The Aconitum species, which mainly contain bioactive Aconitum alkaloids, are frequently administered concomitantly with other herbal medicines or chemical drugs in clinics. The potential risk of drug–drug interactions (DDIs) arising from co-administration of Aconitum alkaloids and other drugs against specific targets such as P-glycoprotein (P-gp) must be evaluated. This study focused on the effects of three representative Aconitum alkaloids: aconitine (AC), benzoylaconine (BAC), and aconine, on the expression and activity of P-gp. We observed that Aconitum alkaloids increased P-gp expression in LS174T and Caco-2 cells in the order AC > BAC > aconine. Nuclear receptors were involved in the induction of P-gp. AC and BAC increased the P-gp transport activity. Strikingly, intracellular ATP levels and mitochondrial mass also increased. Furthermore, exposure to AC decreased the toxicity of vincristine and doxorubicin towards the cells. In vivo, AC significantly up-regulated the P-gp protein levels in the jejunum, ileum, and colon of FVB mice, and protected them against acute AC toxicity. Taken together, the findings of our in vitro and in vivo experiments indicate that AC can induce P-gp expression, and that co-administration of AC with P-gp substrate drugs may cause DDIs. Our findings have important implications for Aconitum therapy in clinics.

Lung adenocarcinoma (LAC), predominant subclassfication of lung cancer, leads high incidence and mortality annually worldwide. During the premalignant transition from lung adenomas to LAC, cellular senescence is regard as a critical physiological barrier against tumor progression. Nevertheless, the role of senescence in tumorigenesis is controversial and few senescence inducers are extensively determined. In this study, we used two classical cell lines A549 and H1299 and two NSCLC xenograft models on Balb/c-nude mice to reveal the pro-senescence effects of shikonin and the corresponding underlying mechanism in LAC. Shikonin, a pure compound isolated from the herbal medicine Lithospermum erythrorhizon, remarkably stimulated cellular senescence including increased SAHF formation, enlarged cellular morphology, and induced SA-β-Gal positive staining. Further mechanism study revealed that the pro-senescence effect of shikonin was dependent on the increased intercellular ROS generation, which subsequently triggered DNA damage-p53/p21waf axis without activating oncogenes such as Ras and MEK-1. Meanwhile, Kdm2b, an H3K36me2-specific demethylase effectively suppressed ROS generation, was also notably suppressed by shikonin treatment. Moreover, shikonin at 10 mg/kg significantly inhibited tumor weights by 55.84% and 50.98% in A549 and H1299 xenograft model, respectively (P < 0.05) through activating cellular senescence. Our study suggested that shikonin, a ROS-dependent senescence inducer, could serve as a promising agent for further lung cancer treatment.

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Raw Pinelliae Rhizoma (RPR) is a representative toxic herb that is widely used for eliminating phlegm or treating cough and vomiting. Given its irritant toxicity, its processed products, including Pinelliae Rhizoma Praeparatum (PRP) and Pinelliae Rhizoma Praeparatum cum Zingibere et Alumine (PRPZA), are more commonly applied and administered concomitantly with other chemical drugs, such as cough medications. This study aimed to investigate the effects of RPR, PRP, and PRPZA on CYP3A activity. Testosterone (Tes) and buspirone (BP) were used as specific probe substrates ex vivo and in vivo, respectively. CYP3A activity was determined by the metabolite formation ratios from the substrates. Ex vivo results show that the metabolite OPEN ACCESSMolecules 2015, 20 793 formation ratios from Tes significantly decreased, indicating that RPR, PRP, and PRPZA could inhibit CYP3A activity in rats. CYP3A protein and mRNA levels were determined to explore the underlying mechanism. These levels showed marked and consistent down-regulation with CYP3A activity. A significant decrease in metabolite formation ratios from BP was also found in PRPZA group in vivo, implying that PRPZA could inhibit CYP3A activity. Conclusively, co-administration of PR with other CYP3A-metabolizing drugs may cause drug-drug interactions. Clinical use of PR-related formulae should be monitored carefully to avoid adverse interactions.

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