Cancer Therapy Interactions With Foods and Dietary Supplements (PDQ®): Integrative, alternative, and complementary therapies - Health Professional Information [NCI]

Overview

This cancer information summary provides an overview on cancer therapy interactions with different foods and dietary supplements.

This summary contains the following key information:

• The combination of cancer drugs taken by patients and the complementary and alternative medicine used may interact, causing adverse outcomes.
• Research on dietary supplement and cancer drug pharmacokinetics (PK) interactions is limited, but there is evidence for several possible interactions and adverse reactions.
• For many specific antioxidant supplements, there is insufficient information available to determine if they are safe and effective as a complementary therapy to standard cancer treatment.
• Certain constituents of foods and dietary supplements (e.g., St. John's wort, grapefruit juice, and epigallocatechin gallate from green tea) can alter the PK of specific types of drugs.
• Some research has shown a dietary supplement/food and drug PK interaction between grapefruit juice and imatinib.

General Information

For adult cancer patients in the United States, the frequency of complementary and alternative medicine (CAM) use is approximately 36%.[1] It is possible that the combination of cancer drugs taken by these patients and the CAM they use may interact, causing adverse outcomes.[2,3,4] When dietary supplements /herbs and cancer drugs are taken together, there is always a risk of the supplement having an impact on the pharmacokinetics (PK) or pharmacodynamics (PD) of the drug. Many drug interactions occur from the effects of the supplement on specific enzymes or on components involved in the PK of the drug, such as how the drug is metabolized and transported. Reporting and studying these interactions is important, so health care professionals can help patients navigate CAM usage with standard cancer therapies, thus avoiding preventable adverse outcomes. Integrative oncology consultations available in a number of cancer care settings can engage patients in evidence-based discussions about recommending or stopping supplements, as well as addressing questions about alternative therapies.[5]

In the United States, dietary supplements are regulated by the U.S. Food and Drug Administration (FDA) as a separate category from foods, cosmetics, and drugs. Unlike drugs, dietary supplements do not require premarket evaluation and approval by the FDA unless specific disease prevention or treatment claims are made. The quality and amount of ingredients in dietary supplements are also regulated by the FDA through Good Manufacturing Practices (GMPs). The FDA GMPs requires that every finished batch of dietary supplement meets each product specification for identity, purity, strength, composition, and limits on contamination that may adulterate dietary supplements. Because dietary supplements are not formally reviewed for manufacturing consistency every year, ingredients may vary considerably from lot to lot and there is no guarantee that ingredients claimed on product labels are present (or are present in the specified amounts). The FDA has not approved the use of dietary supplements as a treatment for cancer patients.

Cytochrome P450 Inhibitors/Inducers

One of the main group of enzymes involved in the metabolism of many cancer drugs is the cytochrome P450 (CYP) superfamily of enzymes. These enzymes play an important role in the activation and inactivation of various drugs. Another component involved in the metabolism and excretion of many drugs is the transport protein, P-glycoprotein (P-gp). P-gp works in the intestine as a drug efflux pump regulating the bioavailability of the drug. Various anticancer drugs are substrates of P-gp; thus, if P-gp or any CYP enzyme is impacted, the drug it is processing will also be impacted.

The PK of a drug predicts therapeutic outcomes for the patient. Various herbs and dietary supplements are known to influence the PK of certain drugs, such as St. John's wort. Currently, research on dietary supplement and cancer drug PK interactions is limited, but there is evidence for several possible interactions and adverse reactions.[1,6,7]

References:

1. Collado-Borrell R, Escudero-Vilaplana V, Romero-Jiménez R, et al.: Oral antineoplastic agent interactions with medicinal plants and food: an issue to take into account. J Cancer Res Clin Oncol 142 (11): 2319-30, 2016.
2. Wolf CPJG, Rachow T, Ernst T, et al.: Interactions in cancer treatment considering cancer therapy, concomitant medications, food, herbal medicine and other supplements. J Cancer Res Clin Oncol 148 (2): 461-473, 2022.
3. Lee RT, Kwon N, Wu J, et al.: Prevalence of potential interactions of medications, including herbs and supplements, before, during, and after chemotherapy in patients with breast and prostate cancer. Cancer 127 (11): 1827-1835, 2021.
4. Harrigan M, McGowan C, Hood A, et al.: Dietary Supplement Use and Interactions with Tamoxifen and Aromatase Inhibitors in Breast Cancer Survivors Enrolled in Lifestyle Interventions. Nutrients 13 (11): , 2021.
5. D'Andre SD, Bauer BA, Hofmann MB, et al.: Dietary supplement use and recommendations for discontinuation in an integrative oncology clinic. Support Care Cancer 31 (1): 40, 2022.
6. He SM, Yang AK, Li XT, et al.: Effects of herbal products on the metabolism and transport of anticancer agents. Expert Opin Drug Metab Toxicol 6 (10): 1195-213, 2010.
7. Meijerman I, Beijnen JH, Schellens JH: Herb-drug interactions in oncology: focus on mechanisms of induction. Oncologist 11 (7): 742-52, 2006 Jul-Aug.

Antioxidants

General Information

Some common dietary antioxidants include the following:

• Vitamin C (ascorbate).
• Vitamin E.
• Flavonoids (e.g., soy isoflavones, green tea catechins).
• Beta-carotene.
• Glutathione.

Numerous anticancer agents generate reactive oxygen species, which cause decreased levels of antioxidants, deoxyribonucleic acid damage, and cancer cell death. Antioxidants are taken by many cancer patients because it is thought that the substances will protect and repair healthy cells damaged by cancer therapy.[1] There is insufficient information for many specific antioxidant supplements to determine if they are safe and effective as a complementary therapy to standard cancer treatment.

Laboratory/Animal/Preclinical Studies

A study published in 2018 examined the pharmacokinetic interactions between imatinib (25 mg /kg orally) and vitamin A (12 mg retinol /kg orally), vitamin E (400 IU /kg orally), vitamin D3 (100 IU/kg orally), and vitamin C (500 mg/kg orally) when coadministered in rat animal models. The results showed that there was an increase in the bioavailability of imatinib with vitamins A, E , and D, and a decrease in the bioavailability of imatinib with vitamin C.[2]

A study that examined the oxidized form of ascorbate, dehydroascorbate, as a complementary supplement with chemotherapeutic drugs (i.e., doxorubicin, cisplatin, vincristine, methotrexate, and imatinib) initially found that dehydroascorbate given before doxorubicin treatment caused a reduction of therapeutic efficacy in mice with lymphoma (RL) cell–derived xenogeneic tumors. This form of ascorbate is not generally available as a dietary supplement and is not used clinically, and it has different properties and pharmacology from unoxidized or reduced ascorbate; thus, the potential clinical implications of these findings are unknown.[3]

An in vivomouse model study observed a possible interaction between vitamin C (40 mg/kg/d) and bortezomib. There was a significant reduction in bortezomib's anticancer activities with consumption of vitamin C.[4]

Human/Clinical Studies

A study examined pre- and post-diagnosis antioxidant dietary supplement (selenium; multivitamins; zinc; and vitamins A, C, and E) use in postmenopausal breast cancer survivors. The results showed an increased risk of total mortality and worsened recurrence -free survival with antioxidant dietary supplement use during chemotherapy or radiation therapy.[5] A similar study investigated the outcomes for breast cancer patients using antioxidant supplements (vitamins A, C, and E; carotenoids; and coenzyme Q10) before and during treatment with cyclophosphamide, doxorubicin, and paclitaxel. The results showed an increase in hazards of recurrence and death in these patients. Though these hazard ratios are not statistically significant, they both trended in the same direction as those seen in the previous study.[6] This evidence does give reason to use these supplements with caution and indicates that more research on this topic is needed.

Alpha-tocopherol, one of eight vitamin E compounds, was investigated in a clinical trial for its impact on adverse effects from chemotherapy and radiation therapy. Initially, some research suggested that alpha-tocopherol may reduce toxicity caused by radiation therapy for head and neck cancer. Two randomized, controlled clinical trials of patients with head and neck cancer who received vitamin E supplementation at a dose of 400 IU/day have shown an association with a higher risk of tumor relapse and a decrease in cancer-free survival.[7,8]

References:

1. Ozben T: Antioxidant supplementation on cancer risk and during cancer therapy: an update. Curr Top Med Chem 15 (2): 170-8, 2015.
2. Maher HM, Alzoman NZ, Shehata SM: Ultra-performance LC-MS/MS study of the pharmacokinetic interaction of imatinib with selected vitamin preparations in rats. Bioanalysis 10 (14): 1099-1113, 2018.
3. Heaney ML, Gardner JR, Karasavvas N, et al.: Vitamin C antagonizes the cytotoxic effects of antineoplastic drugs. Cancer Res 68 (19): 8031-8, 2008.
4. Perrone G, Hideshima T, Ikeda H, et al.: Ascorbic acid inhibits antitumor activity of bortezomib in vivo. Leukemia 23 (9): 1679-86, 2009.
5. Jung AY, Cai X, Thoene K, et al.: Antioxidant supplementation and breast cancer prognosis in postmenopausal women undergoing chemotherapy and radiation therapy. Am J Clin Nutr 109 (1): 69-78, 2019.
6. Ambrosone CB, Zirpoli GR, Hutson AD, et al.: Dietary Supplement Use During Chemotherapy and Survival Outcomes of Patients With Breast Cancer Enrolled in a Cooperative Group Clinical Trial (SWOG S0221). J Clin Oncol 38 (8): 804-814, 2020.
7. Bairati I, Meyer F, Gélinas M, et al.: A randomized trial of antioxidant vitamins to prevent second primary cancers in head and neck cancer patients. J Natl Cancer Inst 97 (7): 481-8, 2005.
8. Bairati I, Meyer F, Jobin E, et al.: Antioxidant vitamins supplementation and mortality: a randomized trial in head and neck cancer patients. Int J Cancer 119 (9): 2221-4, 2006.

Herbs

Ginseng

General information

Ginseng root has commonly been used as a dietary supplement in traditional Asian medicine. There are several types of ginsengs. While there is no conclusive evidence for the health benefits of ginseng, people currently use it for the following reasons:[1,2]

• To increase overall well-being and concentration.
• To strengthen the immune system.
• To improve health conditions, such as heart disease, depression, and anxiety.

Laboratory/animal/preclinical studies

Most in vitro research on ginseng's pharmacokinetic (PK) interactions found little evidence of any effects, determining a low risk of cytochrome P450 (CYP)-dependent herb -drug reactions. Overall, the evidence is mixed and inconclusive.[3,4,5]

Case study

Ginseng was suspected of being responsible for an incident of hepatotoxicity that occurred in a 26-year-old male taking imatinib. The hypothesized mechanism for this interaction was inhibition of hepatic CYP3A4, the enzyme primarily responsible for metabolizing imatinib. The ginseng was ingested through a ginseng energy drink, which creates uncertainty about whether the ginseng or the other ingredients in the drink caused the adverse effect. Clinical research is needed to confirm if there are any PK interactions between imatinib and ginseng.[6]

Scutellaria baicalensis/wogonin

General information

Scutellaria baicalensis, also known as wogonin, Chinese skullcap, or Huang Qin, is a plant used in traditional Chinese medicine to treat various medical conditions, such as the following:[7]

• Diarrhea.
• Hepatitis.
• Infections.
• Inflammation.

In traditional Chinese medicine, there are some herbal mixtures that contain Scutellaria baicalensis, one being Huang Qin Tang. PHY906, a patented formula derived from Huang Qin Tang, is being studied as a potential adjuvant for cancer therapy; there is some evidence that this herbal mixture potentiates the anticancer effects of certain cancer drugs such as sorafenib.[8] Some research has shown the inhibitory effect of wogonin on the activity of CYP, but more research is needed to determine interactions with specific drugs.[9]

Laboratory/animal/preclinical studies

A 2016 study investigated the effects of a Scutellariae radix decoction on methotrexate pharmacokinetics in rats. The study revealed an increased systemic methotrexate exposure when given together with the Scutellariae radix decoction. Giving them together is thought to have effects on multidrug resistance –associated proteins and breast cancer resistance protein.[10]

A 2018 study examined the PK profile and herb-drug interactions of oral wogonin and intravenous docetaxel in rats with mammary tumors. The investigators found that in rats receiving oral wogonin and docetaxel, the area under the concentration versus time curve (AUC), initial peak serum concentration (C_max), and half-life for docetaxel increased. The investigators speculated that these increases resulted from the inhibitory effect of wogonin on CYP3A and P-glycoprotein (P-gp). More research is needed with human clinical trials, but these results suggest a possible interaction between wogonin and docetaxel.[11]

St. John's Wort

General information

The flower of the St. John's wort (SJW) (Hypericum perforatum) plant is used traditionally for wound healing, insomnia, and kidney and lung problems, and most commonly today for depression. This flower can be taken through teas, tablets, capsules, and extracts. Currently, the evidence for the clinical efficacy of SJW is varied, but there have been reports of interactions and adverse effects with several drugs.[12]

Laboratory/animal/preclinical studies

A 2012 study observed the effects of SJW on the PK of methotrexate in a rat animal model. After coadministration of SJW (300 mg /kg and 150 mg/kg) and methotrexate, animals that received 300 mg/kg of SJW had a 163% increase in AUC and a 60% increase in C_max for methotrexate. For animals that received 150 mg/kg of SJW, an increase in AUC (55%) for methotrexate was observed. Overall, the mortality of the rats treated with SJW combined with methotrexate was higher. The researchers suggested using extreme caution if coadministering these two substances.[13]

Human/clinical studies

There are two well-known examples of herb-drug interactions impacting drug PK that have clinical evidence. These two interactions are between SJW and both irinotecan and imatinib. After patients were treated with both irinotecan (350 mg/m²) and SJW (900 mg/d), one study found a 42% decrease in plasma levels of SN-38, the active metabolite of irinotecan. The researchers hypothesized that components of SJW extract, pseudohypericin and hyperforin, interacted with CYP3A4 isoform and P-gp, causing reduction in SN-38. This interaction may cause a loss of irinotecan efficacy.[14]

A similar outcome occurred in two studies that examined treatment with imatinib (400 mg) and SJW (300 mg 3 times a day). In one study, SJW caused a 32% decrease in AUC, a 29% decrease in C_max, and a 21% decrease in half-life after two weeks of combined treatment with SJW and imatinib.[15] The second study found that SJW use caused a 43% increase in the clearance of imatinib and a 30% decrease in AUC. This interaction is also thought to be caused by the impact of SJW on CYP3A4, the major enzyme that metabolizes imatinib.[16]

Another CYP3A4 substrate that may be impacted by SJW is docetaxel. A 2014 study with ten cancer patients investigated the PK interactions of docetaxel (135 mg IV for 60 min) in combination with SJW (300 mg orally for 14 days). The results showed a statistically significant decrease of 12% in mean AUC and an increased clearance of docetaxel.[17]

Although there is a lack of published research, the use of SJW in patients undergoing treatment with ixabepilone is not recommended. SJW may cause a decrease in plasma concentrations of ixabepilone. The drug label for ixabepilone states a warning for this possible interaction.[18]

Thunder God Vine

General information

Thunder god vine, also known as Tripterygium wilfordii Hook f, is an herb traditionally used in Chinese medicine for its possible anti-inflammatory, immunosuppressant, and anticancer effects.[19] Studies have found that triptolide and celastrol, the active components of thunder god vine, are responsible for these possible effects. Clinical observations, mostly from China, reported significant multiorgan toxicities from the traditional raw material or the extracts. Deaths associated with ingesting these materials have been frequently reported.[20,21] Frequency of severe-grade adverse events from the extracts ranged from 5% to 8%,[22,23] with the global incidence of adverse events at 30.8% (95% confidence interval, 21.2–40.3).[23] The most frequently reported adverse events are intestinal toxicity (13.9%), reproductive toxicity (10.2%), hepatotoxicity (6.8%), nephrotoxicity (13.6%), hematotoxicity (5.7%), and cutaneous toxicity (<5%).[23] Evidence varies for herb-drug interactions and toxicity, which are potentially caused by inhibiting effects on the activity of the CYP450 enzyme system.[24] Specifically, celastrol inhibits five cytochrome P450 isoenzymes (CYP1A2, CYP2C19, CYP2D6, CYP2E1, and CYP3A4) in vitro.[25] In addition, a study also found that the coadministration of the CYP3A4 inhibitor, ritonavir, or the inducer, dexamethasone, leads to a significant increase or decrease of the plasma concentration levels of triptolide.[26]

Laboratory/animal/preclinical studies

A 2017 study investigated the effects of triptolide (10 mg/kg) on the PKs of three different sorafenib doses (20, 50, and 100 mg/kg) in rats. The results showed an increase in C_max and AUC for each sorafenib dose and a decrease in clearance with pretreatment of triptolide. It is hypothesized that this interaction occurred due to triptolide's possible inhibiting effects on P-gp and CYP3A4 enzymatic activity.[27]

References:

1. Wang CZ, Yuan CS: Ginseng, American. In: Coates PM, Betz JM, Blackman MR, et al., eds.: Encyclopedia of Dietary Supplements. 2nd ed. Informa Healthcare, 2010, pp 339-47.
2. Jia L, Soldati F: Ginseng, Asian. In: Coates PM, Betz JM, Blackman MR, et al., eds.: Encyclopedia of Dietary Supplements. 2nd ed. Informa Healthcare, 2010, pp 348-62.
3. Collado-Borrell R, Escudero-Vilaplana V, Romero-Jiménez R, et al.: Oral antineoplastic agent interactions with medicinal plants and food: an issue to take into account. J Cancer Res Clin Oncol 142 (11): 2319-30, 2016.
4. Goey AK, Mooiman KD, Beijnen JH, et al.: Relevance of in vitro and clinical data for predicting CYP3A4-mediated herb-drug interactions in cancer patients. Cancer Treat Rev 39 (7): 773-83, 2013.
5. Haefeli WE, Carls A: Drug interactions with phytotherapeutics in oncology. Expert Opin Drug Metab Toxicol 10 (3): 359-77, 2014.
6. Bilgi N, Bell K, Ananthakrishnan AN, et al.: Imatinib and Panax ginseng: a potential interaction resulting in liver toxicity. Ann Pharmacother 44 (5): 926-8, 2010.
7. Wang ZL, Wang S, Kuang Y, et al.: A comprehensive review on phytochemistry, pharmacology, and flavonoid biosynthesis of Scutellaria baicalensis. Pharm Biol 56 (1): 465-484, 2018.
8. Lam W, Jiang Z, Guan F, et al.: PHY906(KD018), an adjuvant based on a 1800-year-old Chinese medicine, enhanced the anti-tumor activity of Sorafenib by changing the tumor microenvironment. Sci Rep 5: 9384, 2015.
9. Li T, Li N, Guo Q, et al.: Inhibitory effects of wogonin on catalytic activity of cytochrome P450 enzyme in human liver microsomes. Eur J Drug Metab Pharmacokinet 36 (4): 249-56, 2011.
10. Yu CP, Hsieh YC, Shia CS, et al.: Increased Systemic Exposure of Methotrexate by a Polyphenol-Rich Herb via Modulation on Efflux Transporters Multidrug Resistance-Associated Protein 2 and Breast Cancer Resistance Protein. J Pharm Sci 105 (1): 343-9, 2016.
11. Wang T, Long F, Jiang G, et al.: Pharmacokinetic properties of wogonin and its herb-drug interactions with docetaxel in rats with mammary tumors. Biomed Chromatogr : e4264, 2018.
12. Field HL, Monti DA, Greeson JM, et al.: St. John's Wort. Int J Psychiatry Med 30 (3): 203-19, 2000.
13. Yang SY, Juang SH, Tsai SY, et al.: St. John's wort significantly increased the systemic exposure and toxicity of methotrexate in rats. Toxicol Appl Pharmacol 263 (1): 39-43, 2012.
14. Mathijssen RH, Verweij J, de Bruijn P, et al.: Effects of St. John's wort on irinotecan metabolism. J Natl Cancer Inst 94 (16): 1247-9, 2002.
15. Smith P, Bullock JM, Booker BM, et al.: The influence of St. John's wort on the pharmacokinetics and protein binding of imatinib mesylate. Pharmacotherapy 24 (11): 1508-14, 2004.
16. Frye RF, Fitzgerald SM, Lagattuta TF, et al.: Effect of St John's wort on imatinib mesylate pharmacokinetics. Clin Pharmacol Ther 76 (4): 323-9, 2004.
17. Goey AK, Meijerman I, Rosing H, et al.: The effect of St John's wort on the pharmacokinetics of docetaxel. Clin Pharmacokinet 53 (1): 103-10, 2014.
18. IXEMPRA - ixabepilone. Bristol-Myers Squibb Company, 2009. Available online. Last accessed May 26, 2022.
19. Ziaei S, Halaby R: Immunosuppressive, anti-inflammatory and anti-cancer properties of triptolide: A mini review. Avicenna J Phytomed 6 (2): 149-64, 2016 Mar-Apr.
20. Zhang C, Sun PP, Guo HT, et al.: Safety Profiles of Tripterygium wilfordii Hook F: A Systematic Review and Meta-Analysis. Front Pharmacol 7: 402, 2016.
21. Chou WC, Wu CC, Yang PC, et al.: Hypovolemic shock and mortality after ingestion of Tripterygium wilfordii hook F.: a case report. Int J Cardiol 49 (2): 173-7, 1995.
22. Adverse Drug Reaction Information Circular (no. 46) Focuses on the Drug Safety of Triptolide Preparations. National Medical Products Administration, 2012. Available online. Last accessed March 10, 2022.
23. Ru Y, Luo Y, Zhou Y, et al.: Adverse Events Associated With Treatment of Tripterygium wilfordii Hook F: A Quantitative Evidence Synthesis. Front Pharmacol 10: 1250, 2019.
24. Jin C, Wu Z, Wang L, et al.: CYP450s-Activity Relations of Celastrol to Interact with Triptolide Reveal the Reasons of Hepatotoxicity of Tripterygium wilfordii. Molecules 24 (11): , 2019.
25. Jin C, He X, Zhang F, et al.: Inhibitory mechanisms of celastrol on human liver cytochrome P450 1A2, 2C19, 2D6, 2E1 and 3A4. Xenobiotica 45 (7): 571-7, 2015.
26. Xu Y, Zhang YF, Chen XY, et al.: CYP3A4 inducer and inhibitor strongly affect the pharmacokinetics of triptolide and its derivative in rats. Acta Pharmacol Sin 39 (8): 1386-1392, 2018.
27. Wang X, Zhang X, Liu F, et al.: The effects of triptolide on the pharmacokinetics of sorafenib in rats and its potential mechanism. Pharm Biol 55 (1): 1863-1867, 2017.

Foods

Grapefruit

General information

Grapefruit and other similar fruits, such as Seville orange, pomelo, and lime, have been known to interact with a variety of drugs, including some anticancer drugs. These pharmacokinetic interactions may be caused by the furanocoumarin components found in the seeds of grapefruit. These components have been observed impacting the metabolism of substrates of CYP3A4.[1,2,3]

Laboratory/animal/preclinical studies

Grapefruit and its furanocoumarin components have been studied for their potential antioxidative, anti-inflammatory, and anticancer effects in in vitro and in vivo studies.[4]

Human/clinical studies

Some research has shown a dietary supplement/food and drug PK interaction between grapefruit juice and imatinib. Grapefruit juice may cause plasma levels of imatinib to increase by inhibiting CYP3A4, in turn triggering organ toxicity.[5]

An interaction has been observed between grapefruit juice and etoposide. A randomized, crossover, pilot study of six participants examined the bioavailability of the oral chemotherapy drug etoposide after coadministration of grapefruit juice. The data showed a decrease in bioavailability between the control group and the experimental group, who were treated with etoposide and grapefruit juice. The bioavailability of etoposide (50 mg orally) reduced from approximately 73% to 52% after pretreatment with grapefruit juice (100 mL). This resulted in a decrease in the area under the concentration versus time curve (AUC) by 26% for etoposide with grapefruit juice, compared with etoposide alone.[6]

Other studies have found an increase in the bioavailability of sunitinib with grapefruit juice exposure,[7] and an increase in AUC by 29% and an increase in peak serum concentration (C_max) by 60% for nilotinib (400 mg orally) was also observed when combined with grapefruit juice (240 mL).[8]

Green Tea

General information

Green tea, green tea extract, and products of green tea components are commonly taken as foods, dietary supplements, and herbal therapies. Some of the traditional and modern uses of green tea include the following:

• Preventing and treating cancer.
• Lowering cholesterol.
• Promoting weight loss.
• Improving mental alertness.
• Helping with digestive symptoms.

Research has been mixed on whether green tea is safe or effective for these uses as well as for coadministration with anticancer drugs.[9] Current research shows that green tea and the polyphenol epigallocatechin gallate (EGCG), an antioxidant component of green tea, can impact the PK or pharmacodynamics (PD) of certain drugs, thus impacting the metabolism and effectiveness of these drugs.[10]

Laboratory/animal/preclinical studies

As seen in the literature, green tea and its constituent EGCG may be involved in both PK and PD interactions. An interaction between green tea and bortezomib was examined in an in vitro study with human multiple myeloma and glioblastoma cell lines. EGCG blocked bortezomib's protease inhibitory function by binding to the boronic acid structure in bortezomib, causing the inability to induce cancer cell death and consequently blocking its anticancer abilities. The second portion of this study investigated this interaction within a plasmacytoma xenograft nude mouse model. Bortezomib's cancer cell apoptosis -inducing effect was completely prevented with intragastric EGCG administration (50 mg/kg).[11] This interaction was also reported in another animal study that examined human prostate cancer xenografts in immune-deficient mouse models. High intravenous (IV) doses of EGCG along with the coadministration of bortezomib resulted in the abrogation of bortezomib's anticancer effects.[12] Human studies should be conducted to determine clinical significance.

The impact of green tea and EGCG on fluorouracil PK was studied in rats. The results of these studies showed a 151% increase in C_max and a 425% increase in AUC for fluorouracil. The researchers concluded that green tea greatly impacted the PK of fluorouracil.[13]

A similar study examined the PK of irinotecan (10 mg/kg IV) given in combination with EGCG (20 mg/kg IV) in rats and found that EGCG caused elevated plasma levels and reduced hepatobiliary excretion of irinotecan and its metabolite SN-38. This is possibly because of EGCG's inhibitory effects on P-glycoprotein (P-gp).[14]

A 2019 study evaluated the effects of green tea extract on the PK of palbociclib in a rat animal model. The data showed a decrease in the oral bioavailability of palbociclib when it was coadministered with green tea extract, but there was no impact on the elimination of palbociclib. The altered PK was thought to be the result of interference in the absorption of palbociclib. The authors recommended against the coadministration of these compounds.[15]

Research on rat animal models investigated the impact of green tea extract on the oral bioavailability of erlotinib and lapatinib. A decrease in the oral bioavailability for erlotinib and lapatinib was observed after consumption of green tea extract (200 mg/kg). There was a decrease in AUC by 68% for erlotinib and 70% for lapatinib with short-term administration of green tea extract, and a decrease in AUC by 16% for erlotinib and 14% for lapatinib with long-term administration of green tea extract.[16]

An in vivo and in vitro study examined the impacts of intragastric coadministration of sunitinib with EGCG. Coadministration of these two solutions resulted in the formation of a precipitate in the stomachs of the mice, thus decreasing its bioavailability. It was also reported that a decrease in the AUC and C_max of plasma sunitinib with EGCG administration in rats resulted in reduced sunitinib absorption.[17]

A possible interaction was also found between EGCG and tamoxifen. A 2009 study assessed the bioavailability and PK of tamoxifen (2 mg/kg) and its metabolite, 4-hydroxytamoxifen, with coadministration of EGCG (0.5 mg/kg, 3 mg/kg, and 10 mg/kg) in Sprague-Dawley rats. The coadministration of EGCG at doses of 3 mg/kg and 10 mg/kg caused a 49% to 78% increase in the bioavailability of tamoxifen. In addition, EGCG significantly impacted the formation of 4-hydroxytamoxifen. It is believed that this reaction was caused by EGCG's inhibitory effect on P-gp and CYP3A.[18] However, a subsequent study analyzed the effect of a green tea extract (1 g twice daily, 300 mg EGCG) on endoxifen (active metabolite of tamoxifen) levels. The study did not demonstrate a PK interaction between the green tea supplement and endoxifen levels.[19]

The findings of the preclinical studies provide a justification and motivation for human studies to determine appropriate clinical recommendations.

Case study

In addition to the in vitro and in vivo EGCG and sunitinib study mentioned above, the same researchers published a case study that might demonstrate a possible adverse effect of green tea consumption with sunitinib treatment. A male patient with metastatic renal cell carcinoma who received sunitinib reported worsened symptoms of hyperemia and eye swelling near the site of a metastatic lesion when drinking green tea; the symptoms improved when he stopped taking green tea. The authors hypothesized that the lack of symptom control may result from EGCG's effects on sunitinib's anticancer abilities.[17]

References:

1. Mouly S, Lloret-Linares C, Sellier PO, et al.: Is the clinical relevance of drug-food and drug-herb interactions limited to grapefruit juice and Saint-John's Wort? Pharmacol Res 118: 82-92, 2017.
2. Singh BN: Effects of food on clinical pharmacokinetics. Clin Pharmacokinet 37 (3): 213-55, 1999.
3. Paine MF, Widmer WW, Hart HL, et al.: A furanocoumarin-free grapefruit juice establishes furanocoumarins as the mediators of the grapefruit juice-felodipine interaction. Am J Clin Nutr 83 (5): 1097-105, 2006.
4. Hung WL, Suh JH, Wang Y: Chemistry and health effects of furanocoumarins in grapefruit. J Food Drug Anal 25 (1): 71-83, 2017.
5. He SM, Yang AK, Li XT, et al.: Effects of herbal products on the metabolism and transport of anticancer agents. Expert Opin Drug Metab Toxicol 6 (10): 1195-213, 2010.
6. Reif S, Nicolson MC, Bisset D, et al.: Effect of grapefruit juice intake on etoposide bioavailability. Eur J Clin Pharmacol 58 (7): 491-4, 2002.
7. van Erp NP, Baker SD, Zandvliet AS, et al.: Marginal increase of sunitinib exposure by grapefruit juice. Cancer Chemother Pharmacol 67 (3): 695-703, 2011.
8. Yin OQ, Gallagher N, Li A, et al.: Effect of grapefruit juice on the pharmacokinetics of nilotinib in healthy participants. J Clin Pharmacol 50 (2): 188-94, 2010.
9. Sang S, Lambert JD, Ho C, et al.: Green tea polyphenols. In: Coates PM, Betz JM, Blackman MR, et al., eds.: Encyclopedia of Dietary Supplements. 2nd ed. Informa Healthcare, 2010, pp 402-10.
10. Du GJ, Zhang Z, Wen XD, et al.: Epigallocatechin Gallate (EGCG) is the most effective cancer chemopreventive polyphenol in green tea. Nutrients 4 (11): 1679-91, 2012.
11. Golden EB, Lam PY, Kardosh A, et al.: Green tea polyphenols block the anticancer effects of bortezomib and other boronic acid-based proteasome inhibitors. Blood 113 (23): 5927-37, 2009.
12. Bannerman B, Xu L, Jones M, et al.: Preclinical evaluation of the antitumor activity of bortezomib in combination with vitamin C or with epigallocatechin gallate, a component of green tea. Cancer Chemother Pharmacol 68 (5): 1145-54, 2011.
13. Qiao J, Gu C, Shang W, et al.: Effect of green tea on pharmacokinetics of 5-fluorouracil in rats and pharmacodynamics in human cell lines in vitro. Food Chem Toxicol 49 (6): 1410-5, 2011.
14. Lin LC, Wang MN, Tsai TH: Food-drug interaction of (-)-epigallocatechin-3-gallate on the pharmacokinetics of irinotecan and the metabolite SN-38. Chem Biol Interact 174 (3): 177-82, 2008.
15. Paul D, Surendran S, Chandrakala P, et al.: An assessment of the impact of green tea extract on palbociclib pharmacokinetics using a validated UHPLC-QTOF-MS method. Biomed Chromatogr 33 (4): e4469, 2019.
16. Maher HM, Alzoman NZ, Shehata SM, et al.: UPLC-ESI-MS/MS study of the effect of green tea extract on the oral bioavailability of erlotinib and lapatinib in rats: Potential risk of pharmacokinetic interaction. J Chromatogr B Analyt Technol Biomed Life Sci 1049-1050: 30-40, 2017.
17. Ge J, Tan BX, Chen Y, et al.: Interaction of green tea polyphenol epigallocatechin-3-gallate with sunitinib: potential risk of diminished sunitinib bioavailability. J Mol Med (Berl) 89 (6): 595-602, 2011.
18. Shin SC, Choi JS: Effects of epigallocatechin gallate on the oral bioavailability and pharmacokinetics of tamoxifen and its main metabolite, 4-hydroxytamoxifen, in rats. Anticancer Drugs 20 (7): 584-8, 2009.
19. Braal CL, Hussaarts KGAM, Seuren L, et al.: Influence of green tea consumption on endoxifen steady-state concentration in breast cancer patients treated with tamoxifen. Breast Cancer Res Treat 184 (1): 107-113, 2020.

Foods, Dietary Supplements, and Cancer Drug Interaction Tables

Table 1. Foods, Dietary Supplements, and Cancer Drug Interactions

Herbal /Dietary Supplement	Anticancer Therapy	Effect	Study Type
AUC = area under theconcentrationversus time curve; Cmax = peakserumconcentration; EGCG = epigallocatechin gallate; SJW = St. John's wort.
SJW	Irinotecan	Increased activity of CYP3A4 and decreased AUC of activemetaboliteSN38	Clinical trial [1]
SJW	Imatinib	Increased clearance and decreased AUC of imatinib	Clinical trial[2]
SJW	Methotrexate	Increased AUC and Cmax of methotrexate	Animal study [3]
SJW	Docetaxel	Increased clearance and decreased AUC of docetaxel	Clinical trial[4]
SJW	Ixabepilone	May decreaseplasmaconcentrations of ixabepilone	Label warning for ixabepilone[5]
Green tea	Sunitinib	Decreaseddrug absorptionandbioavailabilityof sunitinib	Animal study andcase report [6]
Green tea	Palbociclib	Decreasedoralbioavailability of palbociclib	Animal study[7]
Green tea extract	Erlotinib	Decreased AUC and oral bioavailability of erlotinib	Animal study[8]
Green tea extract	Lapatinib	Decreased AUC and oral bioavailability of lapatinib	Animal study[8]
EGCG	Tamoxifen	Increased bioavailability of tamoxifen	Animal study[9]
EGCG	Irinotecan	Increased plasma concentration of irinotecan and decreasedhepatobiliary excretionof drug and its metabolite SN-38	Animal study[10]
Green tea and EGCG	Fluorouracil	Increased AUC and Cmax of fluorouracil	Animal andin vitro study[11]
Grapefruit	Imatinib	May increase plasma levels of imatinib by inhibiting CYP3A4	Review[12]
Grapefruit	Etoposide	Decreased AUC and bioavailability of etoposide	Randomized,crossover,pilot study [13]
Grapefruit	Sunitinib	Increased bioavailability of sunitinib	Clinical trial[14]
Grapefruit	Nilotinib	Increased AUC and Cmax of nilotinib	Clinical trial[15]
Vitamin A	Imatinib	Increased bioavailability of imatinib	Animal study[8]
Vitamin E	Imatinib	Increased bioavailability of imatinib	Animal study[8]
Vitamin D3	Imatinib	Increased bioavailability of imatinib	Animal study[8]
Vitamin C	Imatinib	Decreased bioavailability of imatinib	Animal study[8]
Scutellaria baicalensis	Docetaxel	Increased AUC of drug and exposure to both drug and herb	Animal study[16]

Table 2. Foods, Dietary Supplements, and Cancer Drug Interactions

Anticancer Therapy	Herbal/Dietary Supplement	Effect	Study Type
AUC = area under the concentration versus time curve; Cmax = peak serum concentration; EGCG = epigallocatechin gallate; SJW = St. John's wort.
Docetaxel	Scutellaria baicalensis	Increased AUC of drug and exposure to both drug and herb	Animal study[16]
Docetaxel	SJW	Increased clearance and decrease AUC of docetaxel	Clinical trial[4]
Erlotinib	Green tea extract	Decreased AUC and oral bioavailability of erlotinib	Animal study[8]
Etoposide	Grapefruit	Decreased AUC and bioavailability of etoposide	Randomized, crossover, pilot study[13]
Fluorouracil	Green tea and EGCG	Increased AUC and Cmax of fluorouracil	Animal andin vitro study[11]
Imatinib	Grapefruit	May increase plasma levels of imatinib by inhibiting CYP3A4	Review[12]
Imatinib	Vitamin A	Increased bioavailability of imatinib	Animal study[8]
Imatinib	Vitamin E	Increased bioavailability of imatinib	Animal study[8]
Imatinib	Vitamin D3	Increased bioavailability of imatinib	Animal study[8]
Imatinib	Vitamin C	Decreased bioavailability of imatinib	Animal study[8]
Imatinib	SJW	Increased clearance and decreased AUC of imatinib	Clinical trial[2]
Irinotecan	SJW	Increased activity of CYP3A4 and decreased AUC of active metabolite SN38	Clinical trial[1]
Irinotecan	EGCG	Increased plasma concentration of irinotecan and decreased hepatobiliary excretion of drug and its metabolite SN-38	Animal study[10]
Ixabepilone	SJW	May decrease plasma concentrations of ixabepilone	Label warning for ixabepilone[5]
Lapatinib	Green tea extract	Decreased AUC and oral bioavailability of lapatinib	Animal study[8]
Methotrexate	SJW	Increased AUC and Cmax of methotrexate	Animal study[3]
Nilotinib	Grapefruit	Increased AUC and Cmax of nilotinib	Clinical trial[15]
Palbociclib	Green tea	Decreased oral bioavailability of palbociclib	Animal study[7]
Tamoxifen	EGCG	Increased bioavailability of tamoxifen	Animal study[9]
Sunitinib	Grapefruit	Increased bioavailability of sunitinib	Clinical trial[14]
Sunitinib	Green tea	Decreased drug absorption and bioavailability of sunitinib	Animal study and case report[6]

Table 3. Foods, Dietary Supplements, and Cancer Therapies Adverse Reaction

Herbal/Dietary Supplement	Cancer Therapy	Adverse Reaction	Study Type
EGCG = epigallocatechin gallate.
Vitamin C	Doxorubicin,cisplatin,vincristine, methotrexate, and imatinib	Dose-dependentdecrease inapoptosiswith allchemotherapeutic drugstested	Animal study[17]
Vitamin C	Bortezomib	Decreased bortezomib's anticancer activities	Animal study[18]
Dl-alpha-tocopherol (vitamin E)	Radiation therapy	Higher risk oftumor relapseand increased all-causemortality	Clinical trial[19,20]
Ginseng	Imatinib	Incident of hepatotoxicity	Case report[21]
EGCG or green tea extract	Bortezomib	Decreased anticancer effect by neutralizing effects of bortezomib	In vitro and animal study[22]
EGCG	Bortezomib	Decreased bortezomib's anticancer effect	Animal study[23]
Green tea	Sunitinib	Decreased anticancer effect, worsenedsymptoms	Preclinical researchand case report[6]

References:

1. Mathijssen RH, Verweij J, de Bruijn P, et al.: Effects of St. John's wort on irinotecan metabolism. J Natl Cancer Inst 94 (16): 1247-9, 2002.
2. Frye RF, Fitzgerald SM, Lagattuta TF, et al.: Effect of St John's wort on imatinib mesylate pharmacokinetics. Clin Pharmacol Ther 76 (4): 323-9, 2004.
3. Yang SY, Juang SH, Tsai SY, et al.: St. John's wort significantly increased the systemic exposure and toxicity of methotrexate in rats. Toxicol Appl Pharmacol 263 (1): 39-43, 2012.
4. Clairet AL, Boiteux-Jurain M, Curtit E, et al.: Interaction between phytotherapy and oral anticancer agents: prospective study and literature review. Med Oncol 36 (5): 45, 2019.
5. IXEMPRA - ixabepilone. Bristol-Myers Squibb Company, 2009. Available online. Last accessed May 26, 2022.
6. Ge J, Tan BX, Chen Y, et al.: Interaction of green tea polyphenol epigallocatechin-3-gallate with sunitinib: potential risk of diminished sunitinib bioavailability. J Mol Med (Berl) 89 (6): 595-602, 2011.
7. Paul D, Surendran S, Chandrakala P, et al.: An assessment of the impact of green tea extract on palbociclib pharmacokinetics using a validated UHPLC-QTOF-MS method. Biomed Chromatogr 33 (4): e4469, 2019.
8. Maher HM, Alzoman NZ, Shehata SM: Ultra-performance LC-MS/MS study of the pharmacokinetic interaction of imatinib with selected vitamin preparations in rats. Bioanalysis 10 (14): 1099-1113, 2018.
9. Shin SC, Choi JS: Effects of epigallocatechin gallate on the oral bioavailability and pharmacokinetics of tamoxifen and its main metabolite, 4-hydroxytamoxifen, in rats. Anticancer Drugs 20 (7): 584-8, 2009.
10. Lin LC, Wang MN, Tsai TH: Food-drug interaction of (-)-epigallocatechin-3-gallate on the pharmacokinetics of irinotecan and the metabolite SN-38. Chem Biol Interact 174 (3): 177-82, 2008.
11. Qiao J, Gu C, Shang W, et al.: Effect of green tea on pharmacokinetics of 5-fluorouracil in rats and pharmacodynamics in human cell lines in vitro. Food Chem Toxicol 49 (6): 1410-5, 2011.
12. He SM, Yang AK, Li XT, et al.: Effects of herbal products on the metabolism and transport of anticancer agents. Expert Opin Drug Metab Toxicol 6 (10): 1195-213, 2010.
13. Reif S, Nicolson MC, Bisset D, et al.: Effect of grapefruit juice intake on etoposide bioavailability. Eur J Clin Pharmacol 58 (7): 491-4, 2002.
14. van Erp NP, Baker SD, Zandvliet AS, et al.: Marginal increase of sunitinib exposure by grapefruit juice. Cancer Chemother Pharmacol 67 (3): 695-703, 2011.
15. Yin OQ, Gallagher N, Li A, et al.: Effect of grapefruit juice on the pharmacokinetics of nilotinib in healthy participants. J Clin Pharmacol 50 (2): 188-94, 2010.
16. Wang T, Long F, Jiang G, et al.: Pharmacokinetic properties of wogonin and its herb-drug interactions with docetaxel in rats with mammary tumors. Biomed Chromatogr : e4264, 2018.
17. Heaney ML, Gardner JR, Karasavvas N, et al.: Vitamin C antagonizes the cytotoxic effects of antineoplastic drugs. Cancer Res 68 (19): 8031-8, 2008.
18. Perrone G, Hideshima T, Ikeda H, et al.: Ascorbic acid inhibits antitumor activity of bortezomib in vivo. Leukemia 23 (9): 1679-86, 2009.
19. Bairati I, Meyer F, Gélinas M, et al.: Randomized trial of antioxidant vitamins to prevent acute adverse effects of radiation therapy in head and neck cancer patients. J Clin Oncol 23 (24): 5805-13, 2005.
20. Bairati I, Meyer F, Jobin E, et al.: Antioxidant vitamins supplementation and mortality: a randomized trial in head and neck cancer patients. Int J Cancer 119 (9): 2221-4, 2006.
21. Bilgi N, Bell K, Ananthakrishnan AN, et al.: Imatinib and Panax ginseng: a potential interaction resulting in liver toxicity. Ann Pharmacother 44 (5): 926-8, 2010.
22. Golden EB, Lam PY, Kardosh A, et al.: Green tea polyphenols block the anticancer effects of bortezomib and other boronic acid-based proteasome inhibitors. Blood 113 (23): 5927-37, 2009.
23. Bannerman B, Xu L, Jones M, et al.: Preclinical evaluation of the antitumor activity of bortezomib in combination with vitamin C or with epigallocatechin gallate, a component of green tea. Cancer Chemother Pharmacol 68 (5): 1145-54, 2011.

Summary of the Evidence for Cancer Therapy Interactions With Foods and Dietary Supplements

To assist readers in evaluating the results of human studies of integrative, alternative, and complementary therapies for cancer, the strength of the evidence (i.e., the levels of evidence) associated with each type of treatment is provided whenever possible. To qualify for a level of evidence analysis, a study must:

• Be published in a peer-reviewed scientific journal.
• Report on a therapeutic outcome or outcomes, such as tumor response, improvement in survival, or measured improvement in quality of life.
• Describe clinical findings in sufficient detail that a meaningful evaluation can be made.

Separate levels of evidence scores are assigned to qualifying human studies on the basis of statistical strength of the study design and scientific strength of the treatment outcomes (i.e., endpoints) measured. The resulting two scores are then combined to produce an overall score. For an explanation of the scores and additional information about levels of evidence analysis, see Levels of Evidence for Human Studies of Integrative, Alternative, and Complementary Therapies.

Latest Updates to This Summary (04 / 05 / 2024)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

General Information

Revised text to state that in the United States, dietary supplements are regulated by the U.S. Food and Drug Administration (FDA) as a separate category from foods, cosmetics, and drugs. Unlike drugs, dietary supplements do not require premarket evaluation and approval by the FDA unless specific disease prevention or treatment claims are made. Also added text to state that the quality and amount of ingredients in dietary supplements are also regulated by the FDA through Good Manufacturing Practices (GMPs). The FDA GMPs requires that every finished batch of dietary supplement meets each product specification for identity, purity, strength, composition, and limits on contamination that may adulterate dietary supplements.

This summary is written and maintained by the PDQ Integrative, Alternative, and Complementary Therapies Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® Cancer Information for Health Professionals pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about cancer therapy interactions with foods and dietary supplements in people with cancer.. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.

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This summary is reviewed regularly and updated as necessary by the PDQ Integrative, Alternative, and Complementary Therapies Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

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Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Integrative, Alternative, and Complementary Therapies Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

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PDQ® Integrative, Alternative, and Complementary Therapies Editorial Board. PDQ Cancer Therapy Interactions With Foods and Dietary Supplements. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/about-cancer/treatment/cam/hp/dietary-interactions-pdq. Accessed <MM/DD/YYYY>. [PMID: 33079503]

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Last Revised: 2024-04-05