDX model, results showed significant tumor growth inhibition and prolonged survival
Br J Cancer. 2021 Mar;124(5):893-895.
BALB/c nude mice
BE(2)-C neuroblastoma xenograft model
Intravenous CBL0137, intraperitoneal PNB
60 mg/kg CBL0137, 5 mg/kg PNB
CBL0137 every 4 days for 8 doses, PNB for 7 consecutive days
Evaluate the effect of CBL0137 and PNB combination on tumor growth in neuroblastoma xenograft models
Clin Cancer Res. 2021 Aug 1;27(15):4338-4352.
Nude mice
Orthotopic intracranial xenograft model
Intravenous injection
70 mg/kg
Every four days for 28 days
Significantly suppressed tumor growth and prolonged survival
Cell Death Dis. 2020 Dec 2;11(12):1029.
Swiss-Webster mice
Mouse model of chronic HAT
Oral
80 mg/kg
Once daily for 10 days
Evaluate the efficacy of CBL0137 in a mouse model of chronic HAT, showing a 165-fold reduction in parasite tissue load.
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