Despite improved diagnostic tools for HCC and much better survival rates of patients, the outcomes and prognoses of HCC patients remain poor because of poor liver function and advanced cancer stage. Transcatheter arterial chemoembolization (TACE) is the main treatment for unresectable HCC, and DOX is one of the commonly used drugs in TACE [22–23]. TACE is not, however, ideal as a long-term cure since it often reduces immunity, aggravates the impairment of liver function and reduces life quality of HCC patients. Finding a way to reduce liver injury and improve clinical efficacy and quality of life has thus become a key issue and many patients in Asia are seeking help from traditional herbal medicines.
ADI is composed mainly of Astragalus, A. senticosus, Ginseng and Cantharis. ADI, combined with TACE, is now widely used in the treatment of unresectable HCC in China. It has been reported that this combination can, to some extent, enhance the clinical effect, improve overall survival, increase quality of life for patients and reduce adverse events, including leukopenia, gastrointestinal side effects and liver damage [24]. In a previous study, we found that ADI reduced serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBil) and alkaline phosphatase (ALP) in rats with DEN-induced HCC, confirming its protective effect on liver function [21]. The clinical use of ADI is intravenous drip, 50 to 100 ml of ADI for adults, mixed with 0.9% sodium chloride injection or glucose injection, once a day. When combined with radiotherapy and chemotherapy, the course of treatment is synchronized with radiotherapy and chemotherapy. ADI is used for 10 days before and after surgery. For patients with advanced cachexia, ADI is used for 30 days or depending on the condition. According to human and rat dose conversion and the convenience of practical operation, rats were injected intraperitoneally with 10 mL/kg of ADI for 14 consecutive days.
Our results show that plasma concentrations of DOX and DOXol were significantly higher in the ADI group. AUC of DOX and DOXol in the ADI group was 3.79-fold and 2.92-fold higher than that in the control group. It means there is herb-drug interactions between ADI and DOX. ADI can change the pharmacokinetics of DOX in HCC rats.
To the best of our knowledge, the plasma protein binding rate of DOX very low. Therefore, ADI is unlikely to change the plasma concentration of DOX and DOXol by competing with plasma protein binding. ADI alters DOX's drug metabolism enzymes and transporters is a possible cause. DOX is mainly metabolized in the liver and excreted in bile, 50% of which are parent drugs, and 23% are active metabolites such as DOXol [25]. DOX can be converted into a semiquinone structure through single-electron reduction, and it can also form DOXol through C-13 hydroxylation in the cytoplasm by carbonyl reductase 1 (CBR1), which generally expressed in liver, heart and other tissues [26]. Various transporters, particularly P-gp (ABCB1, MDR1) and ABCC1 (MRP1), are thought to be play a role in resistance to DOX [2]. Generally, increased expression of P-gp results in increased DOX efflux and a number of studies on DOX resistance have shown that resistance can be overcome via inhibition of P-gp [27–29]. The import transporter SLC22A16 has also been shown to be involved in intracellular transport of DOX [30].
In our previous study, ADI also reduced mRNA levels and enzymatic activity of glutathione transferases (GSTs), and decreased protein expression of GST-π in the livers of HCC rats [19]. High expression of GST-π is known to accelerate the transformation and metabolism of anti-tumor drugs, shorten the duration of effective drug concentrations in cells and rapidly reduce the accumulation of drugs in target sites, thus reducing efficacy. GSTs are considered to be potential targets to overcome chemoresistance in solid tumors [31], and reduction of GSTs activity may be the one of underlying mechanisms for the synergistic effect of ADI. Inhibition of GSTs activity cannot, however, explain why administration of ADI leads to elevated levels of DOX and DOXol, since GSTs are not involved in DOX metabolism. In summary, to explain why ADI changed pharmacokinetics of DOX, more experiments with rigorous design are needed.
DOX is an effective chemotherapeutic drug. DOXol is the most important component of DOX-induced cardiotoxicity. Hence, increased blood concentrations of DOX and DOXol, in addition to implying that it may increase the therapeutic effect of DOX and may lead to stronger toxic and side effects. However, many studies have shown that the related ingredients of Astragalus, A. senticosus, Ginseng can play a synergistic effect, protect the heart, and reduce the toxic and side effects of chemotherapy drugs, such as ginsenoside Rg1 [32], ginsenoside Rg3 [33–35], astragalus polysaccharide [36–37], acanthopanax senticosides B [38]. Therefore, whether the combination of ADI and DOX can enhance the efficacy and reduce the myocardial toxicity of DOX requires more experiments to verify.