Anti-Cancer Pectins and Their Role in Colorectal Cancer Treatment

Abstract

A class of plant polysaccharides, pectin is known to display several medicinal properties including in cancer. There is some evidence that pectin from some fruits can reduce the severity of colorectal cancer (CRC) due to its antiproliferative, anti-inflammatory, antimetastatic and pro-apoptotic properties. Pectin fermentation in the colon induces antiproliferative activity via butyrate. Research also showed that pectin acts as a potent inducer of programmed cell death and cell-cycle arrest, thereby selectively targeting cancer cells. Pectin can limit oxidative stress to maintain cellular homeostasis while increasing reactive oxygen species damage to activate cancer cell death. Pectin regulates various signaling cascades, e.g., signal transduction and transcriptional activator and mitogen-activated protein kinase signaling, that contribute to its anticancer activity. By curbing inflammation-activated signaling and bolstering immune-protective mechanisms pectin can eradicate CRC. Due to its chemical structure, pectin can also inhibit galectin-3 and suppress tumor growth and metastasis. Prior reports also suggested that pectin is beneficial to use alongside the CRC standard care. Pectin can increase sensitivity to conventional CRC drugs, alleviate unwanted side effects and reduce drug resistance. Although some preclinical studies are promising, early clinical trials are showing some evidence for pectin’s efficacy in tumor growth inhibition and preventing metastasis in some cancers; however, the clinical use of pectin in CRC therapy is not yet well established. Further studies are needed to confirm the efficacy of pectin treatment as a valid clinical therapy for CRC in humans.

I. INTRODUCTION

A. Phytochemicals

Phytochemicals are structures found in plants that give positive health and anti-cancerous benefits.^1,2 They are found in foods from plants such as fruits, vegetables, nuts, and whole grains² and have been found to decrease the risk of gastrointestinal cancer specifically.¹ Phytochemicals have also been found to have profound health benefits on metabolic conditions and disorders including cardiovascular disease, neurodegenerative diseases and obesity.³ The findings of research and clinical trials dealing directly with phytochemicals have shown the full extent of the anti-carcinogenic effects of phytochemicals, such as their ability to suppress mitosis, promote apoptosis and increase the excretion levels of carcinogens.⁴ Phytochemicals are non-nutritive, as they are produced by specific cells within plants, rather than by any metabolic processes within the plant itself.^5,6 At least 10,000 separate phytochemicals have already been observed and identified, creating the need for phytochemical subclasses such as pre- and pro-biotics, polyphenols, carotenoids, steroids, and thiosulfate, with more phytochemicals being discovered constantly.⁷ Within the processes of plant metabolism, phytochemicals are imperative as they repel insects and help to monitor plant growth.⁸

There are many challenges linked to the study of phytochemicals and their many properties, mainly because most studies involving phytochemicals have been performed in vitro.^9,10 This process involves the selection of specific phytochemicals first, and then approved drugs are compared with the selected phytochemical based on molecular structure and protein target sites, with high similarity between the two being preferable.¹¹ This process makes it difficult to study the overall health benefits that phytochemicals have on the entire body, as the phytochemicals are being studied for their anticancer effects on specific phenotypes, rather than the body as a whole.¹²

B. Phytochemicals in Cancer Research

Research has shown how the addition of phytochemicals during the administration of cancer treatments has improved the prognosis in these patients due to the phytochemicals’ unique ability to trigger many separate selected mechanisms within the body.⁹ Therefore, this begs the question whether the consumption of multiple phytochemicals which trigger numerous mechanisms in the body could improve cancer manifestations.⁹

Due to the limitations in therapeutic efficacy and morbidity associated with cytotoxic therapies, the use of alternatives approaches have been widely tested. For example, the utilization of phyto-nano-technology in anti-cancer drug delivery has shown promising results.¹³ This process involves the combination of a phytochemical-based drug with a synthetic drug to create a more effective and reliable delivery method for these anti-cancer drugs into the body.

II. PECTINS

The term “pectin” describes a large group of polysaccharides that can be found in plants and primary in cell walls.¹⁴ The structure and composition of pectin changes as the plant ages, and different types and structures of pectin can be found within different plant species.^15,16 Since there is a single known structure for pectin, a few possible structures have been proposed and some subunits within pectins have been classified. Three separate pectic polysaccharides have been identified: homogalacturonans, substituted galacturonans and rhamnogalacturonans.^15,16

Rich sources of pectin include citrus fruits such as oranges, lemons, and grapefruits.¹⁶ Pectin can also be found in large amounts in other fruits such as apples, guavas, quince, plums, and gooseberries, and in smaller amounts in softer fruits such as cherries and grapes as well as berries.¹⁷ The approximate levels of pectin in different fruits (weighted when fresh) are as follows: citrus peels: 30%; carrots: 1.4%; oranges: 0.5–3.5%; cherries: 0.4%; apricots: 1%; and apples: 1–1.5%¹⁶). Citrus peel and apple pomace are the main raw materials used for pectin production, as they are pectin-rich, and are easily accessible since they are by-products of the juice production process.¹⁷

The American Cancer Society has suggested that adults consume five servings of fruits and vegetables per day to help reduce the risk of cancer.¹⁸ The polysaccharide extracted using citrus fruit’s peel and pulp and prepared in high pH and temperature called modified citrus pectin (MCP) was tested for anti-cancer activity. The findings showed that MCP was effective against metastatic cancer, with notable effectiveness against solid tumors such as melanoma as well as cancers located in the prostate, colon and breast.^1,19–22 On top of this, MCP has exhibited the ability to suppress angiogenesis and metastasis of different forms of cancer during animal testing, thereby restraining the growth of the cancer itself.^23,24 More research has been carried out with MCP than the regular citrus pectin due to its increased biological properties and overall effectiveness.¹⁶

III. PECTINS AND CRC

Pectin showed therapeutic properties that can delay the progression of chronic illnesses including cancer and enhanced gastrointestinal health. Due to their non-toxicity and modifiable carboxylic and hydroxyl functional groups, pectins alleviate many of the harmful side effects of conventional chemotherapy drugs.²⁵ Pectins decrease the systemic toxicity risk in colon cancer,²⁶ and those derived from citrus,²⁷ pumpkin waste,²⁶ fig skin,²⁸ and gabiroba pulp²⁹ display antitumor activity. Rats undergoing methylnitrosourea or azoxymethane treatment for colon cancers develop fewer tumors when their diets were enriched with the dietary fiber pectin,³⁰ and similar results were obtained with the 1,2-dimethylhydrazine treatment.³¹ Pectin has immense potential for supplemental chemotherapy in colorectal cancer (CRC).

Pectin treatment kills colon cancer cells more effectively than melanoma cells,³² and enzymatically modified pectins showed greater anticancer activity compared with commercial pectin.³³ Modified pectins with lower molar mass tend to decrease tumor size more than naturally large pectins because of their effects on the blood concentration, absorption and secretion.²⁵ A biphasic pectin drug for colon cancer demonstrated efficient in vitro and in vivo absorptions.³⁴ Though pilot clinical trials have found that the enzyme-treated pectin decreases tumor growth and prevents metastasis for various cancer types,^35,36 more studies are needed to confirm the efficacy of pectin treatment as a valid therapy for colon cancer in humans.

A. Antiproliferative Activity of Pectin

Pectin inhibits the proliferation of abnormal lesions in the colon. Azoxymethane (AOM) and dextran sodium sulfate (DSS) developments are an early indicator of carcinogenesis in colon tissue. Pectin treatment reduces DSS colonic disease and inhibits the severity of colitis.³⁷ Colon cancer pathogenesis begins with hyperproliferation of the colonocytes at the crypt base.¹⁴ In rodent models, pectin supplementation in colon carcinogenesis induced by AOM and DSS prevented the formation of aberrant crypt foci and aberrant crypt, thus slowing the growth of pre-neoplastic colon lesions.³⁸

B. Effect of Pectin on CRC Drugs

Pectin facilitates the cytotoxic characteristics of colon cancer drugs. Pectin shields drugs from the harsh environment of the stomach and small intestine and selectively degrades in the colon for successful drug release.³⁹ Specifically, pectin conjugated with cisplatin enhances cancer drug circulation in the blood.⁴⁰ Pectin protects the nano-components of CRC drugs during oral delivery by increasing the binding efficiency, limiting angiogenesis and inhibiting colon cancer cell growth.⁴¹ Pectin increases Dicer-substrate small interfering RNA accumulation,⁴¹ which decreases vascular endothelial growth factor expression and, consequently, hinders angiogenesis.⁴² The antiproliferative activity of pectin is selective toward cancer cells,⁴¹ making it an effective modality of treatment for CRC.

A nanoparticle that shows potential for colon cancer therapy is β-lactoglobulin (BLG) pectin. BLG is an effective drug carrier because of its stability at low pH, resistance to gastric protease, and its binding affinity for hydrophobic molecules.²⁶ Pectin polysaccharides increase the stability of BLG nanoparticles at pH values below their pI because of increased electrostatic attraction and hydrogen bonding.^43,44 With the added negative charge, pectin further increases nanoparticle stability. When complexed to platinum, BLG-pectin nanoparticles significantly increase tumor cell death in the HCT116 colon cancer cell line because of the ability of smaller particles to infiltrate the cells easily and exert their cytotoxic activity.²⁶

Calcium demonstrates antiproliferative activity that can enhance pectin’s cytotoxicity. The oral administration of calcium pectinate matrix reduces CRC severity due to the crosslinking of pectin by calcium ions reducing transit time and blocking drug release in the upper gastrointestinal tract.⁴⁵ Compared with zinc ions, calcium ions are the preferred cross-linking element because they stimulate the enzymatic degradation of pectin and exhibit anti-colon cancer properties.⁴⁵

The use of pectin-based hydrogels that contain CRC drugs is another method by which the anti-cancer properties of pectin can be used therapeutically. Hydrogels loaded with doxorubicin exert cytotoxic effects on HepG2 cells and reduce aggregation of B16 cells in vitro.⁴⁶ Chitosan microgels coated with pectin and containing 5-fluorouracil also showed anti-proliferative activity against two cancer cell lines.⁴⁷ Low methoxyl pectin added to a fentanyl nasal spray can even alleviate chronic cancer pain.⁴⁸

IV. EFFECT OF PECTINS ON THE REDOX SYSTEM

Reactive oxygen species (ROS)-induced lipid peroxidation damages DNA and contributes to colon carcinogenesis,⁴⁹ thus limiting oxidative stress as a viable treatment pathway for CRC. Pectin-inhibited oxidative stress diminishes tumor cell proliferation. Pectin inhibits oxidative stress through several mechanisms and modulation of stress bio-markers. It can directly detoxify ROS and chelate transition metals.³⁸ By reacting with superoxide radicals, pectin can inhibit the formation of endogenous ROS such as hydrogen peroxide.⁵⁰ Pectins increase antioxidant biomarkers and reduce oxidative biomarkers.⁵¹ ROS regulatory mechanisms have demonstrated inhibition of colon tumorigenesis in animal models.⁵² Clinical trials can further shed light on how pectins can regulate the oxidative stress.

Pectin oligosaccharides (POS) maintain cellular homeostasis by normalizing the activity of redox system regulatory enzymes, e.g., glutathione reductase and glutathione peroxidase (GPx).⁵³ The standardization of glutathione reductase catalyzes glutathione disulfide (GSSG) into reduced glutathione (GSH) and GSH helps GPx catalyze hydrogen peroxide into water.⁵⁴ The reduction of hydrogen peroxide also occurs when POS induces CAT as a reductant.⁵⁵ Additionally, increased glutathione-S-transferase activity from POS increases the reduction of plasma CysGly during GSH catabolism.⁵¹ By stabilizing dangerous products of the ROS pathway, POS can decrease CRC risk. Antioxidant activity from pectin can maintain fecal health. Pectin is an antioxidant that reduces fecal transit times in the intestine, thus decreasing the exposure of colonic epithelium to luminal carcinogens.⁵⁶ Pectin decreases fecal lipid peroxidation by reducing malondialdehyde in feces, thus inhibiting the risk of cell injury by oxidative stress.³⁸

On the other hand, certain pectins that elevate ROS often demonstrate anti-cancer properties via activating cancer cell death.⁵⁷ Pectin from gabiroba pulp significantly increases ROS levels, contributing to its cytotoxic effect. Elevated ROS increases the vulnerability of cancer cells to oxidative damage from DNA, proteins, and lipids.⁵⁸ The antioxidant activity of pectin varies among different pectin types. Citrus pectin has antioxidant properties and apple pectin demonstrates prooxidative activity, and both strengthen the ROS production induced by irinotecan that leads to mitochondrial apoptosis.⁵⁹

V. PECTIN FERMENTATION

Pectin fermentation can induce antiproliferative activity. As a soluble dietary fiber, pectin undergoes 100% fermentation in the colon, leading to the generation of short-chain fatty acids.⁶⁰ These fatty acids prevent CRC by lowering the pH of the colon from 7 to 6.5.^45,61 Lowered pH from pectin fermentation can reduce colon cancer risk by inhibiting the production of secondary bile salts while decreasing free bile solubility,⁶⁰ and pectin can reduce bile acids by increasing fecal excretion.⁶² Short-chain fatty acid production from pectin also decreases colonic hyperproliferation induced by deoxycholate by promoting apoptosis in several colon tumor cell lines in vivo.⁶³ Butyrate is partly responsible for the antitumor properties of pectin. Butyrate is a metabolite of its microbial fermentation.⁶⁴ Butyrate reduces the proliferation of CRC cells, inhibits the differentiation of tumor cells via ROS regulatory pathways, and induces apoptosis in a caspase-dependent apoptotic pathway.⁶⁵

VI. EFFECT OF PECTINS ON SIGNALING

A. STAT1 and STAT3

Pectin can activate signaling pathways induced by transcription factors. Signal transduction and transcriptional activator 1 (STAT1) plays an important role in the CRC incidence and intestinal inflammation.⁶⁶ STAT1 activation enhances the antitumor capacity of POS-mediated STAT1 signaling via the leptin receptor.⁵³ Pectin enhances cardiotropin-1 expression, which also enhances the STAT signaling pathway. Ingested pectin induces protein kinase C (PKC) expression, which promotes STAT1 phosphorylation. POS exerts a regulatory role over macrophage STAT pathways by inhibiting the release of relevant cytokines.⁵³ POS can also induce cell apoptosis by activating the STAT3 complex.^53,67

B. MAPK

POS can suppress CRC inflammation by inactivating the mitogen-activated protein kinase (MAPK) signaling pathway.⁶⁸ Pectin can inactivate the MAPK pathway via Gal-3 inhibition.⁶⁹ Pectins rich in ester bonds inhibit MAPK phosphorylation, IKK kinase activity, and NF-κB activation.⁶⁹ The downregulation of MAPK reduces the invasion and angiogenesis of cancer cells.⁷⁰ However, there is also contrasting evidence that POS can activate the MAPK pathway. POS can activate the Raf-MEK-ERK pathway through extracellular receptor binding.⁵³ POS has a high affinity with the lysine motif domain, which is necessary to activate MAP3K, and consequently, MAP2K, leading to the activation of MAPK and related transcription factors.⁵³ Upregulation of MAPK signaling can increase both antioxidant activity⁷¹ and apoptosis of CRC cells.⁵²

C. Inflammation Signaling

Pectin inhibits inflammation-activated signaling, which is linked to CRC incidence, especially in patients with ulcerative colitis.⁵³ With leukocyte invasion of the colonic mucosa, the body overproduces inflammatory cytokines and leads to inflammation of the colon.⁷² Current anti-inflammatory drugs produce negative side effects that reduce the efficacy of treatment,⁵³ so finding viable alternatives that target inflammation can improve CRC patients outcomes. Pectin has shown promising results as an anti-inflammatory agent. Galacturonan derived from the pectin backbone exerts anti-inflammatory activity against neutrophils in the intestinal wall.⁷³ Pectin from sugar beet pulp has an anti-inflammatory properties and significantly reduces the number of viable CRC cells.⁷⁴ POS can significantly ameliorate lipopolysaccharide-induced inflammatory responses.⁷⁵ Pectin is also known to inhibit CRC growth by reducing antioxidant and anti-inflammatory signalings via the AMPK, Nrf2 and NF-κB pathways.⁵³

Pectin can reduce inflammation by altering transcription mechanisms. Nuclear factor-kappa B (NF-κB) is involved in pro-inflammatory cytokine generation, and antioxidant regulation of NF-κB is tied to CRC.⁷⁶ Regulation of NF-κB signaling protects against neuroinflammation and oxidative stress.⁵³ POS derived from apples is an effective CRC treatment because it targets the LPS/TLR4/NF-κB pathway.⁷⁷ Korean red ginseng pectin activates the NF-κB pathway, thus facilitating macrophage and T cell activity.⁷⁸

VII. PECTIN INHIBITION OF GAL-3

MCP is a potent antimetastatic drug that inhibits colon carcinoma both in vitro and in vivo.²² MCP decreased liver metastasis of colon cancer in a mouse model⁷⁹ and reduces cancer cell growth by decreasing the expression of nm23, cyclin B, p34, and cdc2.⁸⁰ MCP activity inhibits galectin-3 (Gal-3), a β-galactoside binding protein that is linked to liver metastasis in colon cancer⁸¹ because of its reduction of tumor cell adhesion and aggregation.⁸² Pectin from papaya fruit inhibits CRC proliferation in its intermediate ripening point by reducing Gal-3-mediated hemagglutination.⁸³ Native-form citrus pectin is unable to interact with Gal-3 because of its insolubility, but MCP that has undergone hydrolysis can serve as a ligand for Gal-3 because it can form water-soluble fibers.^84,85 The water-soluble fraction of pectin derived from jabuticaba, a Brazilian grapetree, inhibits the viability of the colon cell line HCT116 cell in a concentration-dependent relationship.⁸⁶ Both native and modified forms of pectins affect Gal-3 activity.

Pectins containing galactose and arabinose inhibit the Gal-3 hemagglutination, while those composed of RG-1 induce apoptosis via interaction with Gal-3.⁸⁷ Additionally, pectin’s rich RG-1 regions have been linked to their anticancer properties because they maximize the availability of neutral sugar side chains for cellular interaction.⁸⁸ The →4)-β-D-Galp-(1→ units on the branched chain in the RG-1 plays a role in the ability of pectins to inhibit Gal-3.⁸⁵ MCP also inhibits Gal-3 in the RG-1 regions because of its high affinity of the galactan chains to Gal-3.⁸⁹ Gal-3 is also involved in cell growth⁹⁰ and angiogenesis.⁹¹ MCP limits capillary tube formation in HUVEC morphogenesis by inhibiting the binding of Gal-3 to HUVECs.⁹² By cutting off blood supply to tumors, CRC prognosis is improved.

Since MCP is rich in β-galactose, it can inhibit Gal-3 and slow metastasis progression.⁹³ Possible mechanisms of such inhibition occur via the downregulation of cyclin B and cdc2.⁸⁰ Other possible mechanisms of Gal-3 inhibition include modulating the mobility and metastatic properties of Gal-3 or MCP-mediated inhibition of Gal-3 can reduce metastasis by preventing tumor cell attachment and aggregation at the endothelium attachment sites.⁸⁴ One mechanism involves modulating Gal-3 ligand mucin 2 (MUC2), a glycoprotein associated with carcinogenesis and metastasis.²⁵ Since the modified pectin inhibits Gal-3 in colonic epithelial cells, MUC2 activity decreases via downstream pathways.⁹⁴ Pectin competes with Gal-3 recognition of the MUC2 surface sugar chains. The radical form of β-galactose, galactosyl, is another major component of MCP which can inhibit tumor growth and metastasis in vivo and Gal-3 functions in vitro.⁹⁵

Studies have shown that MCP inhibits adhesion to bone marrow endothelium, the breast, and prostate.^96,97 MCP inhibits tumor cell interactions with extracellular matrix proteins necessary for attachment involving the basement membrane and organ stroma. MCP inhibits chemotactic migration induced by Gal-3 and prevents HUVEC-mediated migration responsible for capillary tube migration.⁹⁵ The rate-limiting step of the metastatic pathway is the survival of early metastatic colonies.⁹³ MCP inhibition of Gal-3 reduces the viability of metastatic colonies and significantly increases tumor cell apoptosis.⁹⁸ In mice, MCP treatment reduces angiogenesis by 66% via Gal-3 inhibition, limiting the development of clinically relevant tumors.⁹⁵ By inhibiting Gal-3, pectin can reduce the severity of CRC.

The anticancer activity of pectin through inhibition of Gal-3 is illustrated in Fig. 1.

FIG. 1:

Anti-cancer activity of pectins. Various pectins, such as MCP, low-molecular-weight citrus pectin, and GCS-100 (polysaccharide derived from citrus pectin), inhibit Gal-3 lectin and consequently exert downstream anticancer activity. Red arrows indicate inhibitory mechanisms and blue arrows indicate stimulating mechanisms. Black boxes represent pectin types.

VIII. EFFECT OF PECTINS ON APOPTOSIS

Inducing programmed cell death is crucial in cancer therapy, however, targeting selectively cancer cells is challenging; hence, it is an important strategy in killing CRC cells and delaying tumor progression. Sweet potato pectin and maleoyl-containing pectin derivatives showed anti-cancer activity and inhibited CRC proliferation by initiating apoptosis.^99,100 Notably, maleoyl-rich pectin selectively targeting and killing CRC cells without affecting healthy cells in monkeys.¹⁰⁰ Modifying pectin with maleoyl improves thermal stability because of the greater number of ester bonds.¹⁰⁰ In a pre-clinical study, Avivi-Green et al. found that pectin-enriched diet can enhance the apoptotic index. A 15% diet enriched with citrus pectin caused an increased apoptotic index in rat colons.¹⁰¹ Pectins induce apoptosis though mediating several mechanisms. Downregulation of β-catenin phosphorylation is one of the mechanisms which can induce apoptosis in CRC cells and upregulates the AMPK pathway for cellular homeostasis.⁹ Another mechanism of suppressing tumor growth involves the inhibition of Gal-3 expression.¹⁰² By suppressing the activity of Gal-3, low-molecular-weight citrus pectin increases caspase-mediated apoptosis and, consequently, reduces the metastasis of CRC cells.⁹³

Apoptosis is also induced through modulating caspases and mediating critical signaling mechanisms. MCP has been shown to induce apoptosis via a caspase-8-to-caspase-3 signaling cascade.¹⁰³ In another study, it was shown that dietary pectin increased the expression of caspase-1 in luminal colonocytes from colon crypts.¹⁰¹ Further evidence of citrus pectin’s pro-apoptotic effect was shown in a study that measured the ability of pectin to activate caspase-3, the initiator of the apoptosis pathway.³² When colon adenocarcinoma HT29 cells were treated with pectin oligosaccharides, it was evident of the activation of caspase-3 activity, DNA fragmentation, and apoptosis.¹⁰⁴ GCS-100, a type of modified pectin, activates caspase-3 and caspase-8 cascades and PARP cleavage.⁷⁹ Pectins also promote apoptosis by suppressing the activation of Bcl-xL and Cyclin B as well as regulating the expression of signature microRNA (miRNA).¹⁰⁵

IX. EFFECT OF PECTINS ON DRUG RESISTANCE

Reducing drug resistance can increase the efficacy of CRC treatment. Gal-3 inhibition from pectin activity can prevent chemotherapy drug resistance.¹⁰⁶ MCP inhibition of Gal-3 is critical for the re-sensitization of cancer cells to cytotoxic molecules like doxorubicin and taxol.^93,98 Pectin can reduce drug resistance via apoptotic processes. MCP reduces the ability of Gal-3 to suppress the mitochondrial apoptosis pathway, significantly reducing tumor cell resistance to the cytotoxic drug dexamethasone and increasing sensitivity to the apoptosis-inducing drug bortezomib.¹⁰³ One theory suggests that modified pectins bind extracellular Gal-3, which prevent Gal-3 from interfering with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its receptors and, thus, revert drug-resistant tumor cells back to their drug-sensitive state.¹⁰⁷ Modified pectin inhibits Gal-3–mediated T cell apoptosis, leading to decreased drug resistance and lowered immune tolerance.¹⁰⁸ GCS-100 facilitates tumor-infiltrating lymphocytes because its activity as a Gal-3 ligand can improve T cell function via IFN-gamma secretion.¹⁰⁹

X. PECTIN IN CLINICAL TRIALS

The use of pectin in clinical trials has shown varying success in the treatment of CRC as well as other cancers. In one perspective pilot study, 49 patients with various solid tumors, including 12 with CRC, were treated with oral MCP. Clinical benefit, safety, tumor response and quality of life were assessed. Those who completed two cycles of 4 weeks of treatment showed an improvement in quality-of-life assessments and clinical benefit (pain, functional performance. weight change).³⁶ The clinical trial NCT02575404 explored the use of belapectin, a galectin-3 inhibitor, as a treatment for various cancers. Belapectin was given at doses of 2, 4, or 8 mg/kg IV prior to pembrolizumab while the immune response and safety were investigated. Within the dose range there were no dose-limiting toxicities and an objective response was observed, namely, increased effector memory T-cell activation and reduced mono-cytic myeloid-derived suppressor cells.¹¹⁰ Other trials have been completed and detailed in Table 1.

TABLE 1:

NCTs utilizing pectin

NCT no.	Title	Status	Intervention	Characteristics
N/A	Clinical Benefit in Patients with Advanced Solid Tumors Treated with Modified Citrus Pectin: A Prospective Pilot Study	Completed	Oral MCP	Prospective pilot study
NCT02575404	Phase IB Study of a Galectin Inhibitor (GR-MD-02) and Pembrolizumab in Patients with Metastatic Melanoma, Non-Small Cell Lung Cancer, and Head and Neck Squamous Cell Carcinoma	Completed	Belapectin (GR-MD-02) + pembrolizumab	Interventional phase I
NCT01681823	Phase III, Single-Center, Open Label, Trial Evaluating the Safety and Efficacy of PectaSol-C Modified Cirtus Pectin on PSA Kinetics in Prostate Cancer in the Setting of Serial Increases in PSA	Completed	PectaSol-C modified citrus pectin	Interventional Phase II
NCT02270268	Therapeutic Effects of Pectin Supplementation in Patients with Diarrhea-Predominant Irritable Bowel Syndrome	Completed	Pectin	Interventional Phase III

XI. CONCLUSIONS AND FUTURE DIRECTIONS

The treatment of CRC can be difficult for a variety of reasons including poor prognosis, difficulty in drug delivery, and toxic effects of current treatments. In order to improve current CRC treatment, novel methods of intervention must be explored. Pectin is a large group of naturally occurring polysaccharides found in plants that can be used in the treatment of various cancers alone or in conjunction with standard interventions. With the ability to regulate oxidative stress, anticancer signaling pathways, and gut health while mitigating some of the harmful side effects of conventional therapy, pectin offers itself as a promising candidate for further investigation. Expanded inquiry into the variety of modified pectins yield insights into their individualized uses and further focus their use as a novel treatment for CRC. Currently, there are several mechanisms through which pectin is suspected of affecting tumors and further studies continue to illuminate its effective action. Even though exploring the anti-cancer activity of pectin was initiated about 30 years ago, interest has been gaining in the last decade and promising preclinical results made it possible to move to clinical testing. These pectin compounds also were examined for their effects on standard care. The continued investigations into the mechanisms of action and the synergistic effect with other anti-cancer drugs might prove the wide scope of pectin’s clinical applications.

ABBREVIATIONS:

AOM

azoxymethane

BLG

β-lactoglobulin-pectin

CRC

colorectal cancer

DSS

dextran sodium sulfate

Gal-3

galectin-3

GPX

glutathione peroxidase

GSH

glutathione

GSSG

glutathione disulfide

MAPK

mitogen-activated protein kinase

MCP

modified citrus pectin

miRNA

microRNA

MUC2

mucin 2

NF-κB

nuclear factor-kappa B

PKC

protein kinase C

POS

pectin oligosaccharides

ROS

reactive oxygen species

STAT 1

signal transduction and transcriptional activator 1

TRAIL

tumor necrosis factor-related apoptosis-inducing ligand