Biomedicine & Pharmacotherapy 117 (2019) 109142

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Biomedicine & Pharmacotherapy

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Natural products for treating colorectal cancer: A mechanistic review T

a,1 b,1 a a a,⁎ b,⁎
Xuan-mei Huang , Zhi-jie Yang , Qing Xie , Zi-kang Zhang , Hua Zhang , Jun-ying Ma
a
Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Institute of Laboratory Medicine, Marine Biomedical Research Institute, Guangdong Medical
University, Dongguan 523808, China
b
CAS Key Laboratory of Tropical Marine Bio-Resources and Ecology, Guangdong Key Laboratory of Marine Materia Medica, RNAM Center for Marine Microbiology,
South China Sea Institute of Oceanology, Chinese Academy of Sciences, Guangzhou 510301, China

A R T I C LE I N FO A B S T R A C T

Keywords: Colorectal cancer (CRC) is one of the most common types of cancers in humans and is closely linked to the global
Natural products cancer-related mortalities worldwide. Molecular pathological epidemiology studies can reveal the risk factors of
Colorectal cancer CRC and contribute to biomarker research and precision medicine. The current clinical treatment for CRC mainly
Anti-cancer effects involves surgery and chemotherapy. However, because of the occurrence of side effects and the emergence of
Molecular mechanisms
drug resistance, there is an urgent need to find new and more effective drugs for CRC treatment. An increasing
Regulation networks
number of studies have demonstrated that many natural products possess effective anti-CRC effects and may
serve as alternative chemotherapy agents for CRC treatment. In this review, we summarize the natural products
with anti-CRC effects from different sources based on the chemical structures such as alkaloids, polysaccharides,
polyphenols, terpenoid, unsaturated fatty acids, and discuss the natural product-derived drugs used clinically for
colorectal cancer treatment. Furthermore, natural products of marine origin are also discussed for their en-
ormous potential to serve as the candidate drugs. Notably, we generalize the experiment-based molecular me-
chanisms and the regulatory networks whereby natural products exert anticancer effects on cell proliferation,
metastasis, apoptosis, autophagy, and angiogenesis.

1. Introduction
Colorectal cancer (CRC) is the fourth leading cause of malignant
tumor-related deaths worldwide [1]. According to data from GLOBO-
CAN in 2012, there are 1.6 million new cases of CRC and 694,000
people that die from CRC every year [1]. The occurrence and pro-
gression of colorectal cancer are caused by a combination of multiple
factors, among which age, family history, gender, region, and personal
history are the major risk factors [2–4].
Recently, molecular pathological epidemiology (MPE), a transdis-
ciplinary research field that reveals the relationship between the risk
factors (germline genetics, lifestyle, dietary pattern, microbiome, etc.)
and molecular characteristics, occurrence, development and prognosis
of diseases, has been predominantly applied for epidemiological studies
on cancer to provide new insights into, and strategies for, cancer pre-
vention and treatment. Genetic changes including microsatellite in-
stability (MSI), BRAF mutations, PIK3CA mutations, KRAS mutations
and high-degree CpG island methylator phenotype are the main factors
closely related to the development of CRC [5,6]. More recently, SMAD4
loss has been identified as a promising prognostic marker for CRC pa-
tients due to its significant association with worse clinical outcomes,
chemoresistance, and reduced immune infiltration [7]. Previous studies
have shown that smoking and obesity are risk factors for CRC; however,
MPE studies have revealed that smoking is a risk factor for the CpG
island methylator phenotype-high or MSI-high CRC subtype, while
obesity is a risk factor for the non-MSI-high CRC subtype [5,8,9]. The
dietary pattern is also an important factor in CRC. It has been found that
calcium intake is inversely proportional to the risk of CRC; calcium
functions in the immune prevention of CRC by regulating T cell func-
tion [10–12]. However, alcohol intake has been found to increase the
risk of the KRAS-wild/BRAF-wild and KRAS mutated CRC subtypes
[13]. Fusobacterium nucleatum is a pathogenic microorganism involved
in the development and prognosis of CRC [14,15]. Intensive me-
chanism-based studies have shown that it plays a carcinogenic role by
regulating signaling pathways such as the E-cadherin/β-catenin
pathway and is involved in the metastasis of CRC [16,17]. MPE studies
have also revealed that aspirin could reduce the risk and patient mor-
tality of the PTGS2-positive CRC subtype but not the PTGS2-negative

⁎
Corresponding authors.
E-mail addresses: 1837766853@qq.com (X.-m. Huang), yzjie6@126.com (Z.-j. Yang), 1048271414@qq.com (Q. Xie), 1119129766@qq.com (Z.-k. Zhang),
huazhang@gdmu.edu.cn (H. Zhang), majunying@scsio.ac.cn (J.-y. Ma).
1
These authors contributed equally.

https://doi.org/10.1016/j.biopha.2019.109142
Received 20 March 2019; Received in revised form 14 June 2019; Accepted 14 June 2019
0753-3322/ © 2019 The Authors. Published by Elsevier Masson SAS. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/BY-NC-ND/4.0/).
X.-m. Huang, et al.
CRC subtype [18]. In addition, compared to the PI3KCA-wild subtype,
aspirin has been verified to exert strong anticancer effect against the
PI3KCA-mutated CRC subtype [19,20]. There is no doubt that the ap-
plication of MPE for studying cancer will provide a more precise and
effective strategy for the prevention and treatment of CRC.
The conventional treatments for CRC include surgery and che-
motherapy. Chemotherapeutics can lead to cancer cell death by indu-
cing DNA damage or initiating multiple signaling pathways, including
cell cycle arrest, inhibition of global translation, DNA repair, etc. [21].
However, as many studies, including MPE studies, have shown, the
treatment outcome of chemotherapeutic drugs in CRC patients varies
with the subtype of cancer. The effects of cytotoxicity, drug resistance
and adverse reactions are the main problems associated with che-
motherapy.
Complex and diverse natural products have yielded numerous ef-
fective lead compounds for the discovery of new drugs. Many natural
products have exhibited excellent biological activities against in-
flammation, viruses, bacteria, tumors, etc. [22,23]. The application of
natural product-derived drugs has made a tremendous contribution to
human health, for example, penicillin for the treatment of infectious
bacterial diseases [24], streptomycin for the long-term treatment of
tuberculosis [25], the significant anti-inflammatory plant-derived
monoterpene glycoside, paeoniflorin [26], the natural plant-derived
anti-HIV compound, patentiflorin A [27], cyclosporin, which has im-
munomodulatory effects [28], lovastatin, which has with hypolipi-
demic function [29] and ecteinascidin-743, which has an anti-tumor
activity [30].
Natural products that are well tolerated and have less toxicity will
help patients to achieve better treatment outcomes and improve their
quality of life. Many chemotherapeutic agents have been identified by
investigating potential compounds from plants, animals, and micro-
organisms including marine organisms, and these have been found to
exert anti-cancer effects against a variety of tumors [31–35]. Accumu-
lating evidences from previous studies have shown that natural pro-
duct-derived drugs have broad application prospects for the treatment
of CRC [36–38].
2. Natural products serving as drugs against CRC in clinical
setting
2.1. Natural products as anti-CRC drugs
Natural products have become prolific sources of new anticancer
drugs, and approximately 50% of the currently used anticancer drugs
have been directly or indirectly derived from natural products; these
products, including alkaloids, polysaccharides, polyphenols, diterpe-
noid and unsaturated fatty acids possess various structures [39]. The
continuous discovery of such products has opened up a novel direction
for the prevention and therapy of cancers; the natural product-based
drugs used clinically for CRC treatment are summarized in Fig. 1 and
Table 1.
2.1.1. Alkaloids
Irinotecan (CPT-11) (Fig. 1A), a water-soluble camptothecin deri-
vative, functions as a DNA topoisomerase I inhibitor that blocks DNA
replication and inhibits RNA synthesis [40]. Although it has been used
for first-line therapy or second-line therapy after the failure of fluor-
ouracil treatment, CPT-11 has been shown to have an interesting anti-
tumor activity against metastatic colorectal cancer (mCRC). CPT-11 has
been utilized for standard treatment against CRC worldwide, and clin-
ical studies have reported that CPT-11 has better anti-tumor effect
when combinated with 5-fluorouracil (5-FU)/formyltetrahydrofolate
(CF) for the treatment of advanced mCRC [41–43].
SN38 (Fig. 1B), the active analog of irinotecan, has an inhibitory
effect against the growth of a variety of malignant cells [44]. The anti-
angiogenic activity of SN38 is mainly due to the inhibition of vascular
2
Biomedicine & Pharmacotherapy 117 (2019) 109142
endothelial growth factor (VEGF) and hypoxia-inducible factor 1 alpha
expression. SN38 has dual inhibitory effects, including the suppression
of endothelial cell proliferation or lumen formation, as well as the in-
hibition of the angiogenic activity of glioma cells. Kamiyama H has
reported that SN38 can selectively inhibit three-dimensional tubular
structure formation and endothelial cell proliferation at the con-
centration of 0.01 μM [45].
Although CPT-11 and SN38 have broad-spectrum anti-tumor ac-
tivity against various tumors, CPT-11 and its analogs have significant
toxicity including cholinergic syndrome, neutropenia and delayed
diarrhea [46–48]. An increasing number of studies have been carried
out in recent years to improve the efficacy and safety of these com-
pounds through chemical structure modification and combination
chemotherapy [44].
2.1.2. Polysaccharides
PSK (Krestin) (Fig. 1C) is protein-bound polysaccharide K isolated
from Coriolus versicolor; it has a molecular weight of approximately
100 kDa and a protein content of 18–38% [49]. Tsutsumi et al. have
found that PSK effectively reduced the mortality induced associated
with dextran sodium sulfate-induced colitis and inhibited the devel-
opment of CRC, suggesting that it shows dual antagonism against both
inflammation and CRC [50]. The efficacy of PSK against cancer is
mediated via several pathways, including recovery from im-
munosuppression that is induced by TGF-β and anti-tumor immune
responses, and enhanced efficacy of chemotherapy by inducing apop-
tosis and inhibiting the metastasis of cancer cells [49].
Fucoidan (Fig. 1D) is a sulfated polysaccharide isolated from brown
seaweeds; it has been shown to exhibit a wide range of biological ac-
tivities [51]. A previous study has indicated that fucoidan induces
apoptosis in HT-29 and HCT116 cells [52]. Double-blind, randomized
clinical trials have demonstrated that low-molecular-weight fucoidan
has significant activity against CRC in humans, with relatively few side
effects [53]
2.1.3. Polyphenols
Resveratrol (Fig. 1E) is a polyphenolic compound synthesized by
plants following attack by pathogens, such as bacteria or fungi; peanuts,
grapes, and red wine are highly rich in resveratrol. Evidence from
previous studies has suggested that resveratrol participates in the reg-
ulation of the average life cycle of organisms as the silent information
regulation 2 homolog 1 (SIRT1), and it has significant inhibitory effects
against hepatocellular carcinoma, breast cancer, gastric cancer, leu-
kemia, and other tumor cells [54–58]. Previous research has shown that
resveratrol exerts apoptotic and anti-proliferative effects on CRC via the
induction of Fas redistribution and inhibition of Wnt signaling [59].
Engelbrecht et al. have reported that grape seed extract could inhibit
the PI3K pathway, to induce apoptosis and suppress the viability of
CaCo-2 cells [60].
Curcumin (Fig. 1F), a polyphenol isolated from Curcuma longa, has
been shown to have significant anti-angiogenic properties, and can
reduce the secretory level of TNF-α in the serum, enhance the expres-
sion of the p53 and cip1/p21, and induce the apoptosis of CRC cells
with little effect on the quality of life of the patients [61]. Watson et al.
have found that curcumin induced p21-independent apoptosis in
HCT116 cells [62].
2.1.4. Terpenoids
Andrographolide (Fig. 1G) is a diterpenoid and the major bioactive
component of the plant Andrographis paniculata, which has been used as
a traditional herbal medicine in Asia for thousands of years. Andro-
grapholide has been reported to suppress NF-κB activation and DNA-
binding activity [63,64], and it thus, has various biological activities,
such as anti-inflammatory functions [65,66] and anti-cancer properties
[67,68]. Combination treatment of andrographolide and 5-FU can in-
duce the apoptosis of HCT116 cells via the binding of andrographolide
X.-m. Huang, et al. Biomedicine & Pharmacotherapy 117 (2019) 109142

Fig. 1. Structures of previously discovered natural products drugs used in colorectal cancer.

to the BAX protein and the upregulation of BAX expression [69]. Su
et al. have evidenced the safety and efficacy of the combination of
andrographolides and capecitabine for the treatment of elderly patients
with locally advanced CRC [70].
2.1.5. Unsaturated fatty acids
Marine microalgae are a rich source of polyunsaturated fatty acids
(PUFAs) (> 80%), mainly eicosapentaenoic acid (EPA) and doc-
osahexaenoic acid (DHA) [71]. EPA and DHA inhibit important an-
giogenic factors, such as platelet growth factor, VEGF, and endothelial
cell growth factor, and are thus, effective against CRC, breast cancer,
and pre-existing adenocarcinoma [72]. DHA and EPA (in the form of
acid and phospholipids) have been shown to inhibit the growth of CRC
cells, and PUFAs have been shown to have stronger growth-inhibitory
effects in the HT-29 cell line than in the Caco-2 and DLD-1 cell lines
[73].
2.2. Application of natural product-based drugs for combination
chemotherapy in clinical setting
Metastatic CRC is generally considered to be the terminal stage of
CRC [74–77]. In previous clinical trials, irinotecan treatment has been
reported to markedly increase the survival rate and reduce the in-
cidence of adverse events in patients with advanced mCRC [78]. Since
then, irinotecan has been regarded as a standard chemotherapeutic
drug, especially in patients with advanced mCRC, for whom 5-FU
treatment had failed in the early stage of the disease. As a natural
product-derived drug, irinotecan remains the backbone of combination
chemotherapies for metastatic CRC, including FOLFIRI (levoleucovorin
(LV) and 5-FU plus irinotecan), IROX (irinotecan plus oxaliplatin), and
XELIRI (capecitabine plus irinotecan).
2.2.1. FOLFIRI
FOLFIRI, a combination therapy consisting of levoleucovorin, 5-FU,
and irinotecan, is one of the current standard chemotherapy regimens
for advanced CRC. In the study by Tournigand et al, the objective re-
sponse rate obtained with FOLFIRI as the first-line therapy (consisting
of 200 mg/m2 l-LV or 400 mg/m2 dl-LV as a 2 h infusion, and 180 mg/
m2 irinotecan administered as a 90-minute infusion in 500 mL of 5%
dextrose, followed by 400 mg/m2 FU and a 46 -h infusion of 2400 mg/
m2 FU for two cycles, with the dose being increased to 3000 mg/m2
from cycle 3 in case of no toxicity, repeated every 2 weeks) was 56%.
Sastre J et al. have administered the FOLFIRI regimen to patients with
advanced CRC for whom treatment with 5-FU or FOLFOX (oxaliplatin
and fluorouracil plus formyltetrahydrofolate) had failed, and achieved
satisfactory results: 8.3% complete response rate, 20.8% partial effi-
ciency, and 29% objective efficiency [79]. The side effects of FOLFIRI
treatment mainly include mucositis, nausea, vomiting, and gastro-
intestinal toxicity [80]. Antibody-based drugs, including panitumumab
and bevacizumab, have been shown to effectively increase the safety
and efficacy of mCRC treatment when administered in combination
with FOLFIRI [81–83].

Table 1
Clinical anti-colorectal cancer natural products and derivatives.
Natural Products Source Chemical class Mechanism Phase NCT ID References

EGCG Plant Polyphenol Apoptosis Ⅱ 01360320 [162]

SN-38 Plant Alkaloid Anti-Proliferation Ⅱ 00311610 [44]
Resveratrol Plant Polyphenol Apoptosis, Anti-Proliferation Ⅰ 00256334 [163]
Curcumin Plant Polyphenol Apoptosis, Anti-Angiogenesis, Cell cycle arrest Ⅰ 00973869 [164]
PSK Fungi Polysaccharide Apoptosis, Anti-Proliferation Ⅲ 00497107 [49]
Topotecan Plant Alkaloid Anti-Proliferation Ⅱ 00193167 [165]
Metformin Plant Alkaloid Anti-Proliferation, Anti-Metastasis Ⅱ 01941953 [166]
Everolimus Bacterial Macrolide Anti-Angiogenesis, Anti-Metastasis Ⅱ 00419159 [167,168]
Methotrexate Plant Alkaloid Anti-Proliferation, Cell cycle arrest Ⅱ 00952016 [169]
Andrographolide Plant Diterpenoid Apoptosis, Anti-Proliferation, Cell cycle arrest Ⅱ 01993472 [170]
Irofulven Fungi Sesquiterpene Anti-Proliferation Ⅱ 00003786 [171,172]
Epothilone D Bacterial Macrolide Anti-Proliferation Ⅱ 00077259 [173]
Silymarin Plant Flavonoid Apoptosis, Anti-Proliferation Ⅳ 03130634 [174]
Berberine Plant Alkaloid Anti-Proliferation, Cell cycle arrest Ⅱ/Ⅲ 02226185 [175]
Mitomycin C Streptomyces Ethyleneimines Anti-Proliferation, Cell cycle arrest Ⅱ 03073694 [176]

EGCG: Epigallocatechin Gallate; PSK: Polysaccharide-K; DHA: docosahexaenoic acid; PUFAs: Polyunsaturated fatty acids.

3
X.-m. Huang, et al.
2.2.2. IROX
Oxaliplatin (OXA), a platinum-based drug, forms a cross-link with
DNA, thereby antagonizing its replication and transcription [84]. In
vitro studies have shown that OXA inhibits the growth of cisplatin- and
carboplatin-resistant colorectal tumor cell lines [85]. The efficacy of
IROX (irinotecan plus OXA) in the treatment of CRC has been supported
by numerous clinical phase I/II studies [86–89]. Haller et al. have de-
monstrated that IROX therapy (85 mg/m2 OXA, intravenous infusion
for 120 min, and 200 mg/m2 irinotecan, intravenous infusion for
30 min or 90 min every three weeks) is more effective than the therapy
with irinotecan alone after the failure of 5-FU therapy in advanced CRC
patients [90]. However, compared to the therapy with irinotecan alone,
IROX therapy resulted in a greater incidence of grade 3–4 diarrhea
(28% versus 23%) and severe neuropathy (5% versus 0%) [91]. The
incidence of vomiting, diarrhea, nausea, and febrile neutropenia has
been found to be significantly higher in patients treated with IROX than
in those treated with FOLFOX [92]. In general, IROX is preferred
whenever patients are insensitive to 5-FU, indicating that it is a suitable
second-line therapy for these advanced CRC patients.
2.2.3. XELIRI
Capecitabine, a highly active oral fluoropyrimidine, is an appealing
alternative to 5-FU in the treatment of CRC [93]. Compared with 5-FU/
LV, capecitabine has a higher response rate and better safety [94,95].
Recent clinical trials have shown that the XELIRI regimen (capecitabine
plus irinotecan), as a second-line treatment, exhibited definite efficacy
and safety for the treatment of patients with advanced CRC [96,97]. In
2018, Xu et al. performed a clinical phase III trial involving a modified
XELIRI (mXELIRI)-AXEPT regimen (NCT01996306) [98]. Compared to
FOLFIRI, mXELIRI (200 mg/m2 irinotecan administered intravenously
on day 1, plus 800 mg/m2 capecitabine administered orally twice daily
on days 1–14, repeated every 21 days) has been reported to show highly
satisfactory results: the survival time median of patients in the mXELIRI
group was 16.8 months and that of those in the FOLFIRI group was 15.4
months, with a lower probability of neutropenia; this indicates that
mXELIRI can be used as a potential substitute for FOLFIRI, and as the
standard second-line therapy for mCRC, thus providing a new option
for the treatment of mCRC patients [98].
3. Mechanisms underlying the action of potential natural product-
based drugs against CRC
In this part of the review, we summarize the most recent and closely
related natural products potentially used for CRC treatment. Many
studies have indicated that natural product-derived drugs can exert
anticancer effects by acting on metastasis, invasion, apoptosis, and
angiogenesis, which are the major hallmarks in human cancers
[99–102]. In recent years, drugs derived from natural products have
been widely used for cancer treatment due to their wide range of
sources, better bioactivities, and low toxicity. Here, we generalize the
potential functions of natural products showing anti-CRC effects and
provide a mechanism-based foundation for the development of natural
product-derived drugs against CRC (Fig. 2).
3.1. Proliferation-based regulation
The cell cycle is tightly controlled by checkpoints to ensure that
cells replicate in sequential and correctly oriented steps; the dysregu-
lation of the cell cycle can cause the abnormal proliferation of cancer
cells. Many natural products have been shown to inhibit cancer cell
proliferation by controlling mitosis and the cell cycle, and are thus,
important potential replacements for chemotherapeutic drugs [103].
Methylferulate, which is extracted from Tamarix aucheriana, has
been confirmed to upregulate the expression of p19, p21, and p27 and
downregulate the levels of CDK1 and CDK2, leading to the induction of
S and G2/M phase arrest in SW1116 and SW837 cells. Moreover, the
4
Biomedicine & Pharmacotherapy 117 (2019) 109142
induction of apoptosis and inhibition of cell invasion have been ob-
served following methylferulate treatment [104]. Sulforaphane, an
isothiocyanate, has been found to induce G2/M phase arrest in HCT116
CRC cells by increasing the expression levels of WEE1, CDK2, cyclin A,
and cyclin B, while decreasing the levels of cdc25C and CDK1 [105].
Tripolinolate A, a novel compound isolated from Tripolium vulgare, has
been confirmed to induce apoptosis and G2/M phase arrest in SW620
cells, and inhibit tumor growth in animal models [106].
Lawsonaringenin, a flavonoid extracted from the leaves of Lawsonia
alba Lam, has been shown to trigger S phase arrest and apoptosis via
multiple pathways [107]. Another study has shown that Ent-kaur-2-
one-16β, 17-dihydroxy-acetone-ketal (DEK), a novel ent-kaurane di-
terpenoid isolated from Rubus corchorifolius L. f. leaves, can result in S
phase arrest by decreasing the CDK2, CDK4, and cyclin D1 levels in
HCT116 cells [108]. The extract of Iberis amara (IAE) has been shown to
exhibit an ability to inhibit cell growth and induce G2/M phase arrest in
HT-29 cells by decreasing the levels of regulatory proteins, such as
cyclin A2, cyclin D3, CDK2, CDK4, and CDK6 [109]. Other natural
compounds that exert similar effects are shown in Table 2.
Since combination therapy is a strategy to overcome chemother-
apeutic resistance for CRC treatment, many studies focused on finding
natural drugs for adjuvant therapy are being performed. OXA, a third-
generation platinum agent, has been used to treat CRC in recent dec-
ades and has been used in combination with leucovorin and 5-FU
[110–112]. However, resistance to OXA has been eventually reported in
the treatment of mCRC [113,114]. A previous study has shown that co-
treatment with oxymatrine (OMT) and OXA induced G0/G1 phase ar-
rest via the upregulation of p27 and p21, and the downregulation of
cyclin D; thus, OMT and OXA were combined to explore the efficiency
of this combination therapy for treating colon cancer [115].
3.2. Migration- and invasion-based regulation
Metastasis is one of the most serious features of cancer, and it de-
termines the prognosis and clinical stage of the disease [116]. The
process of metastasis comprises multiple steps, involving adhesion,
migration, invasion of cancer cells, and degradation of the extracellular
matrix (ECM) surrounding the target organ [117]. Epithelial-me-
senchymal transition (EMT) usually occurs during the progression of
various epithelial cell carcinomas and is closely related to the invasion
and metastasis of various tumors including CRC [118]. The activation
of signaling pathways, such as the TGF-β/Smad and JAK2/STAT3
pathways, plays a key role during the growth, progression, and me-
tastasis of a tumor [119–121]. Recently, many experimental studies
have shown that natural products can exert an anti-cancer activity
against the metastasis and invasion of CRC (Table 3).
α-Hederin, which is extracted from the leaves of Hedera helix, is a
monodesmosidic triterpenoid saponin that can suppress the IL-6-in-
duced EMT associated with the disruption of JAK2/STAT3 signaling, to
inhibit the migration and invasion of SW620 cells [122]. Zerumbone, a
cyclic sesquiterpene from Zingiber zerumbet, has the ability to suppress
the migration of, and trigger cell cycle arrest and apoptosis in, SW480
cells [123]. Tea polysaccharide (TPS), which is the major bioactive
component in green tea, has been found to inhibit cancer cell pro-
liferation and invasion, and increase cancer cell apoptosis partially via
the reduction of the expression of cyclin D1, MMP-2, and MMP-9 both
in vitro and in vivo [124]. Curcumin, which is isolated from turmeric,
has been shown to suppress metastasis and tumor growth in case of
both CRC cells and an orthotopic mouse model by regulating signaling
pathways, including the STAT3, FAK/Src, ErK, and Akt pathways,
suggesting its promising use for treating mCRC patients [125].
3.3. Apoptosis-based regulation
Apoptosis is mainly grouped into two pathways: the intrinsic and
the extrinsic pathway. The intrinsic pathway (mitochondrial pathway)
X.-m. Huang, et al. Biomedicine & Pharmacotherapy 117 (2019) 109142

Fig. 2. The experiment-based molecular me-

chanisms and regulation networks of natural
products in colorectal cancer. Natural products
are numbered in the white boxes and listed on
the right of the figure. Natural products from
different sources exert anti-colorectal cancer
effects on apoptosis, proliferation, metastasis,
autophagy and angiogenesis by regulating
various proteins and pathways.

Table 2
Natural products with anti-proliferative effect on colorectal cancer cells.
Compound Source Cell line Mechanism Cell cycle References
phase

Lawsonaringenin Plant HT-29 Downregulate β-catenin and c-Myc S [107]

Ribonucleic acid fraction Fungus HT-29 Increase p21 and p27, decrease Cyclin D1 and Cyclin A S [177]
Ent-kaur-2-one-16β,17-dihydroxy-acetone- Plant HCT116 Increase p21, decrease Cyclin D, CDK2 and CDK4 S [108]
ketal
Tripolinolate A Plant SW620 – G2/M [106]
Extracts of Iberis amara Plant HT-29 Decrease Cyclin A2, Cyclin D3, CDK2, CDK4 and CDK6 G2/M [108]
Kahweol Plant HCT116, SW480 Decrease Cyclin D1 – [178]
Indigocarpan Plant LS174T Increase p21, decrease Cyclin B1 and Cyclin D1 G2/M [179]
Sulforaphane Plant HCT116 Increase CDK1, CDK2, Cyclin B and WEE1, decrease cdc 25C and G2/M [105]
Cyclin A
Methylferulate Plant SW1116, SW837 Increase p19 and p27, decrease CDK1 and CDK2 S and G2/M [104]
Yuanhuacine Plant HCT116 Increase p21 G2/M [180]

can trigger the caspase cascade and leads to apoptosis via the release of
cytochrome C [126]. The extrinsic pathway initiates the activation of
apoptosis by triggering cell death receptors (DRs), such as FasL/CD95 L
and TRAIL, on the cell surface [127,128].
Previous literature has suggested that many natural products exert
an anticancer effect that is mediated by the intrinsic apoptotic pathway
(Table 4). Natural products induce apoptosis mainly by inducing the
generation of ROS, decreasing the mitochondrial membrane potential
and the Bcl2/Bax ratio, and activating the related caspase proteins,
which ultimately results in DNA fragmentation and apoptosis. Alkyl-
resorcinols (ARs) that were isolated from wheat bran have been found
to induce cell cycle arrest and mitochondrial apoptosis by activating
and accumulating p53. AR C15 and AR C17 have been found to
downregulate the levels of Bcl2 and XIAP, and upregulate the levels of
pro-apoptotic factors including cytochrome C, caspase 3/9, and PUMA
in both HCT116 and HT-29 cells [129]. Quercetrin from Toona sinensis
leaves (QTL) has been found to promote apoptosis by upregulating
cytochrome C, Bax, Apaf-1, caspase-3, and caspase-9. In addition, QTL
has also been shown to trigger ROS generation and induce the loss of
mitochondrial membrane potential in the human CRC cell line SW620
[130]. Cardol, which is a major bioactive compound isolated from
Trigona incisa propolis, can activate caspase-3, caspase-9, and PARP,
and induce ROS generation in SW620 cells [131]. Additionally, 6-bro-
moisatin, which was isolated and identified from an Australian marine
gastropod, Dicathais orbita, has been shown to induce apoptosis by in-
creasing the expression of caspase-3 and -7 in both HT-29 and Caco-2

Table 3
Natural products with anti-migration and anti-invasion effects on colorectal cancer cells.
Compound Source Cell line Mechanism References

α-Hederin Plant SW620 Suppress EMT and JAK2/STAT3 [122]

Zerumbone Plant SW480 – [123]
Tea Polysaccharide Plant CT26(mouse) Decrease Cyclin D1, MMP-2 and MMP-9 [124]
Curcumin Plant Colon 26-M01 Inhibit FAK/Src, STAT3, Erk and Akt pathways [125]
Esculetin Plant HCT116 Target Axin2/Ecadherin axis [181]
Polysaccharides Plant Colon 26-M3.1 – [182]
Luteolin Plant HCT116 Inhibit CREB1 and block EMT [183]
Cairicoside E Plant SW480, HCT116 Inhibit the EMT through down-regulation of AQP5 and suppression of p-Smad2/3 [184]
Resveratrol Plant HCT116, SW480 Inhibit FAK activity [185]
Ganoderma lucidum polysaccharides Plant LoVo – [186]
Gypenosides Plant SW620 – [187]
Gypenosides Plant SW480 – [188]

5
 X.-m. Huang, et al.

Table 4
Natural products inducing apoptosis in colorectal cancer cells.
Compound Source Cell line Mechanism References

Zerumbone Plant SW480 Induce ROS, activate caspase-3/8/9 and downgregulate Bcl2 [123]
Alkylresorcinols Plant HCT116, HT-29 Decrease Bcl2 and XIAP, increase PUMA, cytochrome C, cleaved caspase-9 and -3 [129]
Quercetrin Plant SW620 Upregulate Bax, caspase-9, caspase-3 and Apaf-1 [130]
Pteisolic acid G Plant HCT116 Downregualte NF-κB p65 activity, stimulate p53 and promote ROS production [135]
Oblongifolin C and guttiferone K Plant HCT116 Increase cleavage of caspase-3, PARP and JNK phosphorylation and enhance cellular ROS production [189]
Cardol Plant SW620 Increase caspase-3, caspase-9, cleavage of pro-caspase-3 and pro-caspase-9, PARP and ROS [131]
Cuminaldehyde Plant COLO 205 Activate caspase-3 and -9 [190]
BG-4 Plant HCT116, HT-29 Reduce Bcl-2, increase Bax and caspase-3 [191]
Deoxyelephantopin Plant HCT116 Activate caspase-3 and PARP cleavage [192]
Isoledene Plant HCT116 Increase ROS, caspase-8, -9 and -3, upregulate Bid, Bim and cytochrome C, downregulate Bcl-2, Bcl-W, survivn, [193]
xlAP and HSPs pro-survival proteins

6
Gambogic acid Plant HCT-15 Activation of JNK signaling pathway [194]
Hederagenin Plant LoVo Increase ROS, up regulate Bax and decrease Bcl-2, Bcl-xL, procaspase-9, procaspase-3, PARP and survivin [195]
Goniothalamin Plant LoVo Increase death receptor DR5, decrease cFLIP, cleavage of PARP, caspase-3, caspase-8, caspase-9, Bid, Bax and [142]
Bcl2
Procyanidins Plant SW480 –TRAIL-sensitive and SW620- Activate caspase-8 [139]
TRAIL -resistant
Oplopantriol A Plant HCT116, SW480 Up regulate TNFRSF10A, TNF, TNFSF8, CRADD, FADD, TRADD, caspase-3, -7 and -8 [140]
Maslinic Acid Plant Caco-2 p53-Deficient cells Activate caspase-3 and caspase-8 [196]
Calotroposid A Plant WiDr cells Increase caspase-8 [141]
Propolis cinnamic acid derivatives Plant DLD-1 Regulate TRAIL/DR4/5 and/or FasL/Fas death-signaling loops and increase miR-143 [197]
Mertensene Plant HT29 Activate caspase-3 and PARP cleavage and increase TRADD [143]
2-(Pro-1-ynyl)-5-(5,6-dihydroxypenta-1,3diynyl) Plant SW620 ROS-Mediated JNK Activation [133]
Thiophene
Riccardin D Plant HT-29 Upregulate cleaved caspase-3, -9 and the ratio of Bax/Bcl-2, block the NF-κB signaling pathway [134]
Icariin Plant HCT116, HT-29 Suppress the NF-κB activity [198]
Oxymatrine Plant HT-29, SW480 Activate PI3K/AKT/mTOR pathway [115]
Biomedicine & Pharmacotherapy 117 (2019) 109142
X.-m. Huang, et al. Biomedicine & Pharmacotherapy 117 (2019) 109142

Table 5
Natural products regulating autophagy on colorectal cancer cells.
Compound Source Cell line Mechanism References

Thymoquinone Plant Irinotecan-resistant (CPT-11-R) LoVo colon cancer cell line Activate JNK and P38 and MOMP [150]
Peiminine Plant HCT116 Repress the phosphorylation of mTOR [149]
Tanshinones Plant multidrug-resistant colon cancer cells SW620 Ad300 Induce LC3B-Ⅱaccumulation [151]
Epigallocatechin gallate Plant DLD-1 and HT-29 Induce LC3-Ⅱaccumulation [199]
Cardamonin Plant HCT116 Increase p53/JNK [152]
Isothiocyanates Plant CoLo 205 Decrease the phosphorylation of Akt and mTOR [200]
Salvianolic Acid B Plant HCT116 and HT-29 Suppress Akt/mTOR pathway [153]

Table 6
Basic information for marine-derived anti-colorectal cancer natural products.
Natural products Marine organism Chemical class Mechanism Cancer type/cell lines References

Axidjiferosides Axinyssa djiferi β-Galactosylceramide Anti-Angiogenesis, Anti-Proliferation HCT116 [201]

Calothrixins Calothrix sp. Quinonoid Anti-Proliferation HCT116 [202]
Hierridin B Cyanobium sp. Ketone Apoptosis HT-29, HCT116 [203]
Violaxanthin Chlorella ellipsoidea Carotenoid Anti-Proliferation HCT116 [204]
Fucoxanthin Undaria pinnatifida Carotenoid Apoptosis CaCo-2, HT-29, DLD-1 [205]
Astaxanthin Haematococcus pluvialis Terpene Apoptosis, Anti-Proliferation, Cell cycle arrest HCT116 [206]
Salternamide A Streptomyces sp. Alkaloid Cell cycle arrest HCT116 [207]
Milnamide D Cymbastela sp. Peptide Unknown HCT116 [208]
Monactin Streptomyces sp. Macrolide Unknown HCT116 [209]
6-Bromoisatin Dicathais orbita Isatin Apoptosis, Anti-Proliferation HT-29 [210]
Nortopsentin Spongosorites ruetzleri Alkaloid Anti-Proliferation, Cell cycle arrest HCT116 [211]
Peridinin Gonyaulax polyedra Carotenoids Apoptosis, Cell cycle arrest DLD-1 [212]
Stichoposide C Thelenota anax Triterpene glycosides Apoptosis, Anti-Proliferation SNU-C4, HT-29, CT-26 [213]
Caulerpin Caulerpa cylindracea Alkaloid Anti-Proliferation HCT-116, HT-29 [214]
Phorbaketals Phorbas sp. Hydrobenzopyran unknown HT-29 [215]
Sipholenone A Siphonochalina sp. Triterpenoid Cell cycle arrest CaCo-2, HT-29 [216]
Sipholenol A Siphonochalina sp. Triterpenoid Anti-Proliferation, Cell cycle arrest CaCo-2, HT-29 [216]
Sipholenol L Siphonochalina sp. Triterpenoid Anti-Proliferation, Cell cycle arrest HT-29 [216]
Candidaspongiolide Candidaspongia sp. Polyketide Apoptosis HCT116 [217]
Physcion Penicillium janthinellum Anthraquinone Apoptosis HCT116 [218]
Gliotoxin Neosartorya pseufofischeri Epipolythiodioxopiperazine Apoptosis, Anti-Proliferation HCT116 [219]
Caldoramide Caldora penicillata Pentapeptide unknown HCT116 [220]
Renieramycin M Xestospongia sp. Tetrahydroisoquinoline Apoptosis HCT116 [221]
Manzamine A Acanthostrongylophora sp. Alkaloid Apoptosis HCT116 [222]

cells [132]. 2-(Pro-1-ynyl)-5-(5,6-dihydroxypenta-1,3diynyl) thiophene
(PYDDT), a thiophene isolated from the roots of Echinops grijsii, has
been found to induce mitochondrial-mediated apoptosis by regulating
the levels of the related proteins, producing ROS, and activating ERK1/
2 and JNK in SW460 CRC cells [133]. A novel compound extracted from
the Chinese liverwort plant, Riccardin D, has been found to suppress the
proliferation of HT-29 cells and induce their apoptosis via the NF-κB
signaling pathway [134]. Pteisolic acid G, which is a novel ent-kaurane
diterpenoid isolated from Pteris semipinnata, has not only been found to
inhibit the viability of HCT116 cancer cells, but also induce apoptosis
via the generation of intracellular ROS, stimulation of p53, and
downregulation of NF-κB p65 activity [135]. The PI3K/Akt/mTOR
signaling pathway is an important pathway; its dysregulation has been
reported to be associated with the proliferation, survival, metabolism,
and drug resistance of CRC cells [136–138]. It has been confirmed that
OMT and OXA are not only able to inhibit the proliferation of CRC cells
and lead to cell cycle arrest, as mentioned above, but are also able to
induce apoptosis via the PI3K/Akt/mTOR pathway [115].
There are many natural products that exert anticancer effects
mediated by the extrinsic apoptotic pathway (Table 4). Proanthocya-
nidins (Pcys) extracted from 11 berry species have been shown to
trigger the extrinsic apoptosis pathway by activating caspase-8 in
SW620-TRAIL-resistant and SW480-TRAIL-sensitive CRC cells, which
illustrate its potential to serve as an alternative to chemotherapeutic
agents for CRC treatment [139]. Oplopantriol A, which is a compound
isolated from Oplopanax horridus, has been shown to induce apoptosis
by the regulation of the related genes and TNF-mediated cell death
pathways, including the TNF, FADD, TRADD, and caspase-3, -7, and -8
signaling pathways [140]. Calotroposid A, which was isolated from
Calotropis gigantean and determined to be a terpenoid glycoside, has
been found to trigger the extrinsic apoptosis pathway by increasing the
caspase-8 expression in WiDr colon cancer cells [141].
In addition, some natural products can trigger apoptosis via both the
intrinsic and extrinsic pathways (Table 4). Zerumbone, a cyclic ses-
quiterpene from Zingiber zerumbet, can suppress cell growth and en-
hance cell apoptosis via the induction of ROS and activation of caspase-
3, -8, and -9 [123]. Goniothalamin, a major bioactive styryl-lactone
compound that is present in plants, has been found to increase the DR5
expression and reduce cFILP expression, thereby enhancing TRAIL-in-
duced apoptosis in CRC LoVo cells. Moreover, the activation of apop-
tosis pathways, including the caspase-8, Bid-mediated death receptor
apoptosis pathway and the caspase-9, Bcl-2, Bax-mediated mitochon-
drial apoptosis pathway, has been verified to promote apoptosis via the
extrinsic and intrinsic pathways [142]. Mertensene, which is isolated
from the red alga Pterocladiella capillacea, has been demonstrated to
trigger apoptosis by regulating the expression of caspases, PARP, and
TRADD in HT-29 and LS174 cells [143].
3.4. Autophagy-based regulation
Autophagy, which is also known as type II programmed cell death,
is a conserved catabolic process to eliminate excess long-lived proteins,
damaged organelles, and invasive pathogens mediated by autophago-
somes [144,145]. Autophagy can be activated in response to various
cellular stresses, including hypoxia, endoplasmic reticulum stress, ac-
cumulation of ROS, and drug stimulation [146–149]. Here, we

7
X.-m. Huang, et al.
summarize some natural products that regulate the process of autop-
hagy in CRC (Table 5).
Peiminine, which is extracted from Fritillaria thunbergii, can enhance
the autophagic flux by inhibiting the phosphorylation of mTOR in
HCT116 cells [149]. Thymoquinone, a phytochemical from Nigella sa-
tiva, has been shown to cause caspase-independent autophagic cell
death via mitochondrial dysfunction and activate p38 and JNK in ir-
inotecan-resistant LoVo colon cancer cells, thereby exerting an anti-
cancer function [150]. Hu et al. have confirmed that cryptotanshinone
(CTS) and dihydrotanshinone (DTS), which were isolated from the
traditional Chinese medicine Salvia miltiorrhiza, had the ability to in-
duce autophagic cell death in apoptosis-resistant colon cancer cells
[151]. Cardamonin, which was isolated from Alpinia katsumadai
Hayata, has been shown to not only suppress the proliferation of, and
cause G2/M phase arrest in, HCT116 cells, but also induce autophagy in
these cells through the activation of p53/JNK [152]. Salvianolic acid B
(Sal B), isolated from the Chinese herb Salvia miltiorrhiza, has been
found to trigger autophagy via the suppression of the Akt/mTOR
pathway in HT-29 and HCT116 cells [153]. Coroglaucigenin, which is a
natural product extracted from the roots of Calotropis gigantean, disrupts
the association of Hsp90 with Akt and CDK4, leading to Akt depho-
sphorylation and CDK4 degradation, finally resulting in senescence and
autophagy [154].
3.5. Angiogenesis-based regulation
Tumor growth and metastasis are inseparable from cell migration,
invasion, and angiogenesis. Angiogenesis is a normal physiological
process that provides oxygen and nutrients to tissues and involves en-
dothelial cell migration and morphogenesis during neovascularization
[155]. During the process of angiogenesis, VEGF and its receptor play
essential roles, and extracellular factors, such as interleukin-8 (IL-8),
tumor necrosis factor (TNF), and platelet-derived growth factor (PDGF),
are also involved in the process of angiogenesis [156,157]. Conferone,
an active compound isolated from plants in the genus Ferula, has been
shown to inhibit the angiogenic ability of HT-29 cells by regulating the
expression of VEGF and the growth factors angiopoietin-1 and -2.
Moreover, its ability to suppress the migration of HT-29 cells has also
been reported [158].
4. Conclusions and prospects
Natural products have been confirmed to exert undoubted ad-
vantages and have potential use for cancer treatment. In this review, we
summarized the recently explored natural products that have been used
or have great potential for use in the treatment of CRC, and we have
presented experiment-based molecular mechanisms and regulatory
networks whereby natural products exert effects on the proliferation,
metastasis, apoptosis, autophagy, and angiogenesis in CRC.
Drug resistance and side effects remain the major problems asso-
ciated with CRC treatment. Some natural products have been combined
with classical chemotherapeutic agents, such as 5-FU, to enhance the
susceptibility of the cancer cells to conventional therapy, finally re-
inforcing the combined effect; this represents a new strategy for the
treatment of CRC. However, with the identification of more natural
products, it has become very difficult to isolate novel active substances
based on the discovery of traditional natural products from terrestrial
animals, plants, or microorganisms. In particular, an increasing number
of known natural products have been repeatedly identified; this ser-
iously interferes with the discovery of novel compounds. Thus, the
discovery of new structural compounds remains a major challenge.
Marine environments are a new resource that comprise a diversity
of marine life; several organisms from marine environments have been
reported to produce novel secondary metabolites [159]. Marine-derived
natural products have attracted a great amount of interest due to their
novel structures, diverse bioactivities, and new mechanisms of action;
8
Biomedicine & Pharmacotherapy 117 (2019) 109142
therefore, they have become a treasure of lead compounds for the de-
velopment of new drugs. Many anti-tumor compounds, including pep-
tides, macrolides, alkaloids, and polyphenols, derived from marine or-
ganisms have entered the preclinical and clinical research stages
[30,160,161], highlighting that natural products from marine organ-
isms are a constant source of new drugs against cancers including CRC
(Table 6). In recent years, MPE has been used to elucidate the etiology
of diseases at the molecular, individual, and population levels, pro-
viding a more comprehensive understanding of CRC prevention and
treatment. With the development of precision medicine, the combina-
tion of pharmacoepidemiology and MPE can make drugs safer and more
effective in clinical treatment. Furthermore, advanced applications in-
volving genome mining, combinatorial biosynthesis, molecular mod-
ification, and the high-throughput screening (HTS) technology will
provide strong supports for the development of novel promising and
effective anti-CRC drugs and CRC treatment strategies.
Funding
This work was supported by the National Natural Science
Foundation of China (31870046 and 81741166), the Natural Science
Foundation of Guangdong Province (2016A030312014,
2018A0303130005 and 2015A03313528), the Special Support
Program for Training High-Level Talents in Guangdong (201528018)
and Fund of the School of Laboratory Medicine of Guangdong Medical
University.
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