SC144 showed its function through both exhibiting potent cytotoxicity, by itself or synergism with other compounds, against a panel of drug-sensitive and drug-resistant cancer cell lines, and targeting to gp130.
Drug resistance is caused by various cellular mechanism. One of the most important factors is the expression of a group of genes encoding ATP-dependent transporters of particular importance in drug resistance. SC144 showed its function through both exhibiting potent cytotoxicity, by itself or synergism with other compounds, against a panel of drug-sensitive and drug-resistant cancer cell lines, and targeting to gp130. Treatment with SC144 induced p-gp130-S782 in a time (2μM, 5min-6h)- and dose (0.5-2μM)-dependent manner in both OVCAR-8 and Caov-3 cells, suggesting the downregulation of cell surface expression of gp130. Consistent with the induced phosphorylation, the suppression on Stat3 signaling pathway, a downstream signaling cascade of gp130, and its target gene expression, including decrease of constitutive phosphorylation of Stat3, Survivin, MMP-7, D1, Bcl-XL, Bcl-2 and Ape1/Ref-1, can be observed after treatment with SC144 both in vitro and in vivo. For Gp130 is part of the receptor signaling complexes for at least 8 cytokines, suppression of gp130 by SC144 can inhibit downstream signaling induced by gp130 cytokines, including p-Stat3, p-Stat1 and p-Akt induced by LIF or Il-6. Daily intraperitoneal injection of SC144 at 10 mg/kg 5 days on and 2 days off for 58 days significantly inhibited OVCAR-8 tumor growth in mice[1]. Treatment with SC144 alone can cause growth inhibition of HT29 colon cancer cells with IC50 value of 0.9μM. Combined treatment with SC144 significantly enhanced the cytotoxicity of oxaliplatin in oxaliplatin-resistant HTOXAR3 cells. Co-treatment of SC144 with oxaliplatin in HT29 cells caused cell cycle arrest halting at S-phase[2].
Inhibited CFU-Mk colony formation, IC50 of 4.3 ± 0.2 nM
Blood Adv. 2021 Apr 27;5(8):2184-2195
SK-OV-3 cells
1.2 µM
2 hours
To measure hypoxia levels induced by SC144, results showed increased nitroreductase activity
Theranostics. 2020 May 25;10(15):6959-6976
4T1 cells
10 µM
24 hours
SC144 induced apoptosis and immunogenic cell death (ICD) of 4T1 cells, characterized by upregulation of calreticulin (CRT).
Nat Commun. 2023 Aug 8;14(1):4771
MC38 cells
10 µM
24 hours
SC144 induced apoptosis and immunogenic cell death (ICD) of MC38 cells, characterized by increased secretion of HMGB-1 and CXCL-10 and upregulation of calreticulin (CRT).
Nat Commun. 2023 Aug 8;14(1):4771
Bone marrow-derived macrophages (BMDM)
10 µM
24 hours
SC144 treatment increased the frequency of CD206lowMHCIIhighM1-like macrophages and decreased CD206highMHCIIlowM2-like macrophages, indicating polarization of macrophages toward M1 phenotype.
Nat Commun. 2023 Aug 8;14(1):4771
E8
0.05-1 µM
24-48 hours
SC144 significantly inhibited the growth and viability of E8 cells and reduced the expression of survivin.
Br J Cancer. 2015 Jul 14;113(2):242-51
CE2
0.05-1 µM
24-48 hours
SC144 significantly inhibited the growth and viability of CE2 cells and reduced the expression of survivin.
Br J Cancer. 2015 Jul 14;113(2):242-51
CE1
0.05-1 µM
24-48 hours
SC144 significantly inhibited the growth and viability of CE1 cells and reduced the expression of survivin.
Br J Cancer. 2015 Jul 14;113(2):242-51
C4-2B
0.05-1 µM
24-48 hours
SC144 significantly inhibited the growth and viability of C4-2B cells and reduced the expression of survivin.
Br J Cancer. 2015 Jul 14;113(2):242-51
DU145
0.05-1 µM
24-48 hours
SC144 significantly inhibited the growth and viability of DU145 cells and reduced the expression of survivin.
Br J Cancer. 2015 Jul 14;113(2):242-51
PC3
0.05-1 µM
24-48 hours
SC144 significantly inhibited the growth and viability of PC3 cells and reduced the expression of survivin.
Br J Cancer. 2015 Jul 14;113(2):242-51
LNCaP
0.05-1 µM
24-48 hours
SC144 significantly inhibited the growth and viability of LNCaP cells and reduced the expression of survivin and MMP-9.
Br J Cancer. 2015 Jul 14;113(2):242-51
CD8+ T-cells
2 µM
24-72 hours
SC144 exhibited cytotoxicity among activated CD8+ T-cells, leading to reduced cell numbers.
Nat Commun. 2023 Aug 8;14(1):4771
UT7 cells
5 µM
3 days
Inhibited proliferation of CALR DEL and KO UT7 cells, reducing by 63.9% ± 3% and 50% ± 4.1%
Blood Adv. 2021 Apr 27;5(8):2184-2195
UT7/mpl cells
5 µM
3 days
Inhibited proliferation of CALR DEL and KO UT7/mpl cells, reducing by 58.3% ± 1.2% and 57.2% ± 3.6%
Blood Adv. 2021 Apr 27;5(8):2184-2195
LNCaP cells
2 µM
4 hours
To validate transcriptional effects of SC144 in an independent cell line, results showed upregulation of HIF1A-AS2 transcription
Theranostics. 2020 May 25;10(15):6959-6976
OVCAR-8 cells
1.2 µM
4 hours
To assess the effect of SC144 on hypoxia-related gene transcription, results showed upregulation of HIF1A-AS2 transcription
Theranostics. 2020 May 25;10(15):6959-6976
ASPC cells
1, 2 µM
48 hours
To evaluate the effect of SC144 on ASPC cell viability and proliferation. Results showed that 1 and 2 µM SC144 alone significantly inhibited the viability of ASPC cells (p < 0.001). Paclitaxel did not further enhance the effects observed with single SC144 treatment.
Cancers (Basel). 2023 Jan 11;15(2):456
L3.6pl cells
0.1, 0.2, 1, 2 µM
48 hours
To evaluate the effect of SC144 on cell viability and proliferation. Results showed that 1 and 2 µM SC144 alone significantly inhibited the viability of L3.6pl cells (p < 0.01, p < 0.001). However, combined treatment with 0.1, 0.2, and 1 µM SC144 blocked the effect of 10 nM paclitaxel on viability reduction.
Cancers (Basel). 2023 Jan 11;15(2):456
SC144 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Rats
Monocrotaline (MCT)-induced pulmonary arterial hypertension model
Intraperitoneal injection
10 mg/kg
Daily injection, duration not specified
SC144 improved right ventricular function, reduced right ventricular macrophage count, and suppressed NLRP3 inflammasome and STAT3 activation.
Am J Respir Crit Care Med. 2022 Sep 1;206(5):608-624
C57BL/6 mice
High-fat diet-induced obese mouse model
Oral
10 mg/kg
Once daily for one week
Suppressed ATX expression in adipose tissue, decreased plasma ATX and LPA levels, and improved insulin sensitivity and glucose tolerance in high-fat diet-fed obese mice
J Lipid Res. 2017 Nov;58(11):2102-2113
Sprague Dawley rats
MCT-induced pulmonary arterial hypertension model
Intraperitoneal injection
10 mg/kg
Once daily for 10 days
SC144 decreased GP130 activation, which normalized MT-JPH2 protein expression and t-tubule structure in the MCT RV. SC144 also reduced RV hypertrophy and fibrosis and augmented RV-pulmonary artery coupling without altering PAH severity.
Circ Heart Fail. 2022 Jan;15(1):e008574
BALB/c nu/nu mice
Pancreatic ductal adenocarcinoma (PDAC) mouse model
Intraperitoneal injection
100 mg/kg SC144 + 10 mg/kg paclitaxel
SC144 injected daily, paclitaxel injected every four days, for 26 days
To evaluate the effect of SC144/paclitaxel combination therapy on tumor growth in a PDAC mouse model. Results showed that SC144/paclitaxel combination therapy significantly reduced tumor weight and volume (p < 0.05 and p < 0.01). Additionally, SC144/paclitaxel treatment reduced human IL-6 levels in the tumors and plasma of mice (p < 0.05).
Cancers (Basel). 2023 Jan 11;15(2):456
C57BL/6 mice
MOC2-E6/E7 tumor model
Intraperitoneal injection
40 mg/kg
Once daily for two weeks
To evaluate the antitumor efficacy of SC144, results showed significant reduction in tumor burden
Theranostics. 2020 May 25;10(15):6959-6976
C57BL/6 mice
MC38 colon carcinoma model
Intravenous injection
5 mg/kg
Administered on days 11, 13, and 15
SC144@HABN treatment significantly reduced tumor growth, increased the frequency of tumor-infiltrating CD8+ T-cells, and elevated the ratio of M1-like to M2-like macrophages.
Nat Commun. 2023 Aug 8;14(1):4771
Mice
Experimental AD-like skin inflammation model
Intraperitoneal injection
7 mg/kg/day
Once daily (weekdays), continued for 3 weeks
SC144 treatment significantly inhibited the AD-like symptoms in Ets1ΔdLck mice, characterized by reduced pathophysiology and ear thickness. This was associated with reduced lymphocytes infiltration and reduced serum IgE and IgG level. Moreover, SC144 treatment significantly reduced IL-17A and IL-22 production in CD4+ T cells from the dLNs compared with vehicle controls.
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