化合物信息

Description

Cryptotanshinone (CPT) is a STAT3 inhibitor with IC50 of 4.6 μM.

Targets

IC₅₀

In Vitro

Cryptotanshinone, a natural compound isolated from the roots of Salvia miltiorrhiza Bunge (Danshen), significantly inhibits STAT3-dependent luciferase activity, the STAT3 Tyr705 phosphorylation and the dimerization of STAT3, compared to tanshinone IIA which exhibits no activity. Cryptotanshinone (7 μM) dramatically blocks STAT3 Tyr705 phosphorylation but not STAT3 Ser727 phosphorylation in DU145 cells, and significantly inhibits JAK2 phosphorylation with IC50 of ~5 μM without affecting the phosphorylation of upstream kinases c-Src and EGFR, suggesting the inhibition of STAT3 Tyr705 phosphorylation might due to a direct mechanism probably by binding to the SH2 domain of STAT3. Cryptotanshinone significantly inhibits the proliferation of DU145 prostate cancer cells harboring constitutively active STAT3 with GI50 of 7 μM by blocking STAT3 activity, which leads to the down-regulation of cyclin D1, Bcl-xL, and survivin, subsequently the accumulation in the G0-G1 phase. Cryptotanshinone exhibits less growth inhibitory effect on PC3, LNCaP and MDA-MB-468 cells. ^[1]

In Vivo

Cryptotanshinone administration significantly reduces the body weight and food intake of ob/ob mice (C57BL/6J-Lep^ob) and diet-induced obese (DIO) mice in a dose-dependent manner. Cryptotanshinone causes noticeably less fat in the adipose tissues, significant reductions of serum triglycerides and cholesterol levels, and 2.5- to 3-fold higher AMPK activity of the skeletal muscles than in the control mice. Oral administration of Cryptotanshinone at 600 mg/kg/day produces dramatic reductions in blood glucose levels of ob/ob mice (C57BL/6J-Lep^ob), db/db mice (C57BL/KsJ-Lepr^db), and ZDF rats, which occur after 3 days and persist over the entirety of the monitoring period. ^[2]

Clinical Trials

A clinical study to determine whether Cryptotanshinone may prove effective in eradicating Polycystic Ovary Syndrome (PCOS) symptomatology is ongoing.

Features

STAT3-dependent dual-luciferase assay

HCT-116 cells are transiently transfected with reporter plasmid having the STAT3-binding element for regulating luciferase assay. Cells are treated with Cryptotanshinone for 24 hours at a concentration range of 0.2 to 50 μM. After treatment, cells are harvested in 20 μL of passive lysis buffer and luciferase activity is evaluated by the Dual Luciferase Reporter Assay kit on Wallac Victor2. The concentration of Cryptotanshinone that inhibits the luciferase activity by 50% represents IC50 value.

Cell Lines

KATO III, DU145, PC3, LNCaP, MDA-MB-231, MDA-MB-468, MDA-MB-453, MCF-7, MCF-10A, HeLa and HCT-116

Concentrations

Dissolved in DMSO, final concentrations ~50 μM

Incubation Time

24 or 48 hours

Methods

Cells are exposed to Cryptotanshinone for 24 or 48 hours. For the determination of cell proliferation, the cell proliferation reagent WST-1 is added and WST-1 formazan is quantitatively measured at 450 nm using an ELISA reader.

Animal Models

Zucker Diabetic Fatty (ZDF) (male) type 2 diabetic rat, ob/ob mice (C57BL/6J-Lep^ob), db/db mice (C57BL/KsJ-Lepr^db) and male C57BL/6J mice with high-fat diet-induced obesity

Formulation

Dissolved in 0.1% solution of sodium lauryl sulfate

Doses

~600 mg/kg/day

Administration

Orally