AimPemetrexed, a new generation antifolate drug, is approved for the treatment for locally advanced or metastatic breast cancer, but factors affecting the efficacy and resistance of it have yet to be fully explicit. ATP-binding cassette (ABC) transporters have been reported as prognostic and adverse effects predictors of many xenobiotics. This study was designed to explore whether ABC transporters affect pemetrexed resistance and may contribute to treatment regimen optimization for breast cancer.MethodsFirstly, the expression of ABC transporters family members was measured in cell lines, thereafter examined the potential role of ABC transporter in conferring resistance to pemetrexed in primary cancer cell lines isolated from 34 breast cancer patients, and then the role of ABCC5 in mediating transport of pemetrexed and apoptosis pathway in MCF-7 cell line was assessed. Finally, the functions of ABCC5 on therapeutic effect of pemetrexed was evaluated in breast cancer bearing mice.ResultsThe expressions of ABCC2, ABCC4, ABCC5 and ABCG2 were significantly increased in pan-resistance cell line, and the ABCC5, the most obvious one, was 5.21 times higher than that of the control group. The expression of ABCC5 was inversely correlated with sensitivity (IC50) of pemetrexed (r = 0.741; p<0.001) in breast cancer cells from 34 patients. Furthermore, we found that the expression of ABCC5 influenced the efflux and cytotoxicity of pemetrexed in MCF-7 cell line, and the IC50 were 0.06 μg/ml and 0.20 μg/ml in ABCC5 knock-down and over-expression cells, respectively. In in vivo study, we found ABCC5 affected the sensitivity of pemetrexed in breast cancer bearing mice, and the tumor volume was much larger in ABCC5 over-expression group than that in control group (2.7 folds vs 1.3 folds).ConclusionsOur results indicated ABCC5 expression was associated with pemetrexed resistance in vitro and in vivo, and may be a biomarker for regimen optimization of pemetrexed in breast cancer treatment.

Background Chaihu-Guizhi-Ganjiang Decoction (CGGD) is a traditional Chinese medicine (TCM) prescription used to treat viral influenza in China. There is evidence that CGGD can be used to treat irritable bowel syndrome (IBS) but the potential mechanism of action and metabolites produced upon CGGD treatment are not known. Methods Patients with IBS were treated with pinaverium bromide (Dicetel™) and then CGGD after a washout period of 1 week. Both treatments lasted for 30 days. Efficacy and changes in metabolites in plasma after the two treatments were compared. Plasma samples were acquired before and after each treatment, and untargeted metabolics analysis undertaken. Results Efficacy was measured by two systems: the Rome IV criteria and TCM theory. Irrespective of whether the Rome IV criteria or TCM theory were used, CGGD showed significantly better efficacy than Dicetel against IBS. CGGD also had a greater influence on plasma metabolism than Dicetel. Dicetel treatment led to increased tryptophan metabolism (increased levels of 5-Hydroxyindoleacetaldehyde) and increased protein metabolism (increased levels of L-arginine). CGGD use led to increased carnitine metabolism, with increased levels of L-carnitine and acylcarnitine. Such changes in these metabolites could suppress IBS by improving gastrointestinal motility and suppressing pain, depression, and inflammation. Conclusions CGGD appeared to be more efficacious than Dicetel in treating IBS. Metabolomics analysis helped to reveal the biomolecular basis of this beneficial effect.

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