Epigenetic regulation of UDP-Glucuronosyltransferase by microRNA-200a/-183: implications for responses to sorafenib treatment in patients with hepatocellular carcinoma.

Patients receiving sorafenib treatment for hepatocellular carcinoma (HCC) experience different treatment efficacy. Personalized sorafenib treatment should be achieved through the identification of predictors of therapeutic response. In the current study, we found that high UGT1A9 expression indicated better prognosis for HCC patients treated with sorafenib after surgery. In silico analysis predicted microRNA-200a/-183 as potential regulators of the UGT1A gene family via binding to the shared UGT1A9 3'-UTR. A significant inverse correlation between microRNA-200a/-183 and UGT1A9 mRNA level was observed in a panel of HCC specimens. Direct binding was further demonstrated by luciferase reporter gene vector carrying wild-type or binding site truncated UGT1A9 3'-UTR. MicroRNA-200a/-183 downregulated UGT1A9 expression in a dose-dependent manner and significantly reduced sorafenib ß-D-glucuronide formation in HCC cells. These data indicated that UGT1A9, under epigenetic regulation of microRNA-200a/-183, could predict patients who might benefit from adjuvant sorafenib treatment after surgery.

The effects of triptolide on the pharmacokinetics of sorafenib in rats and its potential mechanism.

CONTEXT: Combining sorafenib with triptolide could inhibit tumour growth with greater efficacy than single-agent treatment. However, their herb-drug interaction remains unknown. OBJECTIVE: This study investigates the herb-drug interaction between triptolide and sorafenib. MATERIALS AND METHODS: The effects of triptolide (10 mg/kg) on the pharmacokinetics of different doses of sorafenib (20, 50 and 100 mg/kg) in rats, and blood samples were collected within 48 h and evaluated using LC-MS/MS. The effects of triptolide on the absorption and metabolism of sorafenib were also investigated using Caco-2 cell monolayer model and rat liver microsome incubation systems. RESULTS: The results showed that the Cmax (low dose: 72.38 ± 8.76 versus 49.15 ± 5.46 ng/mL; medium dose: 178.65 ± 21.05 versus 109.31 ± 14.17 ng/mL; high dose: 332.81 ± 29.38 versus 230.86 ± 9.68 ng/mL) of sorafenib at different doses increased significantly with the pretreatment of triptolide, and while the oral clearance rate of sorafenib decreased. The t1/2 of sorafenib increased significant (p < 0.05) from 9.02 ± 1.16 to 12.17 ± 2.95 h at low dose with the pretreatment of triptolide. Triptolide has little effect on the absorption of sorafenib in Caco-2 cell transwell model. However, triptolide could significantly decrease the intrinsic clearance rate of sorafenib from 51.7 ± 6.37 to 32.4 ± 4.43 µL/min/mg protein in rat liver microsomes. DISCUSSION AND CONCLUSIONS: These results indicated that triptolide could change the pharmacokinetic profiles of sorafenib in rats; these effects might be exerted via decreasing the intrinsic clearance rate of sorafenib in rat liver.

Evaluation methods for the efficacy of neoadjuvant chemotherapy for breast cancer.

With the widespread clinical application of neoadjuvant chemotherapy, it has become an essential part of combination therapy for patients with breast cancer. However, a rapid, accurate, and effective approach for assessing the therapeutic efficacy of neoadjuvant chemotherapy is unavailable. Routine physical examinations cannot provide effective clinical evaluation. Although imaging techniques play an important role in evaluating the therapeutic effect of neoadjuvant chemotherapy, this is limited because it only detects morphologic changes. Blood oxygen detection for breast diseases is an emerging diagnostic technique that has distinctive merit in assessing the efficacy of chemotherapy. Biologic markers are becoming more important in assessing the effect of neoadjuvant chemotherapy for patients with breast cancer. This review summarizes the principles and the current applied practice of these approaches to evaluate the effect of neoadjuvant chemotherapy for patients with breast cancer.

Amino acid substitutions in the pore of the Ca(V)1.2 calcium channel reduce barium currents without affecting calcium currents.

Ba(2+) currents through Ca(V)1.2 Ca(2+) channels are typically twice as large as Ca(2+) currents. Replacing Phe-1144 in the pore-loop of domain III with glycine and lysine, and Tyr-1152 with lysine, reduces whole-cell G(Ba)/G(Ca) from 2.2 (wild-type) to 0.95, 1.21, and 0.90, respectively. Whole-cell and single-channel measurements indicate that reductions in G(Ba)/G(Ca) result specifically from a decrease in Ba(2+) conductance and not changes in V(h) or P(O). Half-maximal block of I(Li) is increased by 3.2-, 3.8-, and 1.6-fold in Ca(2+), and 3.8-, 4.2-, and 1.8-fold in Ba(2+) for F1144G, Y1152K, and F1144K, respectively. High affinity interactions of individual divalent cations to the pore are not important for determining G(Ba)/G(Ca), because the fold increases in IC(50) values for Ba(2+) and Ca(2+) are similar. On the contrary, conductance-concentration curves indicate that G(Ba)/G(Ca) is reduced because the interactions of multiple Ba(2+) ions in the mutant pores are altered. The complexity of these interactions is exemplified by the anomalous mole fraction effect, which is flattened for F1144G and FY/GK but accentuated for F1144K. In summary, the physicochemical properties of the amino acid residues at positions 1144 and 1152 are crucial to the pore's ability to distinguish between multiple Ba(2+) ions and Ca(2+) ions.