Drug-Herb Interactions among Thai Herbs and Anticancer Drugs: A Scoping Review

More than half of Thai patients with cancer take herbal preparations while receiving anticancer therapy. There is no systematic or scoping review on interactions between anticancer drugs and Thai herbs, although several research articles have that Thai herbs inhibit cytochrome P450 (CYP) or efflux transporter. Therefore, we gathered and integrated information related to the interactions between anticancer drugs and Thai herbs. Fifty-two anticancer drugs from the 2020 Thailand National List of Essential Medicines and 75 herbs from the 2020 Thai Herbal Pharmacopoeia were selected to determine potential anticancer drug–herb interactions. The pharmacological profiles of the selected anticancer drugs were reviewed and matched with the herbal pharmacological activities to determine possible interactions. A large number of potential anticancer drug–herb interactions were found; the majority involved CYP inhibition. Efflux transporter inhibition and enzyme induction were also found, which could interfere with the pharmacokinetic profiles of anticancer drugs. However, there is limited knowledge on the pharmacodynamic interactions between anticancer drugs and Thai herbs. Therefore, further research is warranted. Information regarding interactions between anticancer drugs and Thai herbs should provide as a useful resource to healthcare professionals in daily practice. It could enable the prediction of possible anticancer drug–herb interactions and could be used to optimize cancer therapy outcomes.


Introduction
According to the World Health Organization, cancer was one of the top 10 causes of worldwide death in 2019 [1]. In 2020, there were 190,636 new cases of patients with cancer and 124,866 deaths from cancer reported in Thailand [2]. Cancer is a group of diseases caused by an abnormality in cell proliferation and differentiation, which results in an invasion into organs, leading to metastasis and death [3]. All cancer survivors are at risk of cancer recurrence despite receiving effective treatments, as some cancer cells remain in their bodies [4]. Currently, patients with cancer are treated with many types of chemotherapeutic agents, which predispose them to high incidences of adverse drug reactions and put them at high risk of drug-drug interactions, resulting in sub-therapeutic effects or increased unwanted toxicities that could potentiate the negative outcomes of

Results
The majority of the anticancer drugs in the 2020 NLEM are alkylating agents (23%) and antimetabolites (19%) ( Figure 1A). Approximately half of the anticancer drugs are metabolized by phase I biotransformation ( Figure 1B). Among phase I metabolism, 80% of anticancer pharmacokinetic profiles involve biotransformation by oxidation, especially via CYP isoforms and, to a lesser degree, by hydrolysis and reduction ( Figure 1C). The major enzyme in anticancer metabolism is CYP3A4 ( Figure 1D). Several anticancer drugs are excreted via the renal tubules and/or the hepatobiliary system by transmembrane transporters, especially P-glycoprotein. The pharmacokinetic profiles of the selected anticancer drugs are shown in Supporting information (Table S1).
The Thai herbs in the 2020 THP are distributed in 33 families and 13% of them are in the Apiaceae or Umbelliferae family ( Figure 2A). Fruits, leaves and rhizomes are common parts that have medicinal properties ( Figure 2B). The major bioactive components in these herbs are volatile oils (28%), followed by terpenoids (including triterpenoid saponins, 19%), flavonoids and phenylpropanoids (16%) ( Figure 2C). Approximately half of the Thai herbs in the 2020 THP (44%) could alter drug metabolizing enzymatic activities in an in vitro setting, especially inhibition of CYP3A4 and CYP2D6. In addition, some Thai herbs could inhibit efflux transporters, particularly P-glycoprotein ( Figure 2D).
Among the 52 anticancer drugs and 75 Thai herbs we selected, there are 565 potential anticancer drug-herb interactions. Approximately 90% of these interactions involve CYP inhibition, while some of the interactions exhibit potent CYP inhibitory activity. Potential anticancer drug-herb interactions might occur via drug metabolizing enzymes and efflux transporter inhibition. When categorized by the level of documentation according to the criteria in Table S2, 15 pairs are classified as good and 550 pairs are classified as fair.     All potential interferences with the activities of drug metabolizing enzymes and transporters by Thai herbs are shown in Table 1.
Andrographis paniculata, Centella asiatica, Curcuma longa, Kaempferia parviflora, and Zingiber montanum are most commonly used in Thai herbal medicine, sometimes referred to as the Thai herbal product champions [106,107]. Our findings have revealed multiple anticancer drugs-herb interactions involving various CYP isoforms and P-glycoprotein transporters. These interactions could have effects on the therapeutic activities and toxicities of anticancer drugs ( Table 2).         Interestingly, many Thai herbs in our study exhibit anticancer activities (Table S3). More than of the half (39 out of 75) have been reported to show cytotoxic effects against cancer cell lines or in in vivo models. The most common cell types used in in vitro studies have been liver (16%), breast (15%) and colorectal (12%) (Figure 3A), whereas only 16 herbs (21%) have shown anticancer activity in in vivo studies. The most reported cell types have been cholangiocarcinoma (14%), lung (14%) and colorectal (9%) ( Figure 3B).
Interestingly, many Thai herbs in our study exhibit anticancer activities (Table S3). More than of the half (39 out of 75) have been reported to show cytotoxic effects against cancer cell lines or in in vivo models. The most common cell types used in in vitro studies have been liver (16%), breast (15%) and colorectal (12%) (Figure 3A), whereas only 16 herbs (21%) have shown anticancer activity in in vivo studies. The most reported cell types have been cholangiocarcinoma (14%), lung (14%) and colorectal (9%) ( Figure 3B).

Discussion
Drug-herb interactions could result in therapeutic failure and lead to severe adverse events. One of the most well-known natural products that interferes with drug metabolic pathways is grapefruit juice. Naringin from this citrus fruit inhibits major drug metabolizing enzymes, including CYP3A4 [109]. In our database, piperine in pepper (Piper nigrum) also showed strong inhibitory properties against CYP3A4. Therefore, it is possible that the levels of anticancer drugs metabolized mainly by this enzyme would be increased, resulting in more side effects. However, anticancer drugs given as prodrugs (for example, tamoxifen) present decreased efficacy after CYP inhibition due to the reduction in active metabolite [110][111][112][113][114][115][116]. Surprisingly, some of the Thai herbs differentially inhibit several CYP isoforms. For example, Atractylodes lancea markedly inhibits CYP1A2 and moderately inhibits CYP2C19, with weak inhibition of CYP2D6 and CYP3A4. This herb may also interfere with the metabolism of several anticancer drugs [117,118]. The majority of DHIs found in this study are related to CYP inhibition [53]. Therefore, the increased levels of anticancer drugs after concomitant use of some herbs and anticancer drugs should be monitored carefully.
Several Thai herbs that are commonly used as food ingredients show CYP inhibitory properties. Curcuma longa contains curcuminoids as bioactive ingredients, which have been found to be CYP inhibitors (for example, CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) [19,65,66]. Thus, anticancer drug-spice interactions should also be a concern for patients with cancer due to the ability of these herbal products to inhibit drug metabolizing enzyme. Curcuminoids have recently been proposed as a bioenhancer for several conventional drugs [119]. Hence, elevated anticancer drug bioavailability and toxicity might occur during the coadministration of Curcuma longa and anticancer drugs.
Centella asiatica, a major herbal product of Thailand, has a bioactive component consisting of a triterpenoid glycoside and triterpenic acid. This herbal extract has shown mild-to-moderate inhibitory properties against several CYP isoforms, including CYP2C9 and CYP2C19 [38,61,62,120,121]. Moreover, there are reports of increased blood clotting time after the coadministration of Centella asiatica with warfarin [122]. Thus, practitioners are aware of and are vigilant of potential toxicities in patients taking Centella asiatica with a narrow therapeutic window of drugs metabolized via CYP2C9 or CYP2C19.
Allium sativum, commonly called garlic, is a widely used herb and spice in Thailand that affects anticancer drug levels. A clinical study of patients with breast cancer receiving docetaxel as monotherapy showed that the drug clearance was reduced after garlic administration. Moreover, there were genetic polymorphisms associated with the decline in docetaxel clearance [123]. Although the finding did not reach statistical significance due to a small number of participants and possible compensatory metabolic mechanisms of the drug, these findings suggest that coadministration of garlic and docetaxel affect the anticancer drug pharmacokinetics. Further investigation is required to provide clinical evidence of the undesirable adverse effects due to anticancer drug-herb pharmacokinetic interactions.
Considering pharmacodynamic interactions, several herbs in the 2020 THP show anticancer activity. The majority of the reports have focused on in vitro apoptotic cell death of cancer cell lines via various mechanisms. In addition, some major Thai herbal products (both pure compounds and extracts) show promising in vivo antiproliferative activity. Andrographis paniculata extract and andrographolide inhibit tumor-specific angiogenesis by regulating the production of various pro and antiangiogenic factors such as proinflammatory cytokines, nitric oxide, vascular endothelial growth factor (VEGF), interleukin (IL)-2 and tissue inhibitor of metalloproteinase-1 [124,125]. Co-administration of or pre-treatment with pure compounds from tropical herbs such as curcumin from Curcuma longa, thymoquinone from Nigella sativa, capsaicin from Capsicum annuum, or andrographolide from Andrographis paniculata together with anticancer drugs enhances anticancer activity via a synergistic effect. There are several common anticancer drugs that show synergistic effects when co-administered with herbs, including fluorouracil, topotecan, paclitaxel, docetaxel, and cisplatin. The interaction effect when curcumin is co-administered with anticancer drugs has reviewed by Tan and Norhaizan [126]. Thymoquinone and topotecan separately arrest the S phase of the cell cycle. The combination of thymoquinone and topotecan increases the amount of fragmented DNA and induces apoptosis through p53and Bax/Bcl2-independent mechanisms [92]. Capsaicin also enhances in vitro and in vivo inhibitory effects and induces autophagy of 5-FU and cisplatin [55,59]. The combination of andrographolide and topotecan, gemcitabine, vincristine, cisplatin, arsenic trioxide, and paclitaxel promotes apoptosis in various cancer cell lines [26,28,29,31,36,[43][44][45]. The chemical structures of major compounds from commonly used Thai herbs with potential anticancer-herb interactions are shown in Figure 4.
Pharmacodynamic research in the clinical context is needed to determine the anticancer activities of Thai herbs. An evaluation of benefits and risks should be conducted by considering both pharmacokinetic interactions and pharmacodynamics to optimize cancer therapy.
The management of potential DHI between anticancer drugs and Thai herbs seems to be one of the major problems in patient care in some countries, especially in Thailand. Both phytopharmaceutical products and food ingredients from Thai herbs could affect the outcomes of cancer therapies and increase the side effects. Thus, patient education and consultation from healthcare professionals (i.e., physicians or pharmacists) are necessary before the co-administration of anticancer drugs and Thai herbs. The algorithm 'ask, check and consult' could increase the safety of the co-administration of anticancer drugs and Thai herbs [127].
This review on interactions between anticancer drugs and Thai herbs provides healthcare professionals with comprehensive information for patient consultation. This study is limited by the number of anticancer drugs: there are only 52 anticancer drugs on the 2020 NLEM. This might not represent all commercially available anticancer drugs Since these are the drugs covered by Thailand's universal health insurance, and thus they are used extensively. Another limitation is that we considered only 75 herbs derived from the 2020 THP. We did not include mixtures of preparations of several herbs in this study. Further investigation is needed to complete our database of interactions between anticancer drugs and Thai herbs.

Selection of Anticancer Drugs and Herbs
Fifty-two anticancer drugs from the 2020 NLEM and 99 Thai herbs from the 2020 THP were selected. Twenty-four herbal items were excluded due to the fact that they were part of herbal preparations (mixtures of multiple herbs). The selection procedure and lists of anticancer drugs and Thai herbs are shown in Figure 5 and Table 3, respectively.

Selection of Anticancer Drugs and Herbs
Fifty-two anticancer drugs from the 2020 NLEM and 99 Thai herbs from the 2020 THP were selected. Twenty-four herbal items were excluded due to the fact that they were part of herbal preparations (mixtures of multiple herbs). The selection procedure and lists of anticancer drugs and Thai herbs are shown in Figure 5 and Table 3, respectively.
Angelica sinensis 10. We collected pharmacokinetic, pharmacodynamic, toxicological, and drug interaction data of anticancer drugs by using the Micromedex database, which we accessed under the copyright license of Chulalongkorn University (2020). If the drug data were not available in the database, we used PubMed, Science Direct, and Web of Science to find information on metabolic pathways and drug interactions. For the pharmacologic information on Thai herbs, we used the herb database from the Faculty of Pharmacy, Mahidol University, Thailand, and also available online databases (PubMed, Science Direct, and Web of Science). These data provide the pharmacodynamic activities and the possibility of drug-herb interactions. All data were gathered and analyzed from 1 January to 31 December 2020. The keywords for data collection were: 1.
('Scientific name of herbs' OR 'Common name of herbs' OR 'major components of herbs'); 2.
('In vitro' OR 'In vivo' OR case reports OR clinical trials); 3.
('anticancer drug name') The classification criteria of the severity level and documentation are reported in Table  S2. We matched two sets of collected data (anticancer drugs and Thai herbs) and analyzed them individually for potential of anticancer drug-herb interactions. We then evaluated the information on the severity, documentation, and mechanisms of these interactions.

Supplementary Materials:
The following are available online at https://www.mdpi.com/article/10 .3390/ph15020146/s1. Table S1: Pharmacokinetic profiles of anticancer drugs; Table S2. Definition and classification of the severity level and documentation; Table S3: Thai herbs with anticancer activities.