This cancer information summary provides an overview of the use of foods, dietary supplements, and cancer therapy interactions.
This summary contains the following key information:
For adult cancer patients in the United States, the frequency of complementary and alternative medicine (CAM) use is approximately 36%. It is possible that the combination of cancer drugs taken by these patients and the CAM they use may interact, causing adverse outcomes. 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 components involved in the PK of the drug, such as how the drug is metabolized and transported. It is important that these interactions are reported and studied to allow health care professionals to help patients navigate CAM usage with standard cancer therapies, thus avoiding preventable adverse outcomes.
Cytochrome P450 Inhibitors/Inducers
One of the main group of enzymes involved in the metabolism of many cancer drugs is the cytochrome P450 (CYP450) 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 CYP450 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.[1,2,3]
Some common dietary antioxidants include the following:
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. 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.
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.
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.
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.
A study examined antioxidant dietary supplement use pre- and post-diagnosis 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. This evidence does not seem strong enough to determine for certain the safety of taking antioxidants during breast cancer treatment. However, the 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 has shown an association with a higher risk of tumor relapse and a decrease in cancer-free survival.[6,7]
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.
A 2012 study observed the effects of SJW on the pharmacokinetics (PK) of methotrexate in a rat animal model. After coadministration of SJW (300 mg /kg and 150 mg/kg) and methotrexate, it was found that animals that received 300 mg/kg of SJW had a significant increase in area under the concentration versus time curve (AUC) by 163% and peak serum concentration (Cmax) by 60% for methotrexate. For animals that received 150 mg/kg of SJW, there was a significant increase in AUC (55%) for methotrexate. 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.
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-glycoprotein, causing this reduction in SN-38. This interaction may cause a loss of irinotecan efficacy.
A similar outcome occurred in another study that examined treatment with imatinib (400 mg) and SJW (300 mg 3 times a day). 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.
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.
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.
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:
Research has been mixed on whether green tea is safe or effective for these uses as well as for coadministration with anticancer drugs. Current research shows that green tea and the polyphenol epigallocatechin gallate (EGCG), an antioxidant component of green tea, can impact the pharmacokinetics (PK) or pharmacodynamics (PD) of certain drugs, thus impacting the metabolism and effectiveness of these drugs.
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). 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. 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 peak serum concentration (Cmax) and a 425% increase in the area under the concentration versus time curve (AUC) for fluorouracil. It was concluded that green tea greatly impacted the PK of fluorouracil.
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.
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.
Research on rat animal models investigated the impact of green tea extract on the oral bioavailability of erlotinib and lapatinib. A decrease was observed in the oral bioavailability for erlotinib and lapatinib after consumption of green tea extract (200 mg/kg). There was a decrease in AUC by 67.60% for erlotinib and 70.20% for lapatinib with short-term administration, and a decrease in AUC by 16.03% for erlotinib and 13.53% for lapatinib with long-term administration.
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 these mice, thus decreasing its bioavailability. It was also reported that a decrease in the AUC and Cmax of plasma sunitinib with EGCG administration in rats resulted in reduced sunitinib absorption.
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 significant 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-glycoprotein and CYP3A.
The findings of the preclinical studies provide a justification and motivation for human studies to determine appropriate clinical recommendations.
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.
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 (PK) interactions are thought to be caused by specific components in these fruits, such as the flavonoid naringenin and furanocoumarins. These components have been observed impacting the metabolism of substrates of CYP3A4.[1,2] Grapefruit and its furanocoumarins components are used as supplements for the antioxidative, anti-inflammatory, and anticancer effects demonstrated in some in vivo and in vitro 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 CPY3A4, in turn triggering organ toxicity.
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, reducing from approximately 73.2% to 52.4% the bioavailabilty of 50 mg of oral etoposide after pretreatment with 100 mL of grapefruit juice. This resulted in a decrease in the area under the concentration versus time curve (AUC) by 26.2% for etoposide with grapefruit juice, compared with etoposide alone.
Other studies have found an increase in the bioavailability of sunitinib with grapefruit juice exposure, in addition to an increase in AUC by 29% and an increase in Cmax by 60% for nilotinib (400 mg orally) when combined with grapefruit juice (240 mL).
Ginseng root has commonly been used as a dietary supplement in traditional Asian medicine. There are several types of ginseng. While there is no conclusive evidence for the health benefits of ginseng, people currently use it for the following reasons:[1,2]
Most in vitro research on ginseng's pharmacokinetic (PK) interactions found little evidence of any effects, determining a low risk of CYP-dependent herb -drug reactions. Overall, the evidence is mixed and inconclusive.[3,4,5]
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.
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:
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. Some research has shown the inhibitory effect of wogonin on the activity of cytochrome P450, but more research is needed to determine interactions with specific drugs.
A 2018 study examined the pharmacokinetic profile and herb-drug interactions of oral wogonin and intravenous docetaxel in rats. The results found that in rat models receiving oral administration of wogonin in addition to docetaxel, there was an increase in the area under the concentration versus time curve initial Cmax and half-life for docetaxel which the investigators speculated was due to the inhibitory effect of wogonin on CYP3A and P-glycoprotein. More research is needed with human clinical trials, but these results suggest a possible interaction between wogonin and docetaxel.
|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 |
|SJW||Imatinib||Increased clearance and decreased AUC of imatinib||Clinical trial|
|SJW||Methotrexate||Increased AUC and Cmax of methotrexate||Animal study |
|SJW||Docetaxel||Increased clearance and decreased AUC of docetaxel||Clinical trial|
|SJW||Ixabepilone||May decreaseplasmaconcentrations of ixabepilone||Label warning for ixabepilone|
|Green tea||Sunitinib||Decreaseddrug absorptionandbioavailabilityof sunitinib||Animal study andcase report |
|Green tea||Palbociclib||Decreasedoralbioavailability of palbociclib||Animal study|
|Green tea extract||Erlotinib||Decreased AUC and oral bioavailability of erlotinib||Animal study|
|Green tea extract||Lapatinib||Decreased AUC and oral bioavailability of lapatinib||Animal study|
|EGCG||Tamoxifen||Increased bioavailability of tamoxifen||Animal study|
|EGCG||Irinotecan||Increased plasma concentration of irinotecan and decreasedhepatobiliary excretionof drug and its metabolite SN-38||Animal study|
|Green tea and EGCG||Fluorouracil||Increased AUC and Cmax of fluorouracil||Animal andin vitro study|
|Grapefruit||Imatinib||May increase plasma levels of imatinib by inhibiting CPY3A4||Review|
|Grapefruit||Etoposide||Decreased AUC and bioavailability of etoposide||Randomized,crossover,pilot study |
|Grapefruit||Sunitinib||Increased bioavailability of sunitinib||Clinical trial|
|Grapefruit||Nilotinib||Increased AUC and Cmax of nilotinib||Clinical trial|
|Vitamin A||Imatinib||Increased bioavailability of imatinib||Animal study|
|Vitamin E||Imatinib||Increased bioavailability of imatinib||Animal study|
|Vitamin D3||Imatinib||Increased bioavailability of imatinib||Animal study|
|Vitamin C||Imatinib||Decreased bioavailability of imatinib||Animal study|
|Scutellaria baicalensis||Docetaxel||Increased AUC of drug and exposure to both drug and herb||Animal study|
|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|
|Docetaxel||SJW||Increased clearance and decrease AUC of docetaxel||Clinical trial|
|Erlotinib||Green tea extract||Decreased AUC and oral bioavailability of erlotinib||Animal study|
|Etoposide||Grapefruit||Decreased AUC and bioavailability of etoposide||Randomized, crossover, pilot study|
|Fluorouracil||Green tea and EGCG||Increased AUC and Cmax of fluorouracil||Animal andin vitro study|
|Imatinib||Grapefruit||May increase plasma levels of imatinib by inhibiting CPY3A4||Review|
|Imatinib||Vitamin A||Increased bioavailability of imatinib||Animal study|
|Imatinib||Vitamin E||Increased bioavailability of imatinib||Animal study|
|Imatinib||Vitamin D3||Increased bioavailability of imatinib||Animal study|
|Imatinib||Vitamin C||Decreased bioavailability of imatinib||Animal study|
|Imatinib||SJW||Increased clearance and decreased AUC of imatinib||Clinical trial|
|Irinotecan||SJW||Increased activity of CYP3A4 and decreased AUC of active metabolite SN38||Clinical trial|
|Irinotecan||EGCG||Increased plasma concentration of irinotecan and decreased hepatobiliary excretion of drug and its metabolite SN-38||Animal study|
|Ixabepilone||SJW||May decrease plasma concentrations of ixabepilone||Label warning for ixabepilone|
|Lapatinib||Green tea extract||Decreased AUC and oral bioavailability of lapatinib||Animal study|
|Methotrexate||SJW||Increased AUC and Cmax of methotrexate||Animal study|
|Nilotinib||Grapefruit||Increased AUC and Cmax of nilotinib||Clinical trial|
|Palbociclib||Green tea||Decreased oral bioavailability of palbociclib||Animal study|
|Tamoxifen||EGCG||Increased bioavailability of tamoxifen||Animal study|
|Sunitinib||Grapefruit||Increased bioavailability of sunitinib||Clinical trial|
|Sunitinib||Green tea||Decreased drug absorption and bioavailability of sunitinib||Animal study and case report|
|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|
|Vitamin C||Bortezomib||Decreased bortezomib's anticancer activities||Animal study|
|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|
|EGCG or green tea extract||Bortezomib||Decreased anticancer effect by neutralizing effects of bortezomib||In vitro and animal study|
|EGCG||Bortezomib||Decreased bortezomib's anticancer effect||Animal study|
|Green tea||Sunitinib||Decreased anticancer effect, worsenedsymptoms||Preclinical researchand case report|
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This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the use of foods, dietary supplements, and cancer therapy interactions in people with cancer.. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.
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PDQ® Integrative, Alternative, and Complementary Therapies Editorial Board. PDQ Foods, Dietary Supplements, and Cancer Therapy Interactions. 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>.
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Last Revised: 2020-10-14
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