10058-F4 inhibits the growth of leukemic cells and the dimerization of Myc and Max. It induces cell-cycle arrest and apoptosis of AML cells, primarily arresting them at the G0/G1 phase. Moreover, 10058-F4 downregulates c-Myc expression and upregulates CDK inhibitors, such as p21 and p27. Additionally, it induces apoptosis through the activation of the mitochondrial pathway, characterized by the downregulation of Bcl-2, upregulation of Bax, release of cytoplasmic cytochrome C, and cleavage of caspase 3, 7, and 9. Furthermore, 10058-F4 promotes myeloid differentiation, possibly via the activation of multiple transcription factors. Similarly, 10058-F4-induced apoptosis and differentiation are also evident in primary AML cells [1]. 10058-F4 reduces c-Myc protein levels and inhibits proliferation of HepG2 cells, likely by upregulating the cyclin-dependent kinase (cdk) inhibitor, p21WAF1, and decreasing intracellular levels of alpha-fetoprotein (AFP). Treatment with 10058-F4 also suppresses human telomerase reverse transcriptase (hTERT) at the transcriptional level. Moreover, besides inhibiting the proliferation of HepG2 cells, 10058-F4 enhances sensitivity to conventional chemotherapeutic agents, including doxorubicin, 5-fluorouracil (5-FU), and cisplatin [2].
体内研究
Following a single intravenous dose, peak plasma concentrations of 10058-F4 reach approximately 300 μM at 5 minutes and decline below the detection limit by 360 minutes. Plasma concentration versus time data are best fitted by a two-compartment, open, linear model. The highest concentrations of 10058-F4 are observed in fat, lung, liver, and kidney tissues. Tumor concentrations of 10058-F4 peak at levels 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 hour, and the volume of distribution exceeds 200 mL/kg. No significant inhibition of tumor growth is observed after intravenous treatment of mice with either 20 or 30 mg/kg 10058-F4 [3].
体外研究
10058-F4 inhibits the growth of leukemic cells and the dimerization of Myc and Max. It induces cell-cycle arrest and apoptosis of AML cells, primarily arresting them at the G0/G1 phase. Moreover, 10058-F4 downregulates c-Myc expression and upregulates CDK inhibitors, such as p21 and p27. Additionally, it induces apoptosis through the activation of the mitochondrial pathway, characterized by the downregulation of Bcl-2, upregulation of Bax, release of cytoplasmic cytochrome C, and cleavage of caspase 3, 7, and 9. Furthermore, 10058-F4 promotes myeloid differentiation, possibly via the activation of multiple transcription factors. Similarly, 10058-F4-induced apoptosis and differentiation are also evident in primary AML cells [1].
10058-F4 reduces c-Myc protein levels and inhibits proliferation of HepG2 cells, likely by upregulating the cyclin-dependent kinase (cdk) inhibitor, p21WAF1, and decreasing intracellular levels of alpha-fetoprotein (AFP). Treatment with 10058-F4 also suppresses human telomerase reverse transcriptase (hTERT) at the transcriptional level. Moreover, besides inhibiting the proliferation of HepG2 cells, 10058-F4 enhances sensitivity to conventional chemotherapeutic agents, including doxorubicin, 5-fluorouracil (5-FU), and cisplatin [2].
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