Cranberry

The ASCO Post’s Integrative Oncology series is intended to facilitate the availability of evidence- based information on integrative and complementary therapies commonly used by patients with cancer. In this installment, authors Gary Deng, MD, PhD, and Jyothirmai Gubili, MS, present the case study of a woman with a history of endometrial cancer and urinary tract infections (UTIs), and they discuss evidence concerning the role of cranberry in managing UTIs as well as its reported anticancer effects.

Gary Deng, MD, PhD

Jyothirmai Gubili, MS

Scientific Name: Vaccinium macrocarpon

Common Names: Mossberry, sassamanash, bounceberry

Case Study

M.C. is a 55-year-old woman with a history of stage I endometrial cancer, diagnosed and curatively treated 5 years ago. Since then, she has been having urinary tract infections from time to time. They have become more frequent lately. The patient is otherwise healthy and takes no medications on a regular basis.

Nitrofurantoin is offered but declined by the patient, due to fear of chronic use of antibiotics. The patient asks whether there is anything “natural” that would be helpful, in addition to local hygienic care. She asks specifically about cranberry extract, as she has heard from friends that it can be helpful.

Overview

Cranberry is a woody perennial vine native to the northeastern part of North America. Native Americans were the first to use cranberries as food who consumed the red, edible fruits in both fresh and dried forms. The berries were also used medicinally to treat fevers, wounds, swelling, blood disorders, and seasickness.

Today, cranberries continue to be popular for preventing urinary tract infections (UTIs)—the vast majority of which are caused by the bacterium Escherichia coli—and Helicobacter pylori infections, which can lead to gastric cancer. They are also used as antioxidants.

Current clinical evidence on the ability of cranberry to prevent UTIs is mixed. And data to determine its value in treating existing infections are lacking. But some studies have shown that cranberries are useful in preventing dental plaque formation and subsequent gum disease, as well as in suppressing H pylori infection. Its use should be based on a risk/benefit assessment against alternatives.

Because cranberries are hard and bitter, the majority are processed into sauces, juices, drinks, or jams, which are available online and in health food stores. They are also marketed as dietary supplements in the form of extracts, capsules, or tablets.

The Science

Pharmacologic investigations have revealed that cranberries are rich in flavonoids, anthocyanins, proanthocyanidins, catechin, and triterpenoids.¹ In preclinical studies, cranberry juice extracts and constituents demonstrated antimicrobial,² antifungal,³ anti-inflammatory,⁴ antioxidant,⁵ and anti-adherence⁶ effects.

Findings from some studies suggest the utility of cranberry extracts in preventing UTIs in women,⁷ children,⁸ and patients with prostate cancer undergoing radiation therapy.^9,10 But a trial involving older adults did not report such benefits,¹¹ and a subsequent analysis showed increased costs with no significant reduction in UTI rates in a geriatric nursing home environment.¹² Just-published data from randomized studies involving patients having pelvic surgery¹³ and patients with hip fractures undergoing urinary catheterization¹⁴ also indicate the ineffectiveness of cranberry in reducing postoperative bacteriuria.

However, cranberry was found useful in preventing plaque formation and the development of gum disease.¹⁵ Furthermore, regular consumption of cranberry juice suppressed H pylori infection,¹⁶ a major factor in peptic ulcer disease, which may lead to gastric cancer; it also improved cardiovascular disease risk factors in diabetic men.¹⁷

In addition, cranberry extracts and proanthocyanidins have been reported to exert antiproliferative effects against cancers of the esophagus, stomach, colon, bladder, and prostate, as well as glioblastoma and lymphoma, in vivo.¹⁸ Human trials have yet to be conducted.

Mechanistic studies have shown that proanthocyanidins inhibit the adherence of E coli fimbriae to uroepithelial cells,¹⁹ and A-type linkages in these compounds may enhance urinary bacterial anti-adhesion activities to prevent UTIs.²⁰ Cranberry also prevents H pylori–induced stomach ulcers by inhibiting bacterial adhesions in the stomach lining.²¹

The anticancer effects of cranberry are thought to be exerted via many different mechanisms, which include inhibition of cancer cell growth by decreasing cyclins, cyclin-dependent kinase expression,²² and matrix metalloprotease activity.²³ Dose-response inhibition of gastric cancer cells was shown to be in part due to decreased expression of proliferating cell nuclear antigen induction of apoptosis.²⁴ In neuroblastoma cells, proanthocyanidins induced apoptosis and reactive oxygen species generation, and increased retention of cyclophosphamide, with synergistic cytotoxic benefits.²⁵

Increased risk of uric acid stone formation with cranberry juice results from its acidifying effect and slowing of urate synthesis, thereby reducing urinary pH.²⁶

Adverse Reactions

Consumption of large amounts of cranberry juice (3 cups daily) has been associated with nausea, vomiting, and diarrhea.²⁷

Recurrent kidney stones were reported in a 47-year-old man with severe right renal colic and hematuria who took cranberry concentrate tablets twice daily over 6 months.²⁸

Several cases of increased international normalized ratio occurred due to suspected interactions between warfarin and cranberry juice.^29,30

Internal hemorrhage and subsequent death were reported in two patients with the concurrent use of warfarin and cranberry juice.^31,32

Herb-Drug Interactions

Warfarin: Cranberry juice may increase warfarin-induced anticoagulation, but data are conflicting.^33-35

Uridine 5′-diphospho-glucuronosyltransferase substrates: Cranberry modulates uridine 5′-diphospho-glucuronosyltransferase enzymes in vitro and can increase the risk of side effects of drugs metabolized by them.³⁶

Cytochrome P450 (CYP) substrates: Cranberry inhibits enteric CYP3A activities and may interfere with the absorption of substrate drugs.³⁷ It also inhibits CYP2C9 in vitro, but this activity was not observed in humans.³⁸

Cyclosporine: In a randomized clinical trial, 240 mL of cranberry juice had no clinically significant effect on the disposition of a 200-mg dose of cyclosporine.³⁹

Contraindications

Cranberry use should be limited in patients with a history of nephrolithiasis, because it can increase urinary oxalate excretion and can promote the formation of the most common type of kidney stones (ie, calcium oxalate).²⁶ ■

Disclosure: Dr. Deng and Ms. Gubili reported no potential conflicts of interest.

References

1. Raz R, Chazan B, Dan M: Cranberry juice and urinary tract infection. Clin Infect Dis 38:1413-1419, 2004.

2. Dinh J, Angeloni JT, Pederson DB, et al: Cranberry extract standardized for proanthocyanidins promotes the immune response of Caenorhabditis elegans to Vibrio cholerae through the p38 MAPK pathway and HSF-1. PLoS One 9:e103290, 2014.

3. Rane HS, Bernardo SM, Howell AB, et al: Cranberry-derived proanthocyanidins prevent formation of Candida albicans biofilms in artificial urine through biofilm- and adherence-specific mechanisms. J Antimicrob Chemother 69:428-436, 2014.

4. Tipton DA, Babu JP, Dabbous M: Effects of cranberry components on human aggressive periodontitis gingival fibroblasts. J Periodontal Res 48:433-442, 2013.

5. Denis MC, Desjardins Y, Furtos A, et al: Prevention of oxidative stress, inflammation and mitochondrial dysfunction in the intestine by different cranberry phenolic fractions. Clin Sci (Lond) 128:197-212, 2015.

6. Girardot M, Guerineau A, Boudesocque L, et al: Promising results of cranberry in the prevention of oral Candida biofilms. Pathog Dis 70:432-439, 2014.

7. Kontiokari T, Sundqvist K, Nuutinen M, et al: Randomised trial of cranberry-lingonberry juice and Lactobacillus GG drink for the prevention of urinary tract infections in women. BMJ 322:1571, 2001.

8. Ferrara P, Romaniello L, Vitelli O, et al: Cranberry juice for the prevention of recurrent urinary tract infections: A randomized controlled trial in children. Scand J Urol Nephrol 43:369-372, 2009.

9. Hamilton K, Bennett NC, Purdie G, et al: Standardized cranberry capsules for radiation cystitis in prostate cancer patients in New Zealand: A randomized double blinded, placebo controlled pilot study. Support Care Cancer 23:95-102, 2015.

10. Bonetta A, Di Pierro F: Enteric-coated, highly standardized cranberry extract reduces risk of UTIs and urinary symptoms during radiotherapy for prostate carcinoma. Cancer Manag Res 4:281-286, 2012.