GANT61 (20 μM) induces more significant cell death compared to targeting Smo (cyclopamine). It also inhibits the clonogenic survival of human colon carcinoma cell lines (0, 5, 10, 20 μM). Moreover, GANT61 (20 μM, 0-72 hr) downregulates Gli1 and Gli2 expression in HT29 cells. Additionally, GANT61 (0, 10 μM, or 20 μM) differentially regulates genes involved in the balance between cell death and survival[1]. GANT-61 inhibits cell viability and induces apoptosis in pancreatic CSCs. It also suppresses the expression of downstream targets of the Shh pathway, decreases Gli-DNA interaction, Gli transcriptional activity, and Gli nuclear translocation in pancreatic CSCs. Furthermore, GANT-61 modulates genes associated with cell survival, cell death, and pluripotency, while also inhibiting the motility, invasion, and migration of CSCs[2]. The sensitivity of GANT61 correlates positively with GLI1 and negatively with MYCN expression in the tested neuroblastoma cell lines. GANT61 downregulates the expression of GLI1, c-MYC, MYCN, and Cyclin D1, and induces apoptosis in neuroblastoma cells[3].
体内研究
Administered at a dose of 40 mg/kg via intraperitoneal injection three days per week, GANT-61 inhibits CSC tumor growth in NOD/SCID IL2Rγ null mice[2].
Furthermore, GANT61 (50 mg/kg, per oral) enhances the effects of chemotherapeutic drugs used in neuroblastoma treatment in an additive or synergistic manner. It also reduces the growth of established neuroblastoma xenografts in nude mice[3].
体外研究
GANT61 (20 μM) induces more significant cell death compared to targeting Smo (cyclopamine). It also inhibits the clonogenic survival of human colon carcinoma cell lines (0, 5, 10, 20 μM). Moreover, GANT61 (20 μM, 0-72 hr) downregulates Gli1 and Gli2 expression in HT29 cells. Additionally, GANT61 (0, 10 μM, or 20 μM) differentially regulates genes involved in the balance between cell death and survival[1].
GANT-61 inhibits cell viability and induces apoptosis in pancreatic CSCs. It also suppresses the expression of downstream targets of the Shh pathway, decreases Gli-DNA interaction, Gli transcriptional activity, and Gli nuclear translocation in pancreatic CSCs. Furthermore, GANT-61 modulates genes associated with cell survival, cell death, and pluripotency, while also inhibiting the motility, invasion, and migration of CSCs[2].
The sensitivity of GANT61 correlates positively with GLI1 and negatively with MYCN expression in the tested neuroblastoma cell lines. GANT61 downregulates the expression of GLI1, c-MYC, MYCN, and Cyclin D1, and induces apoptosis in neuroblastoma cells[3].
GANT61 细胞实验
Cell Line
Concentration
Treated Time
Description
References
MCF7-Ctrl
10 µM
48 h
Restores EMT marker expression, inhibits invasion
Nat Commun. 2017 Jun 12;8:15773.
HMLER-Ctrl
10 µM
48 h
Inhibits GLI signaling activation, reduces migration and invasion
Nat Commun. 2017 Jun 12;8:15773.
AML cell lines
20 μM
24 h
Induced apoptosis, resulting in approximately 30% of cells undergoing apoptosis
J Hematol Oncol. 2017 Jan 21;10(1):26.
PANC-1
30 μM
3 days
GANT61 had a more modest effect on the viability and sphere formation of PANC-1 cells, but still significantly reduced cell viability at 30 μM.
Mol Cancer. 2016 Jun 27;15(1):49.
Capan-1 M9
20 μM
3 days
Inhibition of the Hh pathway significantly reduced the expression of stem cell marker CD133 and sphere formation, demonstrating the suppression of CSC-like properties. GANT61 was more effective than the SMO inhibitor cyclopamine in reducing sphere formation and cell viability.
Mol Cancer. 2016 Jun 27;15(1):49.
Human mesenchymal stem cells
10 μM
24-48 h
To investigate the effect of GANT61 on mesenchymal stem cells from MPN patients and healthy donors, results showed that GANT61 significantly reduced the expression of α-SMA and Gli1, and induced apoptosis in MPN-MSCs.
Cell Stem Cell. 2017 Jun 1;20(6):785-800.e8.
NCI-H1299 cells
10, 20, and 30 μM
Inhibited the migration and invasion abilities of NCI-H1299 cells
Acta Pharm Sin B. 2022 Oct;12(10):3877-3890.
HT29 cells
20 µM
72 h
GANT61 induced accumulation of HT29 cells at G1/S and early S-phase, followed by entry into subG1, leading to cell death.
Cancer Res. 2011 Sep 1;71(17):5904-14.
WB-F344 cells
2 μM
4 days
Inhibition of Gli1 expression reduced the expression of KRT19 and Ki67, as well as proinflammatory cytokines including IL-6 and TNF-α, thereby suppressing the differentiation of HPCs into cholangiocytes.
Theranostics. 2024 Mar 25;14(6):2379-2395.
GANT61 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Nude mice
Capan-1 M9 xenograft model
Intraperitoneal injection
40 mg/kg
3 times a week for 25 days
Combination treatment with GANT61 and the mTOR inhibitor rapamycin significantly inhibited tumor growth in the Capan-1 M9 xenograft model.
Mol Cancer. 2016 Jun 27;15(1):49.
Mice
Jak2(V617F)-induced myelofibrosis model
Subcutaneous injection
50 mg/kg
Every other day for 9 weeks
To investigate the therapeutic effect of GANT61 on Jak2(V617F)-induced myelofibrosis, results showed that GANT61 significantly reduced the number of Gli1+ cells, inhibited the development of bone marrow fibrosis, and improved splenomegaly and hemoglobin levels.
Cell Stem Cell. 2017 Jun 1;20(6):785-800.e8.
BALB/c nude mice
NSCLC metastasis model
Intraperitoneal injection
50 mg/kg
Every two days for a total of 30 days
GANT-61 significantly suppressed the lung and liver metastasis of NSCLC
Acta Pharm Sin B. 2022 Oct;12(10):3877-3890.
Mice
Breast cancer xenograft model
Subcutaneous injection
50 mg/kg
Every other day for 18 days
Inhibits metastasis and growth of non-EMT cells
Nat Commun. 2017 Jun 12;8:15773.
Mice
Unilateral ureteral obstruction model
Subcutaneous injection
50 mg/kg
Administered on days 1, 2, 3, 5, 7, and 9 after surgery
GANT61 reduced renal fibrosis by decreasing GLI1 and GLI2 protein levels.
J Clin Invest. 2015 Aug 3;125(8):2935-51
Nude mice
NSCLC xenograft model
Intraperitoneal injection
50 mg/kg
Every other day for 24 days
To evaluate the effect of GANT61 on tumor angiogenesis and tumor growth in NSCLC, the results showed that GANT61 significantly inhibited tumor angiogenesis and tumor growth.
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