Botanical Medicines and Phytochemicals in Colorectal Cancer Prevention

Abstract

Botanical medicines may prevent or hamper colon carcinogenesis through a variety of mechanisms, such as induction of apoptosis or cell cycle regulation. As evidenced by primary and secondary prevention studies using aspirin, inflammation and COX-2 expression are important drivers of colon carcinogenesis, promoting both the initiation and progression of colon cancer. Some botanical medicines may exert a protective effect by quelling such inflammation. This article reviews pertinent clinical or preclinical evidence for the preventive effects of garlic, curcumin, berberine, Boswellia, ginseng, ginger, resveratrol, and rosmarinic acid, in reference to colorectal cancer. While the data for medicinal plants and their constituents remain largely preclinical, there are several areas of interest that warrant additional study.

Introduction

In a previous article, the role of nutrition in the prevention of colorectal cancer was reviewed. As discussed in that article, diet may play a preventive role through several mechanisms. These include modulation of the microbiome, provision of specific nutrients involved in methylation, and regulation of inflammation, among others.

As with dietary factors, medicinal plants and their variety of bioactive constituents may prevent or hamper colon carcinogenesis through a variety of mechanisms. Some plant constituents may induce apoptosis or serve as cell cycle regulators. While the data for plant medicines remain largely preclinical, there are several areas of interest that are promising and worthy of additional study. Inflammation is an important driver of colon carcinogenesis, promoting both initiation and progression of colon cancer.¹ Some botanical medicines may exert their protective effects by quelling such inflammation.

In this article, we will review the clinical and preclinical evidence for several botanical medicines or phytochemicals in the prevention of colon cancer, including garlic, curcumin, berberine, Boswellia, and ginseng. We will also explore the role of cyclooxygenase (COX) enzyme inhibition in colorectal cancer prevention, and the potential effects of botanical medicines or phytochemicals on this important pathway.

Inflammation and COX Inhibition: A Potential Role for Botanical Medicines or Phytochemicals

As mentioned earlier, inflammation is an important driver of colon cancer development, promoting both colon tumor initiation and progression. Anti-inflammatory medications, such as aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs), have been shown to have a preventive effect on colorectal cancer, for both primary and secondary prevention. Examining the data on aspirin provides important insights about colorectal cancer prevention, and about the role of COX inhibition in colon carcinogenesis.

Beginning with primary prevention, a case–control analysis utilizing data taken from national health registries in Denmark demonstrates the preventive effect of aspirin and NSAIDs. The analysis included 10,280 people with a first-time diagnosis of colorectal cancer, and 102,800 controls with no cancer history selected through risk set sampling, between 1994 and 2011. Continuous long-term use of low-dose aspirin (doses ranging from 75 to 150 mg) for five years or more was associated with 27% reduction in the risk of colorectal cancer (odds ratio [OR] 0.73, confidence interval [CI] 0.54–0.99). In addition, consistent long-term use of NSAID medications (people receiving two or more prescriptions per year) was associated with a 35% reduction in the risk of colorectal cancer (OR 0.57, CI 0.44–0.74).²

Longer term studies also confirm this effect for primary prevention. In an analysis of pooled data from five clinical trials (four of which were randomized and controlled) of aspirin utilized for prevention of vascular events, the effects of aspirin (doses ranging from 75 to 300 mg daily) on colorectal cancer risk over a 20-year period was assessed. This analysis included data from the Thrombosis Prevention Trial, the British Doctors Aspirin Trial, the Swedish Aspirin Low Dose Trial, UK-TIA Aspirin Trial, and the Dutch TIA Aspirin Trial.

In the four trials that assessed aspirin, compared with control, 391 of 14,033 participants (2.8%) were diagnosed with colorectal cancer during a median follow-up period of 18.3 years. Aspirin therapy reduced the 20-year risk of colon cancer (hazard ratio [HR] 0.76, P = 0.02), but did not reduce risk of rectal cancer (HR 0.90, P = 0.35). The benefit of aspirin increased with increasing duration of use. Allocation to aspirin therapy for five years or more was associated with 70% reduction in the risk of proximal colon cancer (HR 0.35, P < 0.0001) as well as a reduced risk of rectal cancer (HR 0.58, P = 0.02). There was no increase in benefit with higher doses of aspirin (>75 mg daily), compared with low dose.³

Who benefits the most from aspirin in regard to primary prevention? Guo et al.'s 2021 pooled analysis of two large U.S. cohort studies (the Nurses' Health Study and the Health Professionals Follow-Up Study) included 94,540 participants age 70 or older who were followed from 1986 to 2014. Over 996,463 person-years of follow-up, 1431 cases of colorectal cancer were identified. After adjusting for other risk factors, regular aspirin users had a significantly lower risk of colorectal cancer, compared with nonusers (HR 0.80), but the benefit was limited to people who started aspirin before age 70 (HR 0.80). There was no association of lower risk of colorectal cancer for people who started aspirin at or after age 70 (HR 0.92). In addition, the beneficial association of aspirin was limited to those who took aspirin for five years or more (HR 0.76).⁴

Regarding secondary prevention, aspirin also demonstrates a considerable benefit. In a population-based retrospective cohort study utilizing data taken from national health registries in Norway, researchers sought to determine whether use of aspirin in people with a history of colorectal cancer impacted either colorectal cancer-specific survival, or overall survival (OS). The analysis included 23,162 subjects ages ≥18 years who were diagnosed with any stage colorectal cancer between 2004 and 2011. The mean age of participants was 71.5 years. The vast majority of subjects (89%) had undergone surgical resection of their colorectal tumors.

During the follow-up period, there were 2071 deaths from any cause in aspirin users, and 7218 deaths from any cause in nonaspirin users. Among aspirin users, 19% of deaths were related to colorectal cancer, while among nonaspirin users, 31.5% of deaths were attributed to colorectal cancer. Aspirin use was associated with a 15% reduction in the risk of colorectal cancer-specific death (HR 0.85, CI 0.79–0.92, P < 0.001). The protective effect was strongest among people who had taken aspirin both before and after diagnosis of colorectal cancer, with these individuals experiencing a 14% improvement in OS and a 23% improvement in colorectal cancer-specific survival (P < 0.001 for both). The authors also performed a time-dependent coefficient model, demonstrating that aspirin use was most beneficial during the first two to three years postdiagnosis.⁵

Additional NSAIDs have also been shown to have preventive benefits. In people with familial adenomatous polyposis (FAP), use of various NSAIDs results in a reduction in polyp size, polyp burden, or mean polyp number. This includes rofecoxib, celecoxib, and sulindac.⁶

What lessons can be learned from these positive studies on aspirin (and other NSAIDs) for the prevention of colorectal cancer? These medications work through COX enzyme inhibition. COX enzymes (including COX-1 and COX-2) are responsible for the synthesis of prostaglandins, important mediators of inflammation, from precursor arachidonic acids. This includes prostaglandin E2 (PGE2), the most abundant prostaglandin of the colon.⁷

The COX-2 isoform has been demonstrated to be overexpressed in a variety of premalignant and malignant lesions, both epithelial and nonepithelial.⁸ This includes colon cancer, in which COX-2 expression promotes progression, is significantly associated with disease stage, and is demonstrated to be an important prognostic factor. In fact, COX-2 expression is a key mediator in colon cancer development.⁹ COX-2 is induced by various proinflammatory cytokines, oncogenes, tumor promoters, and growth factors.⁸

Prostaglandins, once produced through the COX system, help promote inflammation, contribute to tumor angiogenesis, and play a strong role in regulating the tumor microenvironment. Prostaglandin-driven inflammation also leads to a positive feedback loop, further increasing levels of proinflammatory cytokines.¹⁰ PGE2 has been found to promote angiogenesis, and to increase growth, invasiveness, migration, and resistance to apoptosis in colon cancer cell lines.^7,11 Increased prostaglandin production is also thought to contribute to immune suppression seen in people with cancer.⁸

For these reasons, COX inhibition appears to be an attractive option for the chemoprevention of colon cancer. In addition, because of the (largely gastrointestinal or vascular) side effects associated with long-term aspirin or NSAID use, finding alternatives to these medications may be important. Several herbs or phytochemicals appear to exert anti-inflammatory effects through COX inhibition (see Table 1) in preclinical models of colon carcinogenesis.

Table 1.

Preclinical Evidence for Cyclooxygenase Inhibition in Colon Carcinogenesis

Plant source(s)	Part or extract utilized in study	Model	Author
Allium sativum	Aqueous suspension of fresh garlic	Rat colon carcinogenesis	Sengupta et al.¹⁹
Curcuma longa	Curcumin	Human colon cancer cells	Goel et al.²⁹
Genus Berberis and other genera	Berberine	Human colon cancer cells	Fukuda et al.³⁶; Tai et al.³⁷; Liu et al.³⁸
Boswellia carteri	Resin	Human colon cancer cells	Alf (2013)⁴⁶
Panax ginseng C.A. Meyer	Root	Mouse colon cancer	Shin et al.⁵³
Zingiber officinale	Root	People at normal or increased risk of colon cancer	Zick et al.⁵⁵; Jiang et al.⁵⁷; Zick et al.⁵⁸
Camellia sinensis	EGCG	Human colon cancer cells; human colon mucosa cells	Shimizu et al.⁶²; Hong et al.⁶³
Vitis vinifera, Reynoutria japonica (also called Fallopia japonica or Polygonum cuspidatum), and others	Resveratrol	Human colon cancer cells; human colon epithelial cells	Gong et al.⁶⁸; Zykova et al.⁶⁹
Rosmarinus officinalis	Rosmarinic acid	Human colon cancer cells; mouse colitis	Scheckel et al.⁷²; Jin et al.⁷¹; Jaksevicius et al.⁷³

EGCG, epigallocatechin gallate.

Garlic

Humble yet potent, garlic (Allium sativum) has been used as both food and medicine in cultures around the world for millennia, and is rich in antioxidants and organosulfur compounds, containing roughly 1% (by dry weight) allyl sulfur. Preclinical data on garlic or its allyl sulfur compounds point to a variety of preventive effects in colon carcinogenesis. These include:

Induction of apoptosis in colon cancer cell lines by allicin¹²

Inhibition of angiogenesis and prevention of colorectal cancer cell migration and invasion by aged garlic extract (AGE)¹³

Reduction of carcinogen-induced colon tumor volume¹⁴

Alteration of gene expression for epidermal growth factor receptor and integrin-alpha 6, with promotion of cell cycle arrest, by aqueous garlic extract.¹⁵

Beyond the preclinical data, human case control and cohort studies demonstrate a protective association between dietary raw or cooked garlic intake and the incidence of colorectal cancer.¹⁶ In addition, AGE has been shown to have a preventive benefit in people with a history of colorectal adenomas (benign polypoid lesions, which are the precursors to colorectal adenocarcinoma).

In a small double-blind randomized trial, 51 people with a history of colorectal adenomas were randomized to either a lower dose (control group) or higher dose AGE supplement for 12 months. The low-dose group took 0.16 mL AGE daily, while the high dose group took 2.4 mL AGE daily. The number and size of adenomas at baseline was then compared with that after 6 and 12 months of AGE supplementation. Thirty-seven participants were included in the final analysis.

At 12 months, 47.4% of people in the high-dose group had ≥1 adenoma, while 66.7% of people in the low-dose group had ≥1 adenoma, yielding a relative risk (RR) of 0.71. Overall, with high-dose AGE, there was a 29% reduction in the risk of developing at least one new colorectal adenoma.¹⁷ Additional analysis of this same group by these authors found that adenomas increased linearly in the low-dose AGE group after 12 months, but that the number and size of colon adenomas was significantly decreased with high-dose AGE (P = 0.04).¹⁸

Garlic also displays some activity related to COX inhibition. In a rat model of colon carcinogenesis, an aqueous suspension of fresh garlic not only induced apoptosis and significantly inhibited cellular proliferation (P < 0.01 and P < 0.01), but it also suppressed COX-2 expression, leading to a reduction in the appearance of aberrant crypt foci by 45%.¹⁹

Curcumin

Because of its anti-inflammatory effects, curcumin, a bioactive compound from the medicinal plant Curcuma longa, has been proposed to have a number of benefits related to colorectal cancer. These include beneficial alterations to deoxyribonucleic acid methylation, regulation of noncoding ribonucleic acid, and histone modification. Curcumin may also affect cell signaling through regulation of nuclear factor erythroid-2-related factor 2 (Nrf2) or nuclear factor-kappa B (NF-κB).²⁰

One concern with curcumin supplements is their varying bioavailability, with clinical trials in some situations demonstrating low or undetectable serum curcumin levels with oral supplementation. It may be that rapid metabolism impacts serum curcumin levels. Once absorbed, curcumin appears to undergo fairly rapid hepatic conjugation to glucuronide or sulfate metabolites.²¹

Poor absorption itself may also be a factor. In fact, animal studies have demonstrated >90% of curcumin is excreted in the feces after oral supplementation.²² Perhaps, in the case of colon cancer, this is actually therapeutic, since orally supplemented curcumin that is not systemically absorbed may, therefore, exert effects locally and topically in the gastrointestinal tract, or even accumulate in gastrointestinal tissues with repeated administration. It is also possible that nonabsorbed curcumin benefits the colon by modulating the gut microbiome.²³

Despite these concerns about bioavailability, supplementation has been found to result in varying detectable plasma levels of either curcumin or its metabolites in people both with and without colon cancer. In a pilot study of 26 subjects who were scheduled for either endoscopic biopsy or colorectal resection, curcumin was supplemented at a dose of 2.35 g curcuminoids daily for 14 days before scheduled procedure. The supplement utilized in this trial was a curcumin C3 complex consisting of 80% curcumin and 20% desmethoxycurcumin/bisdesmethoxycurcumin. Twenty-four participants completed the trial. Curcuminoids were detectable in the plasma of 37.5% of subjects, in the urine of 100% of participants, and in the colonic mucosa of 100% of biopsied subjects. Curcumin glucuronide, the major conjugate of curcumin, was detectable in 82.9% of biopsied samples. In addition, high concentrations of topical curcumin were persistent in the colonic mucosa for up to 40 hours after oral supplementation. Levels of curcumin found in the bowel mucosa were determined to be pharmacologically active at this dose level.²⁴

Among people with metastatic colorectal cancer receiving fluorouracil/oxaliplatin (FOLFOX) chemotherapy, similar doses of curcumin also result in detectable plasma levels of curcumin metabolites. Twenty-eight participants were randomized to either FOLFOX alone, or FOLFOX plus 2 g daily of the same curcumin C3 complex mentioned earlier. Curcumin glucuronide was detectable in the plasma at concentrations exceeding 1.00 pmol/mL among 83.3% of people who received the supplement.²⁵

While these studies demonstrate the achievability of therapeutic levels of curcumin in the body with oral supplementation, what about data specific to colon cancer prevention? Animal studies of inflammatory or genetic models of colon cancer demonstrate preventive effects with curcumin,²⁶ but human data remain limited.

In a small 12-month trial (n = 44) in people with FAP, there was no significant difference in polyp size, polyp burden, or mean number of polyps between a placebo group and a group that took 3000 mg pure curcumin daily.²⁷ This was in contrast to a very small uncontrolled study (n = 5) of people with FAP who had undergone either partial or complete colectomy, who were supplemented with 480 mg curcumin (form of curcumin not otherwise specified) along with a small dose of the bioflavonoid quercetin (20 mg) three times daily for periods ranging from 3 to 9 months. People in this trial experienced a mean decrease in rectal and ileal polyp number of 60% (P = 0.043) as well as a mean decrease in polyp size of 51% (0.039).²⁸ Trials for prevention in people with more average risk of colorectal cancer are not yet available.

Turning specifically to effects on COX inhibition, curcumin may exert some of its anti-inflammatory effects through this pathway. Treatment of human colon cancer cells with curcumin inhibits cell growth in both a dose- and time-dependent manner, and curcumin is a marked selective inhibitor of COX-2 expression in these cells.²⁹ Curcumin has also been shown to potentiate the effects of celecoxib, with a combination of these two substances shown to decrease both COX-2 expression as well as PGE2 levels in human colon cancer cell lines, when applied in amounts thought to be clinically achievable or relevant.³⁰

While clinical trials examining a direct COX-inhibiting effect of curcumin are not available, it is of some interest that curcumin supplements perform well in trials of people with osteoarthritis (OA), comparing favorably with NSAID medications for pain relief and functional outcomes, while causing fewer gastrointestinal side effects.³¹

Berberine

Berberine is an alkaloid plant compound found in several botanicals, such as goldenseal, European barberry, Oregon grape, Chinese goldthread, and others. Berberine-containing plants have been part of Traditional Chinese Medicine (TCM) herbalism for thousands of years, and have been demonstrated to have a number of antineoplastic properties in vitro. Berberine activates AMP-activated protein kinase in human colon cancer cells, reduces colon cancer cell viability, and increases apoptosis through activation of caspase-3, and has also been found to regulate more than 30 colon adenocarcinoma genes related to cellular differentiation, the cell cycle, and epithelial–mesenchymal transition.^32
–34

In a double-blind randomized placebo-controlled trial from 2020, 1108 participants with a history of colorectal adenoma resected in the preceding six months were randomized to either placebo (n = 555) or berberine at a dose of 300 mg twice daily (n = 553). Subjects then had a colonoscopy after one year, and again at two years if no adenomas were detected. Compliance was assessed by study staff, who counted empty pill packaging returned by subjects. Follow-up data were available for 429 subjects from the berberine group and 462 from the placebo group.

Occurrence of adenomas at follow-up colonoscopy was significantly lower in people who received berberine, compared with those who received placebo, 36% compared with 47% (RR 0.77; P = 0.001). There were no cases of colorectal cancer detected during follow-up. There were also no serious adverse events. Constipation, while rare, was the most frequently experienced side effect with berberine, occurring in 6 of 446 people in the berberine group (1%), compared with 1 of 478 people in the placebo group (<0.5%).³⁵

Berberine may also exert some of its effects through modulation of COX activity, an effect demonstrated in preclinical models. This alkaloid compound effectively inhibits COX expression in human colon cancer cell lines in both a dose- and time-dependent manner.³⁶ This reduction also results in a decrease in PGE2 ceoncentrations.³⁷ This reduction in COX expression also appears to result in favorable downstream alterations in human colon cancer cells. This includes a reduction in JAK2/STAT3 (Janus Kinase two gene/signal transducer and activators of transcription) signaling, leading to decreased tumor cell invasiveness and metastasis.³⁸ This pathway plays a crucial role in colon cancer cell apoptosis through the mitochondrial apoptotic pathway, and activation of STAT3 has been shown to be an important step in malignant cellular transformation.^39,40

Boswellia Extract (Boswellia serrata)

Similar to curcumin, Boswellia extract is well known for its anti-inflammatory properties, many of which are mediated by triterpenic acids (including acetyl-11-keto-β-boswellic acid, or AKBA) found in the plant's resin.⁴¹ Native to dry and mountainous regions of the Middle East, North Africa, and India, the plant has been used ritually, medicinally, topically, and cosmetically for thousands of years.

As a result of its anti-inflammatory effects, Boswellia extract and AKBA protect the intestinal epithelial barrier and reduce the production of reactive oxygen species (ROS) in response to inflammatory stimuli.⁴² Boswellia extract has been shown to reduce colon tumor formation in mice by decreasing the expression of inflammation-associated proteins, reducing cellular proliferation through inhibition of protein kinase B (Akt) phosphorylation, and downregulating cyclin D1.⁴³ AKBA also prevents formation of polyps in mice (in one case, even more effectively than aspirin).^44,45

Boswellia species may also have activity related to COX expression. Constituents from the resin of Boswellia inhibit both COX-1 and COX-2 isoforms in human cancer cell lines.⁴⁶ Clinical trials specific to COX inhibition by Boswellia extracts have not been performed. Despite this, it is perhaps noteworthy that even short-term supplementation of Boswellia results in a significant reduction in multiple markers of inflammation, including PGE2 (in this case, in people who were survivors of ischemic stroke).⁴⁷ In addition, data indicate a clinically meaningful reduction of inflammation in other conditions. This includes demonstrated efficacy in people with Crohn's disease and ulcerative colitis, chronic inflammatory conditions that are associated with a greater risk of colorectal cancer development.⁴⁸

Ginseng

Panax ginseng, also called Korean ginseng or Chinese ginseng, has a long history of medicinal use in TCM dating back thousands of years.⁴⁹ While P. ginseng (and other related Panax species) contain a number of bioactive constituents, ginsenosides (triterpene saponins) are thought to be the major medicinal compounds present in the plant. Ginsenosides are reported to have various antitumor effects, including inhibition of angiogenesis as well as tumor invasion and metastasis.⁵⁰ Ginseng also appears to induce apoptosis through both the intrinsic and extrinsic pathways, inhibit NF-κB, and inhibit matrix metalloproteinase.⁵¹

In a rat model of colon carcinogenesis, P. ginseng powder supplemented orally has been found to have a number of effects. When supplemented early in the process of carcinogenesis (during initiation), ginseng produces only a modest inhibition of the formation of aberrant crypt foci. When ginseng is supplemented during the postinitiation phase, however (after aberrant crypt foci appear), ginseng supplementation results in a significant inhibition of progression of crypt-containing foci.⁵²

While clinical trials examining the question of a preventive effect of ginseng against colorectal cancer in people are not available, clinical data do indicate that P. ginseng extract at a dose of 3 g daily dosed for three months in the adjuvant setting in people with stage III colon cancer exerts a number of immunologic effects. This includes enhanced recovery of interleukin-2 (IL-2), as well as normalization of IL-8 and IL-10.⁵⁰

Specific to COX inhibition, Korean red ginseng (P. ginseng C.A. Meyer), or KRG, has been shown to impact COX activity in a mouse model of colon cancer and colitis. Mice were fed a standard diet plus 1% standardized KRG powder, or standard diet alone, throughout the experiment. In the colitis model, KRG inhibited COX-2 expression and suppressed NF-κB and STAT3. In the colon cancer model, mice fed with KRG had a lower incidence and volume of colonic tumors, and KRG normalized COX expression in response to carcinogen exposure.⁵³

Ginger

Ginger root, Zingiber officinale, has been studied in clinical trials for its pain-relieving effects in a variety of situations. This includes dysmenorrhea, muscular pain, OA, chronic low back pain, and migraine headache. Inhibition of prostaglandin synthesis through the COX and lipoxygenase pathways is thought to be principally responsible for ginger's anti-inflammatory effects. This COX inhibiting effect appears to extend to the colonic mucosa; ginger has been shown to reduce the size and number of adenomas in rats through downregulation of COX.⁵⁴

In a Phase II study in people at normal risk of colon cancer, the concept of ginger's COX inhibiting properties was further explored. Thirty subjects were randomized to either a placebo, or 2 g daily ginger root extract for 28 days, and sigmoidoscopy was performed at baseline and day 28 to obtain colon biopsy samples. Ginger supplementation was safe and tolerable, with no difference between groups for total adverse events (P = 0.55). Comparing people who took ginger with those who took placebo, there was a significant decrease in PGE2 and 5-hydroxyeicosatetraenoic acid (5-HETE) (P = 0.05 and P = 0.04). Levels of these eicosanoids would presumably be reduced by an inhibition of synthesis from arachidonic acid.⁵⁵

A similar study was conducted in people at either normal or increased risk of colon cancer. Thirty people at normal risk of colon cancer and 20 people at increased risk were randomized to either a placebo or 2 g ginger root extract daily for 28 days. Again, sigmoidoscopy was performed at baseline and at the completion of the trial to obtain colon biopsy samples.

While COX-1 expression was unchanged in the colonic mucosa of people at normal risk of colorectal cancer, people at increased risk who supplemented with ginger had significantly reduced colonic COX-1 levels, compared with placebo group subjects (P = 0.03). Ginger supplementation did not alter 15-hydroxyprostaglandin dehydrogenase (15-PGDH, a tumor suppressor and inducer of differentiation, and key enzyme participating in the biological inactivation of prostaglandins⁵⁶) expression in the colonic mucosa of people at either normal or increased risk of colon cancer.⁵⁷

Finally, the same group performed a similar study specifically in people at increased risk of colon cancer. Twenty people were randomized to either placebo or 2 g ginger root extract daily, again for 28 days. Levels of PGE2, leukotriene B4 (LTB4), 13-hydroxy-octadecadienoic acids, and 5-HETE, 12-, and 15-hydroxyeicosatetraenoic acid in the colonic mucosa of these subjects was then determined, with sigmoidoscopy performed at baseline and at the completion of the trial to obtain biopsies. In this trial, ginger had no significant impact on eicosanoid levels, but did result in a significant decrease in arachidonic acid, and a significant increase in LTB4 (P = 0.05 and P = 0.04).⁵⁸ LTB4 mainly acts as an activator of inflammatory cells as well as a chemoattractant, with LTB4 having been found to be overexpressed in mouse models of intestinal cancer.⁵⁹

Green Tea/Epigallocatechin Gallate

Polyphenol-rich green tea extracts (GTEs) have been shown in preclinical models to work as chemopreventives for colorectal cancer. In addition, epidemiologic evidence indicates that higher levels of green tea consumption as part of the diet, ≥10 cups daily, are associated with a reduced risk of colorectal cancer.⁶⁰ Studies from Korea and Japan indicate that GTE prevents colon polyp formation in people with a history of colorectal adenomas.

In the Korean trial, Shin et al. randomized 176 people who had undergone resection of colorectal adenomas to either a control group, or a green tea group (taking 900 mg GTE daily) for 12 months. Follow-up colonoscopy was performed at 12 months in 143 subjects, 71 controls and 72 who took GTE. The incidence of metachronous adenoma at 12 months was 42.3% in the control group and 23.6% in the GTE group (RR 0.56, 95% CI: 0.34–0.92). Relapsed adenomas were also reduced in the GTE group, compared with controls (0.7 ± 1.1 vs. 0.3 ± 0.6, P = 0.01). Dietary intake, serum lipids, body mass index, C-reactive protein, and fasting blood sugar were not significantly different between groups (P > 0.05 for all).⁶¹

In the Japanese trial, Shimizu et al. recruited 136 people whose polyps were removed endoscopically, with polyp-free status confirmed one year later at repeat colonoscopy. At that point, subjects were then randomized into two groups, while being asked to maintain their baseline level of green tea drinking. Seventy-one people supplemented with 1500 mg GTE daily for 12 months, while 65 people were randomized as controls without supplementation. After 12 months, follow-up colonoscopy was performed on 60 people in the GTE group and 65 in the control group. At completion of the trial, 31% of people in the control group experienced metachronous adenoma, while 15% of people in the GTE group did (P < 0.05). The size of recurrent adenomas was also decreased in people who took GTE, compared with controls (P < 0.001).⁶⁰

While these studies did not specifically assess COX expression, other preclinical studies indicate that epigallocatechin gallate reduces COX-2 expression as well as PGE2 production in human colon cancer cell lines, even at low concentrations.⁶² In addition, green tea polyphenols inhibit arachidonic acid metabolism through COX pathways in normal human colon mucosa cells.⁶³

Resveratrol

Resveratrol is a plant polyphenol found in fruits (including grapes, apples, and berries) and red wine. The antioxidant effects of resveratrol have been thought to play a role in the “French Paradox,” with consumption of red wine in moderation among the French assumed to be partially responsible for low rates of cardiovascular disease, despite high rates of smoking and saturated fat consumption.⁶⁴ Scientific study went on to demonstrate that resveratrol supplementation reduces oxidative stress and enhances expression of antioxidative genes, while also improving vascular function.^65
–67

Resveratrol is also thought to exert anti-inflammatory effects through COX-2 inhibition. Application of resveratrol in human colon cancer cells as well as in normal colon epithelial cells results in a reduction of COX-2 expression.⁶⁸ One study even indicated that resveratrol bound directly to COX-2 in human colon cancer cell lines, suppressing anchorage-independent growth of these cells, and reducing PGE2 production. In this study, colon cancer cells that lacked COX-2 expression did not respond to treatment with resveratrol, indicating that at least some degree of resveratrol's anticancer effects may be COX-2 dependent.⁶⁹

It is also important to note that oral dosing of resveratrol, even for shorter durations, results in meaningful tissue concentrations in the human colon. In 20 people with colorectal cancer awaiting surgical resection, dosing resveratrol at 500 or 1000 mg orally daily (a dose not achievable with wine intake) for eight days resulted in detectable concentrations of resveratrol and its metabolites in the colon. Higher levels of resveratrol were found in the right side of the colon versus the left. While this study did not specifically assess for COX-2 expression, resveratrol did reduce tumor cell proliferation by 5% as assessed by KI-67 (P = 0.05).⁷⁰

Rosmarinic Acid

Rosmarinic acid (RA) is a phenol compound found in rosemary (among other plants) and has natural anti-inflammatory and antioxidant activities. In a mouse model of colitis, RA reduces colonic inflammation and reduces levels of COX-2 as well as proinflammatory cytokines.⁷¹ RA inhibits COX-2 expression in human colon cancer cells as well.⁷² Both aqueous and ethanolic extracts of rosemary reduce PGE2 release as a marker of COX expression in HCA-7 (human colon adenocarcinoma) cell lines.⁷³

The effects of rosemary and its compounds certainly extend beyond COX inhibition as well. Rosemary extracts reduce colon cancer cell proliferation, migration, and colony formation, and also promote necrotic cell death by increasing cellular levels of ROS. Rosemary extract is also cytotoxic to colon cancer cells due to a silencing of Nrf2, a human transcription factor that serves as a crucial regulator of antioxidant genes and cellular protection. An antitumor effect of rosemary extract has been confirmed in a xenograft mouse model of colon cancer.⁷⁴

Conclusions

A wide range of botanical medicines have published evidence supporting a preventive effect for colon cancer. Human clinical research remains limited but encouraging. COX inhibition appears to be an attractive option for the chemoprevention of colon cancer, as evidenced by human trials on aspirin. Because of the side effects associated with long-term aspirin or NSAID therapy, the discovery of alternatives to these medications may be an area of promise. Several botanical medicines discussed earlier may exert their anti-inflammatory effects through COX inhibition, which may be relevant for the prevention of colorectal cancer.▪

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