| In vitro |
10058-F4 inhibits growth of leukemic cells and dimerization of Myc and Max. 10058-F4 induces cell-cycle arrest and apoptosis of AML cells. 10058-F4 arrests AML cells at G0/G1 phase, downregulates c-Myc expression and upregulated CDK inhibitors, p21 and p27. Meanwhile, 10058-F4 induces apoptosis through activation of mitochondrial pathway shown by downregulation of Bcl-2, upregulation of Bax, release of cytoplasmic cytochrome C, and cleavage of caspase 3, 7, and 9. Furthermore, 10058-F4 also induces myeloid differentiation, possibly through activation of multiple transcription factors. Similarly, 10058-F4-induced apoptosis and differentiation could also be observed in primary AML cells. [1] 10058-F4 decreases c-Myc protein levels, inhibites proliferation of HepG2 cells likely through upregulation of cyclin-dependent kinase (cdk) inhibitor, p21WAF1 and lowers intracellular levels of [alpha]-fetoprotein (AFP). Treatment with 10058-F4 also downregulates human telomerase reverse transcriptase (hTERT) at the transcriptional level. In addition to inhibiting the proliferation of HepG2 cells, 10058-F4 enhances sensitivity to conventional chemotherapeutic agents, doxorubicin, 5-fluorouracil (5-FU) and cisplatin. [2]
|
| In vivo |
Peak plasma 10058-F4 concentrations of approximately 300 μM are seen at 5 min and declined to below the detection limit at 360 min following a single iv dose. Plasma concentration versus time data are best approximated by a two-compartment, open, linear model. The highest tissue concentrations of 10058-F4 are found in fat, lung, liver, and kidney. Peak tumor concentrations of 10058-F4 are at least tenfold lower than peak plasma concentrations. Eight metabolites of 10058-F4 are identified in plasma, liver, and kidney. The terminal half-life of 10058-F4 is approximately 1 h, and the volume of distribution is >200 ml/kg. No significant inhibition of tumor growth is seen after i.v. treatment of mice with either 20 or 30 mg/kg 10058-F4.[3]
|
COA
HPLC