Evidence-Based Complementary and Alternative Medicine
Volume 2018 (2018), Article ID 9186926, 15 pages
https://doi.org/10.1155/2018/9186926

Review Article

Oplopanax horridus: Phytochemistry and Pharmacological Diversity and Structure-Activity Relationship on Anticancer Effects

Kai Wu,¹ Chong-Zhi Wang,² Chun-Su Yuan,² and Wei-Hua Huang2,3

¹Department of Physiatry, Xiangya Hospital, Central South University, Changsha 410008, China
²Tang Center for Herbal Medicine Research, The Pritzker School of Medicine, University of Chicago; 5841 South Maryland Avenue, MC 4028, Chicago, IL 60637, USA
³Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, China

Correspondence should be addressed to Wei-Hua Huang; endeavour34852@126.com

Received 23 June 2018; Accepted 29 August 2018; Published 13 September 2018

Academic Editor: Yoshiyuki Kimura

Copyright © 2018 Kai Wu et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract.

Oplopanax horridus, well-known as Devil’s club, is probably the most important ethnobotanical to most indigenous people living in the Pacific Northwest of North America. Compared with the long history of traditional use and widespread distribution in North America, the study of O. horridus is relatively limited. In the past decade, some exciting advances have been presented on the phytochemistry and pharmacological diversity and structure-activity relationship on anticancer effects of O. horridus. To date, no systematic review has been drafted on the recent advances of O. horridus. In this review, the different phytochemicals in O. horridus are compiled, including purified compounds and volatile components. Animal and in vitro studies are also described and discussed. Especially, the potential structural-activity relationship of polyynes on anticancer effects is highlighted. This review aimed to provide comprehensive and useful information for researching O. horridus and finding potential agents in drug discovery.

1. Introduction

Oplopanax horridus (Sm.) Torr. & A. Gray ex Miq., well-known as Devil’s club, an ethnobotanical, exclusively originates and is distributed in northwestern North America. This understory shrub forming larger populations through layering usually grows in moist, well-drained, dense, and old-growth forests [1]. This herbal plant belongs to the genus Oplopanax, which only consists of three species, the remaining of which are O. japonicus Nakai and O. elatus (Nakai) Nakai [2]. O. elatus is mainly distributed in the temperate regions of Northern China, the south of Primorye, northern part of the Korean Peninsula, and Russia [3], while O. japonicus is endemic to central Japan [4]. The genus Oplopanax is classified to the Araliaceae family, which comprises some world-known botanicals such as Panax ginseng (Asian ginseng, Chinese or Korean ginseng), P. quinquefolius (American ginseng), and P. notoginseng (Sanqi) [5–8]. Occasionally, O. horridus is sometimes marketed as “wild armored Alaskan ginseng,” “Alaskan ginseng,” or “Pacific ginseng”, but the marketing is now forbidden in the United States due to the misleading [2]. Such marketing relies on the presumable speculation that O. horridus share similar chemical ingredients with the herbs in Panax, but the presumption is not supported by related phytochemical investigation [4].

O. horridus has a long history of use for 34 different medical ailments by the Pacific indigenous peoples from over 38 linguistic groups [7]. The extracts of Devil’s club are marketed in North America for respiratory stimulant and expectorant, rheumatoid arthritis, autoimmune conditions, eczema, type II diabetes, external infections, and internal infections [7]. The Pacific native tribes also use O. horridus for spiritual stimulant, while Shaman use it in their religion ceremonial practices. Table 1 summarizes that different part of O. horridus is used for many various ailments by the indigenous people. It implies that the main phytochemicals in different parts of O. horridus are significantly varied.

Table 1: The uses of O. horridus for various treatments.

Part of O. horridus
Application
Preparation
References

Inner barks
Respiratory, cardiovascular, gastrointestinal, cold or infection, diabetes, arthritis, and cancer
Decoction; infusion
[2, 7, 92]

Stems
Respiratory
Decoction
[2, 7, 93]

Roots
Respiratory, diabetes, and arthritis
Decoction; infusion
[2, 4, 94]

Berries
Gastrointestinal
Paste
[7, 19]

Leaves
Arthritis
Decoction; infusion
[7, 29]

Recently, pharmacological studies showed that O. horridus possessed anticancer, antibacterial, antidiabetes, antipsoriasis, antiarthritis, and antifungal and anticonvulsant activities [2]. In the past five years, most of animal and in vitro studies on O. horridus focused on its anticancer effects. At the same time, extensive investigation on the chemical constituents of O. horridus has led to the isolation and identification of compounds 1-47, which include polyynes (polyacetylenes), phenylpropanoids (aglycones and glycosides), lignan glycosides, triterpenoids, sesquiterpenes, and some other compounds. Additionally, forty-eight volatile compounds were identified from the volatile oil by GC/MS. Among these components, polyynes, e.g., falcarindiol (FAD), and oplopantriol A (OPT), have been mostly reported as potentially anticancer natural products from O. horridus.

In the past decade, some exciting advances have been presented on the phytochemistry, pharmacological diversity, and structure-activity relationship on anticancer effects of O. horridus. To date, no systematic review has been drafted on the recent advances of O. horridus. In this review, the different phytochemicals in O. horridus are compiled, including purified compounds and volatile components. Animal and in vitro studies are also described and discussed. Especially, the potential structural-activity relationship of polyynes on anticancer effects is highlighted. This review aimed to provide comprehensive and useful information for researching O. horridus and finding potential agents in drug discovery.

2. Ethnobotanical and Ethnopharmacology

O. horridus is distributed from Alaska along the Pacific Coast down to Oregon, Idaho, and Montana in the south and east to the southwestern Yukon Territory, while some isolated populations grow around Michigan and the islands in Lake Superior (Figure 1) [7, 9]. O. horridus generally is from 1 to 1.5 m tall, while it can grow to 3 to 5 m in some undisturbed moist rainforest. The spines appear around the stems and along the upper and lower surfaces of its leaves, which are palmately lobed with 5-13 lobes, 20 to 40 cm across, and are spirally located on the stems (up to 3 cm diameter). The flowers are blooming in dense umbels from 10 to 20 cm diameter with five greenish-white petals. The fruit is a small red drupe with 4 to 7 mm diameter. The root without spines is similar to the stem [9]. The plant grows and reproduces slowly and take many years to reach seed bearing maturity, and it is very sensitive to human impact [10].

Figure 1: Geographic distribution of O. horridus.

O. horridus has been used for both spiritual and medical practices by the native tribes of Alaska and British Columbia for centuries. Traditionally, the native tribes drink the aqueous decoction of the root or stem bark of O. horridus for the treatments of colds, fever, burns, stomach trouble, body pains, sore throats, swollen glands, constipation, and tuberculosis [11]. The inner bark of the root and stem has been used to stop infection on wounds and reduce swelling [12]. The Alaska Natives from the Alaskan southeast coast, Cook Inlet, Kodiak, Kenai, Prince William Sound, and Tanana Valley use the inner bark of the root and stem to treat colds, cough, and fever [13]. The traditional preparations of O. horridus include either applying the heated inner bark to the wounded area and bandaging it or chewing the root or stem bark and spitting the crude herb on the wound as an emergency analgesic and antiseptic [10]. The infusion of inner bark of O. horridus was described as a possible treatment for cancer by indigenous peoples in North America [7]. Although formal documentation of its traditional use for cancer is lacking, O. horridus extracts and its compounds exhibited the anticancer activities in preclinical investigations [2, 4].

3. Phytochemistry

The main chemical constituents of O. horridus are polyynes (polyacetylenes), phenylpropanoids (aglycones and glycosides), lignan glycosides, triterpenoids, sesquiterpenes, and volatile compounds [4]. Within the different structural skeletons of these groups, a variety of analogues are presented in the aerial and underground parts of the botanical. Generally, the secondary metabolites in O. horridus are consistent with the patterns of chemical constituents from the genus Oplopanax and the family Araliaceae. Polyynes have been mostly reported with high contents in both the stem and the root of O. horridus as potential anticancer and antimycobacterial (antituberculosis) natural products. Due to the limited number of analytical chemistry investigations that have been done, only six polyynes have thus far been quantified in the root of O. horridus [14, 15]. Phenylpropanoids and lignan glycosides are the other two main natural products from the genus Oplopanax. Sesquiterpenes and volatile compounds have also been extracted from the root of this herb. For this species, the chemical profile of the polyynes of the root may be useful for herbal identification since they are very different from the other species in this genus, O. japonicus and O. elatus.

3.1. Polyynes (Polyacetylenes)

Polyynes, also known as polyacetylenes, possess a long chain of carbon atoms with alternating double and triple bonds between them, which occur in natural products containing more than two acetylene groups. Meanwhile, polyynes comprising two to four acetylene groups are usually found in higher plants, most of which contain conjugated diyne in the highly unsaturated lipid chains [16]. These highly unsaturated hydrophobic compounds are generated in the Araliaceae family, which have a high concentration in the roots and a small content in the stem barks. The polyynes which are unstable and oxidized in dried plant material, contain seventeen or eighteen carbons (C17 or C18) in the skeleton chain, and are mostly found in the Araliaceae.

To date, seven polyynes have been purified and identified from the root bark of O. horridus, five of which are also discovered from the stem bark of O. horridus [17, 18]. The identified C17 and C18 polyynes from O. horridus, 1–7, are oplopantriol A, oplopantriol B, (11S, 16S, 9Z)-9,17-octadecadiene-12,14-diyne-1,11,16-triol,1-acetate, oplopandiol acetate, falcarindiol, falcarinol, and oplopandiol (Figure 2). Polyyne has not been reported to be found in the follower, berry, leaves, and seeds of O. horridus. For analytical investigation of polyynes in O. horridus, an HPLC fingerprint method was developed to evaluate the stem and berry extracts of O. horridus, which showed that polyynes are not major components in the stem and berries of O. horridus [19]. For the quantification of polyynes in O. horridus, an online solid-phase extraction HPLC (SPE-HPLC) and a modified reversed migration microemulsion electrokinetic chromatography were validated to quantify polyynes and one polyene in O. horridus [14, 15]. The contents of polyynes in the root bark of O. horridus range from 0.029% to 0.15% (1), 0.025% to 0.13% (2), 0.077% to 0.31% (3), 0.24% to 0.43% (4), 0.26% to 0.67% (5), and 0.26% to 0.67% (6), respectively.

Figure 2: Polyynes of O. horridus.

Although no evidence is found that O. horridus is used to cure cancer in North America in the long history, the extracts and polyynes from O. horridus exhibited their anticancer activities in recent pharmacological research. The extracts mainly containing polyynes from O. horridus root bark showed effective in the inhibition of the proliferation of several ovarian, breast, lung, and colorectal cancer cell lines [20, 21]. The mechanisms of polyynes on anticancer activities are still not well known. To the tested polyynes, Falcarindiol and Oplopantriol A showed the strongest inhibition on the growth of all the examined cancer cell lines [22, 23].

3.2. Phenylpropanoids (Aglycones and Glycosides)

Phenylpropanoids are metabolized by plants from the amino acids phenylalanine and tyrosine. The basic chemical structure of phenylpropanoid consists of the aromatic phenyl group and the three-carbon propene tail of cinnamic acid. Phenylpropanoids are found commonly in the plant kingdom, where they play a vital role as essential components in biosynthesizing polymers, providing protection from ultraviolet light, defending against herbivores and pathogens, and mediating plant-pollinator interactions. Phenylpropanoids including aglycones and glycosides were also obtained from O. horridus [24]. As phenolic compounds, phenylpropanoids and their derivatives were synthesized into thousands of different chemical structures including aromatic rings in several species in the Araliaceae family.

The phenylpropanoids from the root bark of O. horridus were isolated and purified by various chromatographic techniques including silica gel, reverse phase silica gel, sephadex LH-20, and pre-HPLC and identified by their physicochemical properties and spectral data. The phenylpropanoids are obtained and identified from the root bark of O. horridus include ferulic acid (8), 3-acetylcaffeic acid (9), caffeic acid (10), homovanillyl alcohol 4-O-beta-D-glucopyranoside (11), 3-hydroxyphenethyl alcohol 4-O-beta-D-glucopyranoside (12), 3, 5-dimethoxycinnamyl alcohol 4-O-beta-D-glucopyranoside (13), 3, 5-dimethoxycinnamyl alcohol 4-O-beta-D-glucopyranoside (14), oplopanphesides A-E (15-19), oxy]-3,5-dimethoxyphenylpropanoic acid (20), and glycer-2-yl ferulate (21), as well as three coumarins, scopoletin (22), esculetin (23), and 3′-angeloyl-4′-acetyl-cis-knellactone (24) (Figure 3) [25–27]. Phenylpropanoids (15–19) are glycosides that possess a novel feature in their sugar moieties with a 3-hydroxy-3-methylglutaryl moiety connected with C-6 of the beta-D-glucopyranosyl group.

Figure 3: Phenylpropanoids of O. horridus.

Although the phenylpropanoids are only discovered from the root bark of O. horridus several years ago, no phenylpropanoids have been qualitatively and quantitatively determined by any analytical method. Therefore, the contents of the phenylpropanoids in any part of O. horridus are still unknown. These phenylpropanoids showed no cytotoxic effects against human cancer cell lines (HCT-116, HT-29, MDA-231, and MCF-7) by MTT method [26]. Phenylpropanoids have not been found in other parts of O. horridus, while some phenylpropanoids are recently found in the root of O. elatus [28].

3.3. Lignan Glycosides

The lignans are a large group of natural products found in plants, which have also been obtained from the family Araliaceae. Usually, plant lignans are derived from phenylpropanoids via dimerization of substituted cinnamic alcohols, which is catalysed by oxidative enzymes and controlled by dirigent proteins. Due to the rarely investigation on the hydrophobic constituents from O. horridus, no lignan aglycone has been found in O. horridus. Meanwhile, lignan glycosides are firstly purified and identified from the hydrophilic constituents of the root bark of O. horridus [25, 27].

The isolated lignan glycosides from the root bark of O. horridus are identified as (+)-isolaricires-inol-9′-O-beta-D-glucopyranoside (25), 3, 3′-dimethoxy-4, 9, 9′-trihydroxy-4′, 7-epoxy-5′, 8-lignan-4, 9-bis-O-beta-D-glucopyranoside (26), (+)-5, 5′-dimethoxylariciresinol 4′-O-beta-D-glucopyranoside (27), (-)-5,5′-dimethoxylariciresinol 4′-O-beta-D-glucopyranoside (28), (-)-pinoresinol 4′-O-beta-D-glucopyranoside (29), (+)-5, 5′-dimethoxylariciresinol 9′-O-beta-D-glucopyranoside (30), and (+)-[5,6,7,8-tetrahydro-7-(hydroxylmethyl)-10,11-dimehoxydibenzo[a, c][8]annulen-6-yl]methyl beta-D-glucopyranoside (31) (Figure 4). To date, lignan glycoside has not yet been found in other parts of O. horridus, perhaps due to the limited phytochemical study of these parts. No analytical method has been developed to determine lignans in O. horridus so the contents of lignan glycosides in O. horridus are unclear. Little pharmacological research has been reported on the lignan glycosides from O. horridus, so the corresponding bioactivities of these lignan glycosides are yet to be determined.

Figure 4: Lignan glycosides of O. horridus.

3.4. Triterpenoids

Triterpenoids including saponins are the most representative constituents of the family Araliaceae, which have also been found in the genus Oplopanax. Except one dammara-type triterpenoid, all other triterpenoids belong to oleanane- and lupan-type, which are all only discovered in the leaves of the herbs in this genus. Unlike ginseng from the genus Panax, triterpenoid has neither been isolated nor identified from the root of the plants in Oplopanax, but triterpenoids are regarded to be the main bioactive substances in ginseng. Recently, one dammara-type triterpenoid and five lupan-type triterpenoids have been isolated and identified from the leaves of O. horridus [29, 30].

The purified triterpenoids from the leaves of O. horridus are elucidated as 3α-hydroxy-lup-20(29)-ene-23, 28-dioic acid (32), 3-alpha-hydroxy-lup-20(29)-ene-23, 28-dioic acid-3-beta-β-D-glucopyranoside (33), 24-nor-3-oxo-lup-20(29)-en-28-oic acid-28-O-alpha-L-rhamnopyranosyl (34), dammara-20, 24-dien-3beta-ol acetate (35), acankoreagenin (36), and acankoreoside A (37) (Figure 5). Although dammarane triterpenoid is very common in the family Araliaceae, especially in the genus Panax, this triterpenoid is the first time to be found in the family Araliaceae. Compared with 41 triterpenoids obtained from the leaves of O. elatus, only six triterpenoids isolated from O. horridus are limited. The contents of triterpenoids in the leaves of O. horridus are uncertain because of few reports about their determination. It is also blank about the pharmacological research on the triterpenoids from O. horridus.

Figure 5: Triterpenoids of O. horridus.

3.5. Sesquiterpenes

Sesquiterpenes are a group of terpenes including sesquiterpenoids that consist of three isoprene units, which may be acyclic or contain rings, including many unique combinations. Sesquiterpenes are widely found in plants from Araliaceae, most of which were identified by gas chromatography coupled with mass spectrometry (GC/MS). To date, three sesquiterpenes have been purified from the inner stem bark and root bark of O. horridus, which were identified as 3,10-epoxy-3,7,11-trimethyldodeca-1,6-dien-11-ol (neroplomacrol, 38), rel-(3S,6R,7S,10R)-7,10-epoxy-3,7,11-trimethyldodec-1-ene-3,6,11-triol (neroplofurol, 39), and nerolidol (40) (Figure 6)[31]. Among them, neroplomacrol and neroplofurol were isolated from the anti-TB active fractions of the inner stem bark of O. horridus, which were not the main anti-TB active principles but may have synergistic behavior with them. Other sesquiterpenes were identified from the essential oil of O. horridus by GC/MS, the relative contents of which are also calculated.

Figure 6: Sesquiterpenes of O. horridus.

3.6. Volatile Compounds

The volatile oil from O. horridus is regarded to be responsible for some clinical uses of the title plant. Volatile oils from natural medicines are very complicated, and volatile compounds could not be easily purified and obtained from volatile oil by modern chromatographic techniques due to their disadvantages such as lower boiling point, lower polarity, and thermal degradation. Therefore, most volatile compounds are identified before by GC/MS. Volatile oils have been extracted from stem and root of O. horridus.

Shao et al. used a supercritical fluid extraction method to extract the volatile oil from the root bark of O. horridus with a yield of 1.15%, which was much more than the yield of 0.22% when the oil was extracted by the steam distillation method. Then, the volatile oil was subsequently analyzed by GC/MS (Table 2)[32, 33]. Forty-eight volatile compounds were identified by GC/MS analysis and, among all the detectable constituents, (S, E)-nerolidol (52.5%) was the compound with highest content in the volatile oil, followed by τ-cadinol (21.6%) and bicyclogermacrene (4.5%). (S, E)-Nerolidol and τ-cadinol had been purified as simple compounds from the essential oil and their structures were identified by additional spectroscopic techniques. By comparison with the MS data from the Agilent Chemstation the library, one more polyyne, S-falcarinol (3.6%), was also detected and obtained from the essential oil by chromatographic separation. Except for some very common volatile compounds, e.g., α-pinene, β-phellandrene, linalool, 1,3,5-undecatriene, and 1,3,5,8-undecatetraene; most of the constituents identified in the essential oil were sesquiterpenes and oxygenated sesquiterpenes. Some minor constituents were not identified by GC/MS.

Table 2: The volatile compounds of essential oil from the root of O. horridus.

Compound
Molecular formula
Compound
Molecular formula

Pentanol
C₅H₁₂O
Germacrene D
C₁₅H₂₄

Hexanol
C₆H₁₄O
ar-Curcumene
C₁₅H₂₂

Heptanal
C₇H₁₄O
β-Sesquiphellandrene
C₁₅H₂₄

Heptanol
C₇H₁₆O
β-Elemene
C₁₅H₂₄

Octanol
C₈H₁₆O
α-Muurolene
C₁₅H₂₄

Benaldehyde
C₇H₆O
Allo-aromadendrene
C₁₅H₂₄

2-Octenal
C₈H₁₄O
γ -Cadinene
C₁₅H₂₄

2-Methylpentenal
C₆H₁₂O
α-Farnesened
C₁₅H₂₄

α-Pinene
C₁₀H₁₆
1,10-Di-epi-cubenol
C₁₅H₂₄O

β-Phellandrene
C₁₀H₁₆
δ -Cadinene
C₁₅H₂₄

Linalool
C₁₀H₁₈O
Bicyclogermacrene
C₁₅H₂₄

1,3,5-Undecatriene
C₁₁H₁₈
Ishwarane
C₁₅H₂₄

1,3,5,8-Undecatetraene
C₁₁H₂₀
Germacrene B
C₁₅H₂₄

α-Ylangene
C₁₅H₂₄
(S, E)-Nerolidol
C₁₅H₂₆O

Aromadendrene
C₁₅H₂₄
Spathulenol
C₁₅H₂₄O

α-Zingiberene
C₁₅H₂₄
Germacrene D-4-ol
C₁₅H₂₆O

β-Caryophyllene
C₁₅H₂₄
Gleenol
C₁₅H₂₆O

(E)-α-Bergamotene
C₁₅H₂₄
Guaiol
C₁₅H₂₆O

α-Copaene
C₁₅H₂₄
Endo-1-bourbonanol
C₁₅H₂₆O

α-Humulene
C₁₅H₂₄
τ-Cadinol
C₁₅H₂₆O

α-Cadinene
C₁₅H₂₄
τ-Muurolol
C₁₅H₂₆O

Germacrene A
C₁₅H₂₄
S-Falcarinol
C₁₇H₂₄O

(E)-β-Farnesene
C₁₅H₂₄
α-Eudesmol
C₁₅H₂₆O

γ -Muurolene
C₁₅H₂₄
Bulnesol
C₁₅H₂₆O

3.7. Other Compounds

Some fatty acids, steroid, and steroid glycosides were separated and identified from the root bark of O. horridus, i.e., heptacosane acid (41), ethacosane acid (42), beta-sitosterol (43), daucosterol (44), aralia cerebroside (45), usnic acid (46), and protocatechoic acid (47) [24].

4. Biological Activities

Different parts of O. horridus are used to help cope with verified illnesses from type II diabetes to cancer problems by indigenous people, but the pertinent pharmacological researches are very limited. Compared to few biological activity report of the leaves, the extracts of the stem and berries have only been screened for their antiproliferation effects of four human cancer cell lines (SW-480, HCT-116, HT-29, MCF-7, and NSCLC)[19]. Meanwhile, the root has been researched on its antibacterial, antifungal, antidiabetes, and anticancer effects [2, 34]. In the past decade, although no record was found that any part of O. horridus was used to cure cancer in the long history, the extracts and compounds from the root of O. horridus exhibited their anticancer activities in recent investigations [2, 4].

4.1. Antibacterial

The extracts and fractions from the root of O. horridus showed antibacterial activity related with antimycobacterial, the bacteria of which may cause leprosy and tuberculosis in humans [35–37]. The results showed that the ingredients of O. horridus displayed synergistic enhancement on antituberculosis effect [38]. From a methanol extract of the inner bark of O. horridus exhibited antibacterial activity, five polyynes, 1–4, 7, including falcarinol, falcarindiol, oplopandiol, oplopandiol acetate, and (Z)-9,17-octadecadiene-12,14-diyne-1,11,16-triol 1-acetate, are purified and identified. Specifically, falcarindiol and oplopandiol were the main positive antimycobacterial components from the extract [17]. Additionally, all the obtained polyynes displayed potential ability to inhibit the proliferation of M. tuberculosis, M. avium at 10 μg/disk in a disk diffusion assay, as well as two Gram-positive bacteria, Bacillus subtilis and Staphylococcus aureus, two Gram-negative bacteria, Escherichia coli DC2 and Pseudomonas aeruginosa Z61, and the yeast Candida albicans. Among them, falcarindiol has been proved to possess the strongest antibacterial activities [17].

4.2. Antifungal

The methanol extract of O. horridus inner bark was screened for antifungal activity against 9 fungal species, i.e., Aspergillus flavus, Aspergilfus fumigatus, Candida albicans, Fusarium tricuictum, Microsporum cooker, Microsporum gypseum, Saccharomyces cerevisiae, Trichoderma viridae, and Trichophyton mentagrophytes [39, 40]. The extract was demonstrated antifungal activity against all the fungal strains assayed except A. flavus. The extract had only slight activity against A. fumigatus, C. albicans, F. tricuictum, S. cerevisiae, and T. viridae, but it had greater inhibition against M. gypseum. With the assayed fungi, the extract showed the greatest significant antifungal activity on M. cooker and T. mentagrophytes [39]. However, the corresponding natural products with antifungal activity are still unknown.

4.3. Antidiabetes

O. horridus is extensively recommended for the treatment of diabetes in indigenous communities [41, 42]. Without any data, it was claimed that O. horridus, as a pancreatic tonic, is regarded to decrease blood sugar levels by improve the efficiency of insulin [41]. Therefore, it should be cautiously used for diabetes due to the perspective risk and uncertainty. In preclinical research on O. horridus for adult diabetes, a white precipitate isolated from root bark of O. horridus showed a slightly hypoglycemic effect in lab hares [43]. Inconsistently, the O. horridus tea at a certain dosage exhibited no significant hypoglycemic effects in a primary study [44]. Three new phenolic glycosides obtained from the root bark of O. horridus, oplopanpheside A-C, displayed negative activity for their α-glucosidase inhibition (IC₅₀>50 μM, respectively) [26]. Unambiguously, more studies are requested in concerning its antidiabetic effects.

4.4. Anticancer Effect

The infusion of inner bark of O. horridus was described as a possible treatment for cancer by indigenous linguistic people including Alutiiq, Gitxsan, Haida, Tlingit, and Tsimshian [7]. To date, O. horridus has not been reported to have anticancer effects on human bodies, and no human clinical studies have been conducted on this herb. The extracts mainly containing polyynes from the root bark of O. horridus show anticancer effects on several colorectal, breast, lung, ovarian, pancreatic and acute myeloid leukemia cancer cell lfnes, and animal models [4, 45, 46].

4.4.1. Colorectal Cancer

The different extracts from Oplopanax root, stem, berry, root bark, and their fractions were investigated in vitro for their potential antiproliferative effects on human HCT-116, HT-29, and SW-480 colorectal cancer cell lines [19–21, 47]. The results showed that the stem, root, root bark extracts, and lipophilic fractions of root bark possessed potent antiproliferative effects. The observation of the cell cycle distribution suggested that G2/M phase is arrested by the extracts. However, the hydrophilic fractions had much weaker effects on the apoptotic cells [20].

Five polyynes were isolated and evaluated as the bioactive compounds from hydrophobic fractions [47]. Among these polyynes, FAD and OPT showed significant potent effects, and the primary structure-activity analysis suggested that these anticancer activities are related to the ethylenic bonds and acylations in the structures [48, 49]. Firefly luciferase-tagged HCT-116 cells were inoculated into the flanks of athymic nude mice used as the animal model to evaluate the in vivo antitumor potential of FAD and OPT from O. horridus [48]. The results showed that the FAD and OPT treatment groups exhibit significantly decreased xenogeny imaging signal intensities when compared with the control group. Quantitative analysis revealed that the FAD and OPT significantly inhibited xenograft tumor growth after the administration of FAD and OPT [22, 23]. A rat small intestine epithelial cell line, IEC-6, is used to evaluate the safety of FAD and OPT. At concentrations of 1–20 μM, FAD and OPT do not inhibit the IEC-6 cell growth. In contrast, human HCT-116 and HT-29 colorectal cancer cell growth was significantly inhibited at 15 μM of FAD and OPT [23, 49]. Further study showed that FAD-induced cell death was mediated by the induction of endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR). The FAD-induced ER stress and apoptosis was correlated with the accumulation of ubiquitinated proteins, suggesting that FAD functions, at least in part, by interfering with proteasome function, leading to the accumulation of unfolded protein and induction of ER stress [23].

In another study, OPT significantly suppressed malignant cells in both concentration- and time-dependent manner. The IC₅₀ was approximately 5 μM for HCT-116 and 7 μM for SW-480 cells. OPT significantly induced apoptosis and arrested the cell cycle at the G2/M phase. The results showed that OPT significantly upregulated the expression of a cluster of genes, especially the tumor necrosis factor receptor family and the caspase family. The data suggested that the tumor necrosis factor-related apoptotic pathway played a key role in OPT-induced apoptosis [49].

The OPT-induced cancer cell death was also mediated by excessive ER stress. Decreasing the level of ER stress either by inactivating components of the UPR pathway or by expressing the ER chaperone protein GRP78 decreased OPT-induced cell death. OPT induced the accumulation of ubiquitinated proteins and the stabilization of unstable proteins, suggesting that OPT functions, at least in part, function by interfering with the ubiquitin/proteasome pathway [22].

4.4.2. Acute Myeloid Leukemia (AML)

Male and female transgenic C57BL/6J-Foxp3-RFP mice (C57BL/6-Foxp3tm1Flv/J) were employed for in vivo anti-AML. After one week following engraftment, the 70% ethanol extract of Oplopanax root was diluted into the drinking water at a final concentration of 20 μg/mL. The survival of both male and female mice was significantly increased upon the inclusion of the extract in the drinking water [45]. In addition, the extract decreased the Tregs and increased CD4⁺ T cells and the ratio of CD8⁺ T cells to Tregs. These changes are indicative of a responsive immune system correlated as expected with an increase in survival [45].

The 70% ethanol extract was assessed on AML cell line viability and to study the regulation of tyrosine phosphorylation and cysteine oxidation. The root extract displayed better in vitro anti-AML efficacy in addition to a noted anti-tyrosine kinase activity. The extract decreased the viability of murine C1498 cells and human U937, HL-60/VCR, and KG-1 cells with differential effects. In addition, the effect of the extract compared with nerolidol (a major essential oil component of O. horridus) yielded a better anti-AML activity [45].

4.4.3. Breast Cancer

Effects of the extracts and polyynes have also been evaluated using MCF-7 and MDA-MB-231 human breast cancer cell lines [19, 21, 47]. The IC₅₀ of the total extract, 50, 70, and 100% ethanol fractions on MCF-7 cells, were 248.4, 123.1, 44.0, and 31.5 μg/mL, respectively [47]. The 100% ethanol fraction, which possessed the most potent anti-proliferative activity, showed the strongest apoptotic induction activity [19]. Additionally, three phenolic glycosides isolated from the hydrophilic fraction, oplopanphesides A, B, and C, showed no cytotoxic effects on MDA-MB-231 and MCF-7 cell lines [26]. Further, when the MCF-7 cells were treated with 30 μg/mL of the total extract and fractions, the total extract increased the percentage of cells in the G₁-phase to 49% and the decreased S phase to 6.2% [21].

4.4.4. Lung Cancer

The antiproliferative effects of nonsmall cell lung cancer (NSCLC) cells were evaluated. The IC₅₀ of the extract, 50, 70, and 100% ethanol fractions for antiproliferation on NSCLC cells, were 125.3, 271.1, 17.6, and 23.2 μg/mL, respectively [19]. In addition, the extracts from the stem and berry were evaluated. The stem extract had potent antiproliferative effects at a low concentration of 0.1 mg/mL compared to 1 mg/mL for the berry [21].

4.4.5. Ovarian Cancer

An ovarian cancer (Ovcar 10 three-dimensional [3D]) model was utilized to evaluate the antiproliferation activity of 75% ethanol extract and its active compound, alone and in combination. Ovcar 10 cells formed compact 3D spheroids after five days of culture in a rotary culture system [50]. The 3D spheroids were significantly more resistant to killing by the extract when compared to 2D cells. A number of apoptosis-related genes were differentially expressed in these cells. In 3D spheroids, the proportion of cells in the G2/M phase was slightly increased and the S phase was slightly decreased when compared to 2D cells [50].

4.4.6. Pancreatic Cancer

The 70% ethanol extract was investigated on pancreatic endocrine HP62 and pancreatic ductal carcinoma PANC-1 and BxPC-3 cells. The extract significantly inhibited the proliferation of HP62 at low IC₅₀. Apoptosis focused antibody array profile indicated upregulation of cytochrome C, claspin, cIAP-2 and HTRA2/Omi apoptosis-related markers, suggesting that the effect was via targeting the intrinsic mitochondrial apoptosis pathway [51].

The extract was also assessed for its effect on human pancreatic cancer PANC-1 3D spheroids and 2D monolayer cells. PANC-1 3D spheroids were significantly more resistant to killing by this extract with IC₅₀ level closer to that observed in vivo. The extract also significantly enhanced the antiproliferation activity of the antineoplastic medications cisplatin (CDDP) and gemcitabine (GEM). The bioactive compound, identified as a polyyne, showed strong antiproliferation activities. Cell cycle analysis showed that the proportion of cells in S phase was increased and in G2/M phase was reduced in 3D spheroids when compared with 2D cells [52].

5. Structure-Activity Relationship of Polyynes on Anticancer Effects

5.1. Length of Carbon Chain

The structure-activity relationship of carbon chain in polyynes with their anticancer potential is summarized in Table 3. Anticancer activities decrease with the increase of the length of carbon chain in the main chemical structural skeleton of polyynes. To date, hundreds of polyynes have been isolated from bacterial, fungi, microorganisms, marine invertebrates, and high plants, and most naturally occurring polyynes feature a long lipid chain covering from 10 to 42 carbons in their chemical structural skeleton [16, 53, 54].

Table 3: Possible structure–activity relationship of polyynes from O. horridus against cancer.

Polyyne
Structure characteristics
Cancer cell lines
Activit
References

Carbon chain
Hydroxyl group
Double bond

1
18
3
2
HCT-116, HT-29, SW-480, A549, MCF-7, MDA-MB-231, HepG2
Best
[22, 48, 49, 59]

2
18
3
1
HCT-116, HT-29, SW-480, A549, MCF-7, MDA-MB-231, HepG2
Better
[48, 59]

3
18
2
2
HCT-116, HT-29, SW-480, A549, MCF-7, MDA-MB-231, HepG2
Good
[47, 48, 59]

4
18
2
1
HCT-116, HT-29, SW-480, A549, MCF-7, MDA-MB-231, HepG2
Good
[47, 48, 59]

5
17
2
2
HCT-116, HT-29, SW-480, A549, MCF-7, MDA-MB-231, HepG2, DU145
Best
[23, 47, 48, 59]

6
17
2
1
HCT-116, HT-29, SW-480, A549, MCF-7, MDA-MB-231, HepG2
Better
[47, 48, 59]

7
17
1
2
Not available
Not available
[95–97]

1, oplopantriol A; 2, oplopantriol B; 3, (11S,16S,9Z)-9,17-octadecadiene-12,14-diyne-1,11,16-triol,1-acetate; 4, oplopandiol acetate; 5, falcarindiol; 6, oplopandiol; 7, falcarinol. Stereoselectivity also affects the activities discussed in the text.

Among them, C₁₇ and C₁₈-polyynes were predominantly reported for their anticancer effects [55–58]. In the tested cancer lines, the antiproliferation effects of polyyne 1 displayed stronger effects than 3 and 5, while polyyne 2 exhibited greater activities than 4 and 6 [48, 59]. Among these polyynes, 1 (FAD) shows the strongest anticancer activity, suggesting that FAD is a candidate for chemical modification [60–62].

5.2. Ethenyl Group

As shown in Table 3, (R)-falcarinol, a C₁₇-polyyne, is obtained from some other plants, and it has been demonstrated to show antiproliferation effects on several cancer cell lines [63–67]. However, biological study has not been conducted on its derivative, cis-9-heptadecene-4,6-diyne-8-ol, which becomes an easier volatile compound when its terminal double bond is transferred to be single bond [68]. Regarding the chemical structures of these polyynes, they could be divided into three pairs grouped by their terminal bond moieties, i.e., 1 vs. 2; 3 vs. 4; and 5 vs. 6. With regard to their anticancer effects, polyyne 1, 3, and 5 showed greater potent activity, suggesting that the terminal ethenyl group improved anticancer activity [48, 59]. Recently, it is reported that the pharmacokinetic parameters between 1 and 2 had significant differences. Compared with 2, the terminal ethenyl group made 1 easier transformed into other metabolites in vivo [69]. It has been demonstrated that compound 1 could effectively join in chemical carcinogen detoxification by selectively mediating Phase II drug metabolism enzymes and quinone oxidoreductase [70]. Therefore, further studies should be employed to investigate the relationship between its terminal ethenyl group and anticancer behavior.

5.3. Hydroxyl Group

Since polar compounds interact with phospholipid substances in the hydrophilic domain of cell membrane, the entrance orientation of polyynes into membranes is affected by the number and location of alcohol hydroxyl groups [71]. The number and location of hydroxyl groups in polyynes influenced its anticancer activity [72, 73]. In the natural polyynes, if the hydroxyl group at C-1 was substituted with an acetyl group, the antiproliferative effect of polyyne was decreased, but if the hydroxyl group at C-11 or C-16 was acetylated, the antiproliferative activity would be significantly suppressed [59]. The anticancer activities of polyyne 3, 4, 5, and 6 have been systematically compared. Oplopantriol A (5) showed the strongest antiproliferative effects on selected colorectal cancer cell lines and greater inhibition of tumor growth in vivo [22, 49]. Among the four polyynes, oplopantriol A can be considered to be a prochemical.

In order to investigate the contribution of hydroxyl groups to the antiproliferation on cancer cells, sixteen more acetylated derivatives have been synthesized for the evaluation of potential anticancer activities. The polyynes do not have any inhibitory effects of the adopted cancer cells if all the hydroxyl groups of the polyynes were acetylated [59]. However, compared to hydroxyl group at C-1, the terminal ethenyl group contribute more significance for maintaining anticancer potential. For example, compound 5 has 3 to 5-fold relatively stronger antiproliferative effects than compound 6, while compound 5 possesses 1 to 3-fold relatively greater than compound 3 [48]. The elimination of hydroxyl groups of polyynes will yield acetylene alkanes, which have not been subjected to anticancer research.

5.4. Stereoselectivity

With the same planer chemical structures of the polyynes identified from O. horridus, each molecule is able to generate four stereoisomers with (3S, 8S)- or (11S, 16S)-, (3S, 8R)- or (11R, 16S)-, (3R, 8S)- or (11S, 16R)-, and (3R, 8R)- or (11R, 16R)-configuration. However, only (3S, 8S)- or (11S, 16S)- and (3R, 8S)- or (11S, 16R)-stereoisomers have been isolated and identified from natural resources [16]. According to the numbering sequence, the stereochemistry identified for polyynes purified from O. horridus with a (3S, 8S)- or (11S, 16S)-configuration seems to be very different from those with the (3R, 8S)- or (11S, 16R)-configuration reported from Apiaceae and Asteraceae [74–77].

To the (3S, 8S)- and (3S, 8R)-polyynes, (3S, 8S)-1 has only been found in the genus Oplopanax, while (3S, 8R)-1 has been isolated from several plants in different genus [78–81]. Although (3R, 8S)-1 and (3R, 8R)-1 have been synthesized [77], they have not been assayed for their anticancer effects. (3S, 8R)-1 showed the inhibitory activity on various tumor cells proliferation, e.g., K562, Raji, Wish, HeLa, Calu-1, MCF-7 in vitro [66, 82, 83], and tumor growth in different mouse model [67, 84]. Compared with (3S, 8R)-1, (3S, 8S)-1 showed stronger antiproliferative effects against MCF-7 cells [23, 83]. Due to the limited data, the stereochemistry on the anticancer effects of 1 needs further studies.

To the (11S, 16S)- and (11S, 16R)-polyynes, (11S, 16R)-3 has been isolated from the genus Angelica [85–87], while (11S, 16S)-4 has been synthesized [88, 89]. (11S, 16R)-5 has also been isolated from the genus Angelica [90, 91], but (11S, 16S)-6 has only been found in O. horridus. Among these existing C₁₈-polyynes, only (11S, 16S)-polyynes isolated from O. horridus have been tested for their anticancer activities. Therefore, more researches are needed to confirm the stereoselectivity of polyynes on their anticancer effects.

6. Summary and Perspectives

O. horridus, well-known as Devil’s club, is probably the most important ethnobotanical to most indigenous people living in the Pacific Northwest of North America. Different part of O. horridus has a long history to be used for ailments by local people as traditional herbal medicines. In this review, the phytochemicals mainly including polyynes, triterpenoids, sesquiterpenes, diterpenoid, lignans, and phenylpropanoids from different part of O. horridus have been compiled. To date, approximately 47 compounds have been purified from O. horridus, and most of them are discovered for the first time from this genus. However, phytochemistry studies are relatively limited on each part of O. horridus except its root.

Polyynes identified from this herb exhibit pharmacological diversity. Especially, though this botanical has not been reported to have anticancer effects in human clinical studies, polyynes from O. horridus showed effects against colorectal cancer, breast cancer, lung cancer, ovarian cancer, pancreatic cancer, and acute myeloid leukemia in human cancer cell lines and different animal models. Regarding the anticancer effects and mechanisms of polyynes, it is pertinent to several molecular mechanisms and various signaling pathways. Because the bioavailability and metabolism of polyynes are critical important, their plasma concentrations that maybe significantly affect its biological activities in vivo are unknown. Moreover, the pharmacokinetic studies are blank to these polyynes except a few reported pharmacokinetic parameters of facarindiol and oplopandiol in rat [69]. Therefore, in vivo preclinical models are essential and vital to evaluate and predict the clinical function of polyynes.

We propose that the length of lipid chain, terminal ethenyl group, number of hydroxyl groups, and stereoselectivity in polyynes affect their anticancer activity. These relationships could benefit chemical modification of polyynes for discovery of bioactive molecules. Due to the stability of polyynes, C₁₇-polyynes are most researched for their anticancer activities [61]. Our former experiments showed that acetylation of polyynes decreased their activities, but cancer chemopreventive potential may be enhanced by employing other chemical functional groups into polyynes. Although different stereoisomers of polyynes could be synthesized, their potential anticancer effects have not been quantitatively compared. Further investigations are needed to develop novel anticancer candidate in drug discovery.

Conflicts of Interest

All the authors declare that they have no conflicts of interest regarding funding supports in this manuscript.

Acknowledgments

This project is funded by the National Natural Science Foundation of China (no. 31400306), Hunan Provincial Natural Science Foundation of China (no. 2015JJ3156), China Postdoctoral Science Foundation (no. 2015M570692), and NIH grants (nos. AT004418 and AT005362).

Supplementary Materials

Supplementary data associated with this review is the graphic abstract about bioactive polyynes from O. horridus. (Supplementary Materials)

References

T. C. Lantz and J. A. Antos, “Clonal expansion in the deciduous understory shrub, devil's club (Oplopanax horridus; Araliaceae),” Botany, vol. 80, no. 10, pp. 1052–1062, 2002.

T. Calway, G.-J. Du, C.-Z. Wang et al., “Chemical and pharmacological studies of Oplopanax horridus, a North American botanical,” Journal of Natural Medicines, vol. 66, no. 2, pp. 249–256, 2012.

A. N. Shikov, O. N. Pozharitskaya, V. G. Makarov, W.-Z. Yang, and D.-A. Guo, “Oplopanax elatus (Nakai) Nakai: Chemistry, traditional use and pharmacology,” Chinese Journal of Natural Medicines, vol. 12, no. 10, pp. 721–729, 2014.

W.-H. Huang, Q.-W. Zhang, C.-S. Yuan, C.-Z. Wang, S.-P. Li, and H.-H. Zhou, “Chemical constituents of the plants from the genus Oplopanax,” Chemistry & Biodiversity, pp. 181–196, 2014.

E. Ernst, “Panax ginseng: an overview of the clinical evidence,” Journal of Ginseng Research, vol. 34, no. 4, pp. 259–263, 2010.

D.-H. Kim, “Chemical diversity of Panax ginseng, Panax quinquifolium, and Panax notoginseng,” Journal of Ginseng Research, vol. 36, no. 1, pp. 1–15, 2012.

T. C. Lantz and J. A. Antos, “Devil'S Club (Oplopanax Horridus): An Ethnobotanical Review,” HerbalGram, vol. 62, no. 5, pp. 33–48, 2002.

L.-L. Chen, L.-P. Zhou, J. Huang et al., “Single- and multiple-dose trials to determine the pharmacokinetics, safety, tolerability, and sex effect of oral ginsenoside compound K in healthy Chinese volunteers,” Frontiers in Pharmacology, vol. 8, Article ID 965, 2018.

G. W. Smith, “Arctic pharmacognosia II. Devil's club, Oplopanax horridus,” Journal of Ethnopharmacology, vol. 7, no. 3, pp. 313–320, 1983.

N. J. Turner, “Traditional use of Devil's-Club (Oplopanax horridus; Araliaceae) by native peoples in Western North America,” Journal of Ethnobiology, pp. 17–38, 2014.

J. W. Justice, “Use of devil's club in Southeast Alaska.,” Alaska Medicine, vol. 8, no. 2, pp. 36–39, 1966.

N. C. Turner and M. A. M. Bell, “The ethnobotany of the Southern Kwakiutl Indians of British Columbia,” Economic Botany, vol. 27, no. 3, pp. 257–310, 1973.

A. J. Wennekens, Traditional Plant Usage by Chugach Natives Around Prince William Sound and on the Lower Kenai Peninsula, Alaska, University of Alaska, Anchorage, Alaska, 1985.

W. Huang, J. Yang, J. Zhao, C.-Z. Wang, C.-S. Yuan, and S.-P. Li, “Quantitative analysis of six polyynes and one polyene in Oplopanax horridus and Oplopanax elatus by pressurized liquid extraction and on-line SPE-HPLC,” Journal of Pharmaceutical and Biomedical Analysis, vol. 53, no. 4, pp. 906–910, 2010.

Z.-M. Yang, J. Zhao, K.-M. Lao et al., “Determination of six polyynes in Oplopanax horridus and Oplopanax elatus using polyethylene glycol modified reversed migration microemulsion electrokinetic chromatography,” Electrophoresis, vol. 35, no. 20, pp. 2959–2964, 2014.

A. L. K. Shi Shun and R. R. Tykwinski, “Synthesis of naturally occurring polyynes,” Angewandte Chemie International Edition, vol. 45, no. 7, pp. 1034–1057, 2006.

M. Kobaisy, Z. Abramowski, L. Lermer et al., “Antimycobacterial polyynes of Devil's club (Oplopanax horridus), a north american native medicinal plant,” Journal of Natural Products, vol. 60, no. 11, pp. 1210–1213, 1997.

W.-H. Huang, Q.-W. Zhang, C.-Z. Wang, C.-S. Yuan, and S.-P. Li, “Isolation and identification of two new polyynes from a North American ethnic medicinal plant-oplopanax horridus (Smith) Miq,” Molecules, vol. 15, no. 2, pp. 1089–1096, 2010.

C.-Z. Wang, H. H. Aung, S. R. Mehendale, Y. Shoyama, and C.-S. Yuan, “High performance liquid chromatographic analysis and anticancer potential of Oplopanax horridus: Comparison of stem and berry extracts,” Fitoterapia, vol. 81, no. 2, pp. 132–139, 2010.

X.-L. Li, S. Sun, and G.-J. Du, “Effects of Oplopanax horridus on human colorectal cancer cells,” Anticancer Research, vol. 30, no. 2, pp. 295-302.

S. Sun, X.-L. Li, C.-Z. Wang, S. Williams, and C.-S. Yuan, “Improving anticancer activities of Oplopanax horridus root bark extract by removing water-soluble components,” Phytotherapy Research, vol. 24, no. 8, pp. 1166–1174, 2010.

H.-R. Jin, Y. Liao, and X. Li, “Anticancer compound Oplopantriol A kills cancer cells through inducing ER stress and BH3 proteins bim and noxa,” Cell Death & Disease, vol. 5, Article ID e1190, 2014.

H.-R. Jin, J. Zhao, and Z. Zhang, “The antitumor natural compound falcarindiol promotes cancer cell death by inducing endoplasmic reticulum stress,” Cell Death & Disease, vol. 3, 2012.

W.-H. Huang, Chemical investigation on the root barks of Oplopanax horridus, State Key Laboratory for Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, 2012.

W.-H. Huang, Q.-W. Zhang, C.-Z. Wang, C.-S. Yuan, and S.-P. Li, “Phenolic derivatives from the root bark of Oplopanax Horridus,” Helvetica Chimica Acta, vol. 98, no. 2, pp. 201–209, 2015.

W.-H. Huang, Q.-W. Zhang, L.-Z. Meng, C.-S. Yuan, C.-Z. Wang, and S.-P. Li, “Oplopanphesides A-C, three new phenolic glycosides from the root barks of Oplopanax horridus,” Chemical & Pharmaceutical Bulletin, vol. 59, no. 5, pp. 676–679, 2011.

W.-H. Huang, W. Luo, C.-Z. Wang et al., “Phenolic constituents from Oplopanax horridus,” Zhongguo Zhongyao Zazhi, vol. 39, no. 10, pp. 1852–1857, 2014.

L. Shao, M.-K. Nie, M.-Y. Chen et al., “Screening and identifying antioxidants from Oplopanax elatus using 2,2'-diphenyl-1-picrylhydrazyl with off-line two-dimensional HPLC coupled with diode array detection and tandem time-of-flight mass spectrometry,” Journal of Separation Science, vol. 39, no. 22, pp. 4269–4280, 2016.

K. Cao, C. Qiao, X. Chen et al., “Chemical Constituents from Leaves of Oplopanax horridus,” Chinese Herbal Medicines, vol. 6, no. 4, pp. 328–331, 2014.

P.-P. Liu, M. Li, T.-G. Kang, D.-Q. Dou, and D. C. Smith, “New lupane-type triterpenoid saponins from leaves of Oplopanax horridus (Devil's Club),” Natural Product Communications (NPC), vol. 5, no. 7, pp. 1019–1022, 2010.

T. Inui, Y. Wang, D. Nikolic, D. C. Smith, S. G. Franzblau, and G. F. Pauli, “Sesquiterpenes from oplopanax horridus,” Journal of Natural Products, vol. 73, no. 4, pp. 563–567, 2010.

L. Shao, M.-H. Bao, D.-S. Ouyang et al., “Unstable simple volatiles and gas chromatography-tandem mass spectrometry analysis of essential oil from the roots bark of Oplopanax horridus extracted by supercritical fluid extraction,” Molecules, vol. 19, no. 12, pp. 19708–19717, 2014.

F.-X. Garneau, G. Collin, H. Gagnon, F.-I. Jean, H. Strobl, and A. Pichette, “The essential oil composition of devil's club, Oplopanax horridus J. E. Smith Miq,” Flavour and Fragrance Journal, vol. 21, no. 5, pp. 792–794, 2006.

C. M. Burton and P. J. Burton, “Recovery of Oplopanax horridus (Sm.) Miq., an important ethnobotanical resource, after clearcut logging in northwestern British Columbia,” Ethnobotany Research and Applications , vol. 14, pp. 001–015, 2015.

T. Inui, R. Case, E. Chou et al., “CCC in the Phytochemical Analysis of Anti‐Tuberculosis Ethnobotanicals,” Journal of Liquid Chromatography & Related Technologies, vol. 28, no. 12-13, pp. 2017–2028, 2005.

A. R. McCutcheon, T. E. Roberts, E. Gibbons et al., “Antiviral screening of British Columbian medicinal plants,” Journal of Ethnopharmacology, vol. 49, no. 2, pp. 101–110, 1995.

A. R. McCutcheon, S. M. Ellis, R. E. W. Hancock, and G. H. N. Towers, “Antibiotic screening of medicinal plants of the British Columbian native peoples,” Journal of Ethnopharmacology, vol. 37, no. 3, pp. 213–223, 1992.

T. Inui, Y. Wang, S. Deng, D. C. Smith, S. G. Franzblau, and G. F. Pauli, “Counter-current chromatography based analysis of synergy in an anti-tuberculosis ethnobotanical,” Journal of Chromatography A, vol. 1151, no. 1-2, pp. 211–215, 2007.

A. R. McCutcheon, S. M. Ellis, R. E. W. Hancock, and G. H. N. Towers, “Antifungal screening of medicinal plants of British Columbian native peoples,” Journal of Ethnopharmacology, vol. 44, no. 3, pp. 157–169, 1994.

H. M. Hassan, Z.-H. Jiang, T. A. Syed, and W. Qin, “Review: Northern Ontario medicinal plants,” Canadian Journal of Plant Science, vol. 92, no. 5, pp. 815–828, 2012.

J. Green, The Male Herbal: The Definitive, Health Care Book for, 2011.

M. Moore, Medicinal Plants of the Pacific West, Red Crane Books, 1993.

R. G. Large and H. N. Brocklesby, “A hypoglycæmic substance from the roots of the Devil's club (fatsia horrida),” Canadian Medical Association Journal, vol. 39, no. 1, pp. 32–35, 1938.

H. V. Thommasen, R. A. Wilson, and R. G. McIlwain, “Effect of Devil's Club tea on blood glucose levels in diabetes mellitus,” Canadian Family Physician, vol. 36, pp. 62–65, 1990.

C. M. McGill, E. J. Alba-Rodriguez, S. Li et al., “Extracts of Devil's club (Oplopanax horridus) exert therapeutic efficacy in experimental models of acute myeloid leukemia,” Phytotherapy Research, vol. 28, no. 9, pp. 1308–1314, 2014.

Q. Yue, G. Gao, G. Zou, H. Yu, and X. Zheng, “Natural Products as Adjunctive Treatment for Pancreatic Cancer: Recent Trends and Advancements,” BioMed Research International, vol. 2017, Article ID 8412508, 13 pages, 2017.

S. Sun, G.-J. Du, L.-W. Qi, S. Williams, C.-Z. Wang, and C.-S. Yuan, “Hydrophobic constituents and their potential anticancer activities from Devil's Club (Oplopanax horridus Miq.),” Journal of Ethnopharmacology, vol. 132, no. 1, pp. 280–285, 2010.

C.-Z. Wang, Z. Zhang, W.-H. Huang et al., “Identification of potential anticancer compounds from Oplopanax horridus,” Phytomedicine, vol. 20, no. 11, pp. 999–1006, 2013.

Z. Zhang, C. Yu, C.-F. Zhang et al., “Chemopreventive effects of oplopantriol A, a novel compound isolated from oplopanax horridus, on colorectal cancer,” Nutrients, vol. 6, no. 7, pp. 2668–2680, 2014.

J. Xiao, D. Chen, X.-X. Lin et al., “Screening of drug metabolizing enzymes for the ginsenoside compound K in vitro: an efficient anti-cancer substance originating from Panax ginseng,” PLoS ONE, vol. 11, no. 2, Article ID e0147183, 2016.

S. S. C. Cheung, J. Tai, D. Hasman, D. Ou, and G. L. Warnock, “Inhibition of human pancreatic cancer cell proliferation by Devil's club oplopanax horridus and its polyacetylene bioactive compound,” Nutrition and Cancer, vol. 67, no. 6, pp. 954–964, 2015.

J. Tai, S. S. C. Cheung, D. Ou, G. L. Warnock, and D. Hasman, “Antiproliferation activity of Devil's club (Oplopanax horridus) and anticancer agents on human pancreatic cancer multicellular spheroids,” Phytomedicine, vol. 21, no. 4, pp. 506–514, 2014.

J. W. Y. Lam, J. Luo, Y. Dong, K. K. L. Cheuk, and B. Z. Tang, “Functional polyacetylenes: Synthesis, thermal stability, liquid crystallinity, and light emission of polypropiolates,” Macromolecules , vol. 35, no. 22, pp. 8288–8299, 2002.

J. Liu, J. W. Y. Lam, and B. Z. Tang, “Acetylenic polymers: Syntheses, structures, and functions,” Chemical Reviews, vol. 109, no. 11, pp. 5799–5867, 2009.

L. P. Christensen and K. Brandt, “Bioactive polyacetylenes in food plants of the Apiaceae family: occurrence, bioactivity and analysis,” Journal of Pharmaceutical and Biomedical Analysis, vol. 41, no. 3, pp. 683–693, 2006.

B. W. Gung, “Total synthesis of polyyne natural products,” Comptes Rendus Chimie, vol. 12, no. 3-4, pp. 489–505, 2009.

F. Herrmann, F. Sporer, A. Tahrani, and M. Wink, “Antitrypanosomal properties of panax ginseng C. A. Meyer: New possibilities for a remarkable traditional drug,” Phytotherapy Research, vol. 27, no. 1, pp. 86–98, 2013.

A. Rawson, N. P. Brunton, D. K. Rai, P. McLoughlin, B. K. Tiwari, and M. G. Tuohy, “Stability of falcarinol type polyacetylenes during processing of Apiaceae vegetables,” Trends in Food Science & Technology, vol. 30, no. 2, pp. 133–141, 2013.

W.-H. Huang, L. Shao, C.-Z. Wang, C.-S. Yuan, and H.-H. Zhou, “Anticancer activities of polyynes from the root bark of Oplopanax horridus and their acetylated derivatives,” Molecules, vol. 19, no. 5, pp. 6142–6162, 2014.

A. Siddiq and V. Dembitsky, “Acetylenic anticancer agents,” Anti-Cancer Agents in Medicinal Chemistry, vol. 8, no. 2, pp. 132–170, 2008.

C. Dawid, F. Dunemann, W. Schwab, T. Nothnagel, and T. Hofmann, “Bioactive C17-Polyacetylenes in Carrots (Daucus carota L.): Current Knowledge and Future Perspectives,” Journal of Agricultural and Food Chemistry, vol. 63, no. 42, pp. 9211–9222, 2015.

R. E. Minto and B. J. Blacklock, “Biosynthesis and function of polyacetylenes and allied natural products,” Progress in Lipid Research, vol. 47, no. 4, pp. 233–306, 2008.

M. Kobæk-Larsen, L. P. Christensen, W. Vach, J. Ritskes-Hoitinga, and K. Brandt, “Inhibitory effects of feeding with carrots or (-)-falcarinol on development of azoxymethane-induced preneoplastic lesions in the rat colon,” Journal of Agricultural and Food Chemistry, vol. 53, no. 5, pp. 1823–1827, 2005.

J. F. Young, S. J. Duthie, L. Milne, L. P. Christensen, G. G. Duthie, and C. S. Bestwick, “Biphasic effect of falcarinol on CaCo-2 cell proliferation, DNA damage, and apoptosis,” Journal of Agricultural and Food Chemistry, vol. 55, no. 3, pp. 618–623, 2007.

M.-Y. Chen, L. Shao, W. Zhang et al., “Metabolic analysis of Panax notoginseng saponins with gut microbiota-mediated biotransformation by HPLC-DAD-Q-TOF-MS/MS,” Journal of Pharmaceutical and Biomedical Analysis, vol. 150, no. 2, pp. 199–207, 2018.

K. W. Tan, D. P. Killeen, Y. Li, J. W. Paxton, N. P. Birch, and A. Scheepens, “Dietary polyacetylenes of the falcarinol type are inhibitors of breast cancer resistance protein (BCRP/ABCG2),” European Journal of Pharmacology, vol. 723, no. 1, pp. 346–352, 2014.

M. Kobaek-Larsen, R. B. El-Houri, L. P. Christensen, I. Al-Najami, X. Fretté, and G. Baatrup, “Dietary polyacetylenes, falcarinol and falcarindiol, isolated from carrots prevents the formation of neoplastic lesions in the colon of azoxymethane-induced rats,” Food & Function, vol. 8, no. 3, pp. 964–974, 2017.

R. Vanhaelen-Fastré and M. Vanhaelen, “Polyacetyleniques en C17 des racines d'Heracleum mantegazzianum,” Phytochemistry, vol. 12, no. 11, pp. 2687–2689, 1973.

W. Sun, Y.-S. He, L.-H. Xu et al., “Pharmacokinetic profiles of falcarindiol and oplopandiol in rats after oral administration of polyynes extract of Oplopanax elatus,” Chinese Journal of Natural Medicines, vol. 14, no. 9, pp. 714–720, 2016.

T. Ohnuma, E. Anan, R. Hoashi et al., “Dietary diacetylene falcarindiol induces phase 2 drug-metabolizing enzymes and blocks carbon tetrachloride-induced hepatotoxicity in mice through suppression of lipid peroxidation,” Biological & Pharmaceutical Bulletin, vol. 34, no. 3, pp. 371–378, 2011.

C.-X. Sheng, W.-J. Peng, Z.-A. Xia et al., “The impact of ginsenosides on cognitive deficits in experimental animal studies of Alzheimer's disease: a systematic review,” BMC Complementary and Alternative Medicine, vol. 15, Article ID 386, 2015.

D. Listunov, N. Saffon-Merceron, E. Joly et al., “Ethynylogation approach in pharmacophore design: from alkynyl-to butadiynyl-carbinols vs antitumoral cytotoxicity,” Tetrahedron, vol. 72, no. 42, pp. 6697–6704, 2016.

W. Heydenreuter, E. Kunold, and S. A. Sieber, “Alkynol natural products target ALDH2 in cancer cells by irreversible binding to the active site,” Chemical Communications, vol. 51, no. 87, pp. 15784–15787, 2015.

X. Liu, O. Kunert, M. Blunder et al., “Polyyne hybrid compounds from notopterygium incisum with peroxisome proliferator-activated receptor gamma agonistic effects,” Journal of Natural Products, vol. 77, no. 11, pp. 2513–2521, 2014.

L. Kjellenberg, E. Johansson, K. Gustavsson, A. Granstedt, and M. Olsson, “Correlations between Polyacetylene Concentrations in Carrot (Daucus carota L.) and Various Soil Parameters,” Foods, vol. 5, no. 4, p. 60, 2016.

H.-D. Zhao, H.-J. Xie, J. Li, C.-P. Ren, and Y.-X. Chen, “Research progress on reversing multidrug resistance in tumors by using Chinese medicine,” Chinese Journal of Integrative Medicine, vol. 24, no. 6, pp. 474–480, 2018.

S. Ludger, A. Carole, B. Witulski, and T. Hofmann, “Structure determination of bisacetylenic oxylipins in carrots (Daucus carota L.) and enantioselective synthesis of falcarindiol,” Journal of Agricultural and Food Chemistry, vol. 57, no. 22, pp. 11030–11040, 2009.

C. Zidorn, K. Jöhrer, M. Ganzera et al., “Polyacetylenes from the apiaceae vegetables carrot, celery, fennel, parsley, and parsnip and their cytotoxic activities,” Journal of Agricultural and Food Chemistry, vol. 53, no. 7, pp. 2518–2523, 2005.

Y.-C. Chen, P.-Y. Chen, C.-C. Wu, I.-L. Tsai, and I.-S. Chen, “Chemical constituents and anti-platelet aggregation activity from the root of Peucedanum formosanum,” Journal of Food and Drug Analysis, vol. 16, no. 3, pp. 15–25, 2008.

L. Meot-Duros, S. Cérantola, H. Talarmin, C. Le Meur, G. Le Floch, and C. Magné, “New antibacterial and cytotoxic activities of falcarindiol isolated in Crithmum maritimum L. leaf extract,” Food and Chemical Toxicology, vol. 48, no. 2, pp. 553–557, 2010.

B. Adhikari, H. P. Devkota, K. R. Joshi, T. Watanabe, and S. Yahara, “Two new diacetylene glycosides: Bhutkesoside A and B from the roots of Ligusticopsis wallichiana,” Natural Product Research (Formerly Natural Product Letters), vol. 30, no. 14, pp. 1577–1584, 2016.

Y.-C. Kuo, Y.-L. Lin, C.-P. Huang, J.-W. Shu, and W.-J. Tsai, “A tumor cell growth inhibitor from Saposhnikovae divaricata,” Cancer Investigation, vol. 20, no. 7-8, pp. 955–964, 2002.

K.-E. Bae, Y.-W. Choi, S.-T. Kim, and Y.-K. Kim, “Components of rhizome extract of Cnidium officinale makino and their in vitro biological effects,” Molecules, vol. 16, no. 10, pp. 8833–8847, 2011.

M. W. Bernart, J. H. Cardellina II, M. S. Balaschak, M. R. Alexander, R. H. Shoemaker, and M. R. Boyd, “Cytotoxic falcarinol oxylipins from Dendropanax arboreus,” Journal of Natural Products, vol. 59, no. 8, pp. 748–753, 1996.

J.-H. Liu, S. Zschocke, and R. Bauer, “A polyacetylenic acetate and a coumarin from Angelica pubescens f. biserrata,” Phytochemistry, vol. 49, no. 1, pp. 211–213, 1998.

T. Akihisa, H. Tokuda, D. Hasegawa et al., “Chalcones and other compounds from the exudates of Angelica keiskei and their cancer chemopreventive effects,” Journal of Natural Products, vol. 69, no. 1, pp. 38–42, 2006.

Q. Song, D. Fu, J. Liu, D. Zheng, L. Han, and X. Huang, “Chemical constituents from Angelica sinensis,” Zhongcaoyao, vol. 42, no. 10, pp. 1900–1904, 1900.

N. Kumar Bejjanki, A. Venkatesham, K. Balraju, and K. Nagaiah, “First stereoselective total synthesis of oplopandiol,” Helvetica Chimica Acta, vol. 96, no. 8, pp. 1571–1578, 2013.

B. V. S. Reddy, R. Nageshwar Rao, B. Kumaraswamy, and J. S. Yadav, “Stereoselective total synthesis of oplopandiol, oploxyne A, and oploxyne B,” Tetrahedron Letters, vol. 55, no. 33, pp. 4590–4592, 2014.

B.-S. Min, “Coumarins and a polyacetylene from the roots of Angelica purpuraefolia,” Natural Product Sciences, vol. 12, no. 3, pp. 129–133, 2006.

L. Luo, R. Wang, X. Wang, Z. Ma, and N. Li, “Compounds from Angelica keiskei with NQO1 induction, DPPH scavenging and α-glucosidase inhibitory activities,” Food Chemistry, vol. 131, no. 3, pp. 992–998, 2012.

L. M. J. Gottesfeld, “The importance of bark products in the aboriginal economies of Northwestern British Columbia, Canada,” Economic Botany, vol. 46, no. 2, pp. 148–157, 1992.

L. M. J. Gottesfeld, “Wet'Suwet'en ethnobotany: Traditional plant uses,” Journal of Ethnobiology, vol. 14, no. 2, pp. 185–210, 1994.

P. N. Russell, English Bay and Port Graham Alutiiq plantlore, Alaska Native Plant Society, Homer, Alaska, 1991.

Y.-Q. Yang, S.-N. Li, J.-C. Zhong et al., “Total synthesis of each enantiomer of falcarinol and panaxjapyne A via asymmetric catalytic alkynylation of an aldehyde,” Tetrahedron: Asymmetry, vol. 26, no. 7, pp. 361–366, 2015.

S. F. Mayer, A. Steinreiber, R. V. A. Orru, and K. Faber, “Chemoenzymatic asymmetric total syntheses of antitumor agents (3R,9R,10R)- and (3S,9R,10R)-panaxytriol and (R)- and (S)-falcarinol from Panax ginseng using an enantioconvergent enzyme-triggered cascade reaction,” The Journal of Organic Chemistry, vol. 67, no. 26, pp. 9115–9121, 2002.

G. Zheng, W. Lu, H. A. Aisa, and J. Cai, “Absolute configuration of falcarinol, a potent antitumor agent commonly occurring in plants,” Tetrahedron Letters, vol. 40, no. 11, pp. 2181-2182, 1999.