The PI3K/AKT/mTOR signaling pathway is involved in various cellular processes such as cell proliferation, migration, survival and angiogenesis. The phosphatidylinositol-3,4,5-triphosphate (PIP3) binding function of pleckstrin homology (PH) domain is essential for the activation of oncogenic Akt/PKB kinase[3]. SC66 is an allosteric Akt inhibitor that affects AKT/mTOR signaling by a decrease in AKT phosphorylation levels and in total protein levels[4]. After treatment with increasing concentrations of SC-66, activating PIK3CA (E545K, E542K) and inactivating PTEN (R233*) mutations were identified in human cervical cancer. SC-66 effectively inhibited AKT, mTOR and mTOR substrates in C33A cells. SC-66 inhibited glucose uptake via reduced delivery of Glut1 and Glut4 to the cell membrane. SC-66 (1 µg/ml-56%) treatment decreased cell viability through a non-apoptotic mechanism. Decreases in cell viability were enhanced when AKT inhibitors were combined with 2-DG. The scratch assay showed a substantial reduction in cell migration upon SC-66 treatment[5]. A mouse xenograft tumor model of Hep3B cells was used to demonstrate the effectiveness in vivo of SC66 on HCC. Treatment with 25 mg/Kg SC66 via i.p. injection twice a week significantly reduced tumor volume to 37%. SC66 inhibit HCC cell viability with IC50 values of approximately 0.85 and 0.75 μg/ml at 48 and 72 hours, respectively for HepG2, HA22T/VGH and PLC/PRF/5 cells[4].
作用机制
SC66 manifests a dual inhibitory activity that directly interferes with the PH domain binding to PIP3 and facilitates Akt ubiquitination[3].
SC66 细胞实验
Cell Line
Concentration
Treated Time
Description
References
ES-2/CP
0-22 μM
48 h
SC66 inhibited phosphorylation of Akt and its downstream effectors 4EBP1 and p70S6 kinase, and attenuated expression of TWIST1 and Mcl-1.
Cell Death Dis. 2019 Apr 11;10(4):322.
ES-2
0-22 μM
48 h
SC66 inhibited phosphorylation of Akt and its downstream effectors 4EBP1 and p70S6 kinase, and attenuated expression of TWIST1 and Mcl-1.
Cell Death Dis. 2019 Apr 11;10(4):322.
OVCAR-8
0-22 μM
48 h
SC66 inhibited phosphorylation of Akt and its downstream effectors 4EBP1 and p70S6 kinase, and attenuated expression of TWIST1 and Mcl-1.
Cell Death Dis. 2019 Apr 11;10(4):322.
OVCAR-4
0-22 μM
48 h
SC66 inhibited phosphorylation of Akt and its downstream effectors 4EBP1 and p70S6 kinase, and attenuated expression of TWIST1 and Mcl-1.
Cell Death Dis. 2019 Apr 11;10(4):322.
OVCAR-3
0-22 μM
48 h
SC66 inhibited phosphorylation of Akt and its downstream effectors 4EBP1 and p70S6 kinase, and attenuated expression of TWIST1 and Mcl-1.
Cell Death Dis. 2019 Apr 11;10(4):322.
HAC-2
0-22 μM
48 h
SC66 inhibited phosphorylation of Akt and its downstream effectors 4EBP1 and p70S6 kinase, and attenuated expression of TWIST1 and Mcl-1.
Cell Death Dis. 2019 Apr 11;10(4):322.
A2780CP70
0-22 μM
48 h
SC66 inhibited phosphorylation of Akt and its downstream effectors 4EBP1 and p70S6 kinase, and attenuated expression of TWIST1 and Mcl-1.
Cell Death Dis. 2019 Apr 11;10(4):322.
A2780
0-22 μM
48 h
SC66 inhibited phosphorylation of Akt and its downstream effectors 4EBP1 and p70S6 kinase, and attenuated expression of TWIST1 and Mcl-1.
Cell Death Dis. 2019 Apr 11;10(4):322.
5637 cells
0, 2, 4, 6, 8, 10, 12, 14, 16, 18 μM
24 h
SC66 significantly inhibited the proliferation of 5637 cells, and the degree of inhibition was positively correlated with the drug concentration.
J Cell Mol Med. 2021 Nov;25(22):10684-10697.
T24 cells
0, 2, 4, 6, 8, 10, 12, 14, 16, 18 μM
24 h
SC66 significantly inhibited the proliferation of T24 cells, and the degree of inhibition was positively correlated with the drug concentration.
J Cell Mol Med. 2021 Nov;25(22):10684-10697.
HeLa cells
4 μg/mL
1 hour
SC66 significantly reduced the phosphorylation level of Akt
Proc Natl Acad Sci U S A. 2011 Apr 19;108(16):6486-91.
HEK293T cells
1, 2, 4 μg/mL
1 hour
SC66 significantly reduced the phosphorylation level of both Akt and its targets
Proc Natl Acad Sci U S A. 2011 Apr 19;108(16):6486-91.
Primary human RCC cells
3 μM
24 h
SC66 significantly reduced the viability, proliferation, and migration of primary human RCC cells.
Cell Death Dis. 2020 May 11;11(5):353.
A498 cells
3 μM
48-72 h
SC66 decreased cell viability and proliferation, and inhibited A498 cell migration and invasion.
Cell Death Dis. 2020 May 11;11(5):353.
786-O cells
1-30 μM
48-96 h
SC66 dose-dependently reduced the viability of 786-O cells and significantly decreased the number of viable 786-O cell colonies in soft agar.
Cell Death Dis. 2020 May 11;11(5):353.
HCT-116 WT, HCT-116 p53−/−, DLD1
2 μg/ml
24 h
SC66 significantly inhibited the proliferation of HCT-116 WT, HCT-116 p53−/−, and DLD1 cells, and p53 was dispensable in this process.
Cancer Cell Int. 2019 May 9;19:124.
HCT-116
0.5–4 μg/ml
24 h
SC66 significantly inhibited the proliferation of HCT-116 cells in a dose-dependent manner.
Cancer Cell Int. 2019 May 9;19:124.
U251 cells
0, 5, 10, 15, 20, 25, 30 μM
24 h
SC66 inhibited U251 cell proliferation with an IC50 value of 12 umol/L
Front Pharmacol. 2020 Jul 31;11:1102.
U87 cells
0, 5, 10, 15, 20, 25, 30 μM
24 h
SC66 inhibited U87 cell proliferation with an IC50 value of 10 umol/L
Front Pharmacol. 2020 Jul 31;11:1102.
SC66 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
NOD-SCID mice
Ovarian cancer xenograft model
Intraperitoneal injection
5 mg/kg and 15 mg/kg
Once per day for 30 days
SC66 treatment significantly inhibited tumor formation and enhanced the therapeutic efficacy of cisplatin.
Cell Death Dis. 2019 Apr 11;10(4):322.
Balb/c nude mice
T24 tumor model
Intraperitoneal injection
20 mg/kg
Every 2 days for 4 weeks
SC66 significantly reduced the weight and volume of T24 tumors in nude mice, and the combination with cisplatin showed better inhibition.
J Cell Mol Med. 2021 Nov;25(22):10684-10697.
Mice
HEK293T cell xenograft model
Intraperitoneal injection
15, 30 mg/kg
Twice per week for 21 days
SC66 significantly inhibited tumor growth
Proc Natl Acad Sci U S A. 2011 Apr 19;108(16):6486-91.
SCID mice
786-O xenograft model
Oral
10-25 mg/kg
Once daily for 24 days
SC66 significantly inhibited the growth of 786-O xenograft tumors, and AKT-mTOR inhibition, SphK1 inhibition, ceramide accumulation, and JNK activation were detected in SC66-treated 786-O xenograft tumors.
Cell Death Dis. 2020 May 11;11(5):353.
Nude mice
HCT-116 WT xenograft model
Intraperitoneal injection
25 mg/kg
Every 3 days for 15 days
SC66 significantly inhibited the growth of HCT-116 WT xenograft tumors, with an inhibition rate of about 65%.
Cancer Cell Int. 2019 May 9;19:124.
Nude mice
U87 xenograft tumor model
Intraperitoneal injection
25 mg/kg
Every 3 days for 6 times
SC66 significantly suppressed tumor growth, with tumor weights and volume notably smaller than the control group
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