Articles written in Journal of Biosciences

    • Inhibition of CYP3A4 and CYP2C9 by podophyllotoxin: Implication for clinical drug–drug interactions

      Jin-Hui Song Dong-Xue Sun Bin Chen Dai-Hong Ji Jie Pu Jie Xu Feng-De Tian Lin Guo

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      Podophyllotoxin (PPT) and its derivatives exert significant anti-cancer activities, and one derivative etoposide is often utilized to treat various cancers in the clinic. The aim of the present study is to investigate the inhibitory effects of PPT on major cytochrome P450 (CYP) isoforms in human livers. Inhibition of CYP3A4, CYP2C9, CYP2C8, CYP2D6, CYP2E1 and CYP2A6 by PPT was investigated in the human liver microsomal system. Time-dependent inhibition of CYP3A4 by PPT was also evaluated. The results showed that PPT strongly exhibited inhibitory effects on CYP3A4 and CYP2C9 in a concentration-dependent manner. Half inhibition concentration (IC50) was 1.1±0.3 and 4.6±0.3 𝜇M for CYP3A4 and CYP2C9, respectively. Inhibition kinetic analysis showed that PPT exhibited competitive inhibition towards CYP3A4 and CYP2C9 with Ki of 1.6 and 2.0 𝜇M, respectively. Additionally, PPT exerted time-dependent inhibition towards CYP3A4 and the kinetic parameters were 4.4±2.1 𝜇M and 0.06±0.01 min–1 for KI and kinact, respectively. Our experimental data indicate that potential drug–drug interaction (DDI) might exist when PPT is co-administered with the substrates which mainly undergo CYP3A4- or CYP2C9-mediated metabolism.

    • Calycosin down-regulates c-Met to suppress development of glioblastomas


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      The antitumor effect of calycosin has been widely studied, but the targets of calycosin against glioblastomas are stillunclear. In this study we focused on revealing c-Met as a potential target of calycosin suppressing glioblastomas. In thisstudy, suppressed-cell proliferation and cell invasion together with induced-cell apoptosis appeared in calycosin-treatedU251 and U87 cells. Under treatment of calycosin, the mRNA expression levels of Dtk, c-Met, Lyn and PYK2 wereobserved in U87 cells. Meanwhile a western blot assay showed that c-Met together with matrix metalloproteinases-9(MMP9) and phosphorylation of the serine/threonine kinase AKT (p-AKT) was significantly down-regulated by calycosin.Furthermore, overexpressed c-Met in U87 enhanced the expression level of MMP9 and p-AKT and also improved cellinvasion. Additionally, the expression levels of c-Met, MMP9 and p-AKT were inhibited by calycosin in c-Met overexpressedcells. However, an AKT inhibitor (LY294002) only effected on MMP9 and p-AKT, not on c-Met. These datacollectively indicated that calycosin possibility targeting on c-Met and exert an anti-tumor role via MMP9 and AKT.

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