Abstract
Separase, a known oncogene, is widely overexpressed in numerous human tumors of breast, bone, brain, blood, and prostate. Separase is an emerging target for cancer therapy, and separase enzymatic inhibitors such as sepin-1 are currently being developed to treat separase-overexpressed tumors. Drug metabolism plays a critical role in the efficacy and safety of drug development, as well as possible drug–drug interactions. In this study, we investigated the in vitro metabolism of sepin-1 in human, mouse, and rat liver microsomes (RLM) using metabolomic approaches. In human liver microsomes (HLM), we identified seven metabolites including one cysteine–sepin-1 adduct and one glutathione–sepin-1 adduct. All the sepin-1 metabolites in HLM were also found in both mouse and RLM. Using recombinant CYP450 isoenzymes, we demonstrated that multiple enzymes contributed to the metabolism of sepin-1, including CYP2D6 and CYP3A4 as the major metabolizing enzymes. Inhibitory effects of sepin-1 on seven major CYP450s were also evaluated using the corresponding substrates recommended by the US Food and Drug Administration. Our studies indicated that sepin-1 moderately inhibits CYP1A2, CYP2C19, and CYP3A4 with IC50 < 10 μM but weakly inhibits CYP2B6, CYP2C8/9, and CYP2D6 with IC50 > 10 μM. This information can be used to optimize the structures of sepin-1 for more suitable pharmacological properties and to predict the possible sepin-1 interactions with other chemotherapeutic drugs.
Highlights
Separase is an enzyme that resolves chromosomal cohesion and centriole engagement during mitosis
The results of metabolomic analysis on the ions generated from ultra-high performance liquid chromatography (UHPLC)–quadrupole time-of-flight mass spectrometry (QTOFMS) analysis of control and sepin-1 group are shown in Supplementary Figure S1
The S-plot generated from orthogonal projection to latent structures-discriminant analysis (OPLS-DA) displays ion contribution to group separation in human liver microsomes (HLM) (Supplementary Figure S1B)
Summary
Separase is an enzyme that resolves chromosomal cohesion and centriole engagement during mitosis. Sepin selectively inhibits the growth of cancer cell lines including breast cancer, leukemia, and neuroblastoma. Sepin-1 induces apoptosis and its effect on the inhibition of cell growth is positively correlated to the level of separase in the cancer cells and tumors (Zhang et al, 2014). It suggests that sepin-1 possesses a great potential to be used for cancer treatment, to treat separase-overexpressed tumors. The use of inhibitors could resolve the non-canonical functions of separase as well
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