Huang-Qin Decoction(HQD)is a classic prescription for diarrhea in Chinese medicine treatment.Recent studies have demonstrated that HQD and its modified formulation PHY906 could ameliorate irinotecan(CPT-11)induced gastrointestinal(GI)toxicity and enhance its anticancer therapeutic efficacy.Nevertheless,which constituents in HQD are effective is still unclear so far.The study aims to screen out the key bioactive components combination from HQD that could enhance the anticancer effect of CPT-11.First,the potential bioactive constituents were obtained through system pharmacology strategy.Then the bioactivity of each constituent was investigated synthetically from the aspects of NCM460 cell migration,TNF-αrelease of THP-1-derived macrophage and MTT assay in HCT116 cell.The contribution of each constituent in HQD was evaluated using the bioactive index Ei,which taken the content and bioactivity into comprehensive consideration.And then,the most contributing constituents were selected out to form a keycomponent combination.At last,the bioefficacy of the key-component combination was validated in vitro and in vivo.As a result,a key-component combination(HB4)consisting of four compounds baicalin,baicalein,glycyrrhizic acid and wogonin was screened out.In vitro assessment indicated that HB4 could enhance the effect of CPT-11 on inhibiting cell proliferation and inducing apoptosis in HCT116.Furthermore,the in vivo study confirmed that HB4 and HQD have similar pharmacological activity and could both enhance the antitumor effect of CPT-11 in HCT116 xenograft model.Meanwhile,HB4 could also reduce the CPT-11 induced GI toxicity.
Pharmacometabolomics has been already successfully used in toxicity prediction for one specific adverse effect. However in clinical practice, two or more different toxicities are always accompanied with each other, which puts forward new challenges for pharmacometabolomics. Gastrointestinal toxicity and myelosuppression are two major adverse effects induced by Irinotecan(CPT-11),and often show large individual differences. In the current study, a pharmacometabolomic study was performed to screen the exclusive biomarkers in predose serums which could predict late-onset diarrhea and myelosuppression of CPT-11 simultaneously. The severity and sensitivity differences in gastrointestinal toxicity and myelosuppression were judged by delayed-onset diarrhea symptoms, histopathology examination, relative cytokines and blood cell counts. Mass spectrometry-based non-targeted and targeted metabolomics were conducted in sequence to dissect metabolite signatures in predose serums. Eventually,two groups of metabolites were screened out as predictors for individual differences in late-onset diarrhea and myelosuppression using binary logistic regression, respectively. This result was compared with existing predictors and validated by another independent external validation set. Our study indicates the prediction of toxicity could be possible upon predose metabolic profile. Pharmacometabolomics can be a potentially useful tool for complicating toxicity prediction. Our findings also provide a new insight into CPT-11 precision medicine.
