MET inhibitor tepotinib antagonizes multidrug resistance mediated by ABCG2 transporter: In vitro and in vivo study

Overexpression of ABCG2 transporter in cancer cells has been linked to the development of multidrug resistance (MDR), an obstacle to cancer therapy. Our recent study uncovered that the MET inhibitor, tepotinib, is a potent reversal agent for ABCB1-mediated MDR. In the present study, we reported for the first time that the MET inhibitor tepotinib can also reverse ABCG2-mediated MDR in vitro and in vivo by directly binding to the drug-binding site of ABCG2 and reversibly inhibiting ABCG2 drug efflux activity, therefore enhancing the cytotoxicity of substrate drugs in drug-resistant cancer cells. Furthermore, the ABCB1/ABCG2 double-transfected cell model and ABCG2 gene knockout cell model demonstrated that tepotinib specifically inhibits the two MDR transporters. In mice bearing drug-resistant tumors, tepotinib increased the intratumoral accumulation of ABCG2 substrate drug topotecan and enhanced its antitumor effect. Therefore, our study provides a new potential of repositioning tepotinib as an ABCG2 inhibitor and combining tepotinib with substrate drugs to antagonize ABCG2-mediated MDR.

Effect of changes in pH on intracellular Ca2+ and cell length of myocytes / 中国应用生理学杂志

<p><b>AIM</b>To examine the effects of pHi on [Ca2+]i, cell length and Ca2+ sensitivity of myofilaments in rat myocyte.</p><p><b>METHODS</b>We used microscopic spectral imaging approach to monitor simultaneously [Ca2+]i, pHi and cell length with fluorescent indicator indo-1 and SNARF-1 in isolated single rat myocyte.</p><p><b>RESULTS</b>Exposure of cell to 20 mmol/L Sodium Propionate induced an intracellular acidosis which increased slightly systolic and diastolic [Ca2+]i, decreased the cell shortening (CS) and Ca2+ sensitivity of myofilament (P < 0.01). Exposure of cell to 15 mmol/L NH4Cl induced an intracellular alkalosis which decreased systolic and diastolic [Ca2+]i, increased the cell shortening and Ca2+ sensitivity of myofilament (P < 0.01).</p><p><b>CONCLUSIONS</b>In the early time of acidosis, [Ca2+]i, as well as cell length increases respectively. While alkalosis, [Ca2+]i and cell length decreases respectively. The effect of acidosis and alkalosis on Ca2+ sensitivity presents non-linear relationship, i.e. the effect of acidosis on sensitivity, caused by pHi change, is less than that of alkalosis.</p>

Clinical analgesic effect of lappaconitine in 56 patients after cholecystectomy / 中国临床药理学与治疗学

0.05),but there were significant differences on the side-effects such as itch of skin,nausea and vomiting between two groups (P