Biweekly MRI examinations followed to determine volumetric changes in tumor size between the two arms compared with the initial rate of tumor growth (Fig. 5A). After only 2 weeks of treatment, the MRI at week 4 showed a significant difference in volume between the two arms, with the MEK inhibitor arm regressing in volume (vehicle = 108.5% ± 5.3%, PD0325901 = 53.9% ± 9.3%, P < 0.02). The next MRI at week 6 continued to show a significant selleck products difference in tumor volume between the two arms, with the PD0325901 arm demonstrating further

regression in tumor volume (vehicle = 136.3% ± 10.5%, PD0325901 = 51.4% ± 10.2%, P < 0.001). The next series of MRI images at week 8 demonstrated tumor growth with vehicle treatments (141.7 %) and continued regression in tumor volume with PD0325901 (55.9% ± 19.5%). Apoptosis was significantly induced in the PD0325901 arm compared with the vehicle Tyrosine Kinase Inhibitor Library cell line arm (Fig. 5B). Some mortality was observed in both arms of this study, most likely because of the stress of undergoing the MRI procedure in combination with drug treatment. Similar tumor regression was detected by MRI after treatment with a lower dose

of PD0325901 (10 mg/kg; data not shown), Current chemotherapy for HCC has had little success in treating this disease. The future direction of chemotherapy is to target specific pathways that are known to be involved in the particular cancer. The ERK/MAPK pathway is up-regulated in most human HCC tumors; thus, targeting this pathway could suppress tumor growth and in turn increase the life span of HCC patients. Prior attempts at targeting the MEK-ERK 上海皓元 signaling cascade have not proved successful in human trials and have led to the development of newer, more bioavailable MEK inhibitors. PD0325901, a derivative of CI-1040, is potent at nanomolar concentrations

and has greater duration, potency, and solubility, resulting in improved bioavailability and increased metabolic stability over CI-1040.28 The inhibitor binds to MEK1/2 at a non–adenosine triphosphate binding site, causing conformational changes that prevent it from phosphorylating ERK, making it a highly selective inhibitor.28 The current study employed TAMH cells, an immortalized line obtained from the MT42 (CD-1) TGF-α transgenic mouse, as well as HepG2 and Hep3B human HCC cells. In all three cell lines, we demonstrated that PD0325901 effectively reduced P-ERK levels and cell growth in vitro, with effects seen in the nanomolar range. Growth inhibition was associated with the induction of apoptosis in HepG2 and Hep3B cells in vitro. PD0325901 also inhibited TAMH and Hep3B tumor growth in an athymic mouse model in vivo. TAMH flank tumors showed decreases in P-ERK levels 24 hours after a single dose of PD0325901 compared with vehicle control, confirming inhibition of the MEK-ERK pathway.