Alangium Lam.: A Review of Its Botany,Phytochemistry,and Mechanism of Action Against Tumor

Abstract

Background: The Alangium Lam. belongs to the Alangiaceae family and contains over 30 species. Researchers have identified over 300 phytochemicals from these species, including alkaloids, glycosides, terpenes, lignans, flavonoids, and steroids. However, there is no review of the antitumor properties of the Alangium genus, and the subsequent information on the mechanism of its antitumor action is not comprehensive enough. Methods: This article reviews previous studies on the Alangium obtained from various sources, including the CNKI, PubMed, Google Scholar, Connected Paper, and the chemical abstracts service (CAS). Results: Among these compounds, 85 have been found to possess anti-tumor properties, mainly belongs to alkaloids, glycosides, and terpenes. This will provide new insights and a broader perspective for future research on the effects of anti-tumor chemicals and their mechanisms of action within this plant genus.

Keywords

phytochemistry alkaloids bioactivity anti-tumor

Introduction

Cancer, also known as a malignant tumor, is a significant global health issue that poses a serious threat to human life, with increasing rates of both occurrence and death following a consistent pattern. Research indicates that the number of new cancer cases in individuals aged 75 and above is expected to rise by 3 to 4.5 times globally, compared to the statistics from 1990¹; Approximately 19.3 million new cancer cases occur in 2020, resulting in nearly 10 million cancer-related deaths²; Around the globe, there are approximately 20 million new cases of cancer and 9.7 million cancer-related deaths in 2022³; In 2040, it is projected that there will be approximately 28.4 million new cancer cases.⁴ According to the “Report on the Operation Pattern and Investment Strategy of China's Anti-tumor Drugs Industry 2020-2026,” malignant tumors are the leading cause of death in China. Therefore, it is crucial to effectively address malignant tumors. The primary anti-tumor treatments commonly employed in clinical settings include surgery, radiotherapy, chemotherapy, and targeted therapy. These treatments are all effective in reducing the growth of tumor cells. However, chemotherapy has several dangerous side effects, such as long-term damage to the liver, kidneys, and central nervous system. It is also associated with a significant risk of cancer spreading after surgery. Therefore, it is crucial to discover anti-tumor medications that are highly effective, safe, and have low toxicity in current pharmacological research. Traditional Chinese medicine has long utilized natural ingredients to mitigate negative effects and minimize side effects. Moreover, specific elements and principles related to Chinese medicine can synergistically enhance its anti-tumor effectiveness. From 1981 to 2014, the FDA granted approval for the sale of 67% of cancer-fighting drugs derived from natural sources.⁵ The Alangium species are reported to have traditional medicinal value in treating diarrhea, dysentery, inflammation, hypertension, and eczema, while the pharmacological investigations have also revealed that the extracts and phytochemicals of Alangium species possess other therapeutic properties, such as antitumor effects. Researchers in the field of natural pharmacology are currently exploring more potent active ingredients found in herbal products, as they have the potential to be effective modern anticancer medications. Our team has a long-standing interest in identifying naturally components that have anti-tumor properties. Currently, we are conducting research on the antitumor effects of plants belonging to the Alangium genus. Previous studies suggest that the crude extracts of Alangium chinense (Lour.) Harms subsp may contain compounds that can inhibit the growth of tumor cells. However, there is limited detailed research or extensive documentation on the anticancer properties of other plants within this genus. In order to enhance our comprehension and utilization of the antitumor properties of plants belonging to the Alangium genus, as well as to advance the development of anticancer medications, this study aims to conclude the components and mechanisms of action of the Alangium genus.

The Alangium species is a monotypic plant of the Alangiaceae family, named after its leaves that are shaped like an octagon, but in reality, five-lobed or five-cornered leaves are more common.⁶ Most plants in this category have a pungent and bitter taste, a slightly warm nature, and a slight toxicity. They belong to the liver meridian, heart meridian, and kidney meridian. They have the effects of clearing heat and detoxifying, relaxing tendons and activating collaterals, and dispersing stasis and relieving pain.⁷ There is therapeutic potential in various parts of the Alangium genus, including the roots, root bark, leaves, flowers, bark, seeds, and fruits, which can be used for medicinal purposes. Moreover, these herbs have traditional uses as expectorants, for treating diarrhea, dysentery, inflammation, hypertension, and eczema. The plants in the genus Alangium not only have a wide range of traditional uses, but modern pharmacological research has also discovered a new antitumor activity. These types of herbs overcome the resistance of cancer cells by suppressing their growth. But there is no review of the anti-tumor properties of the Alangium genus, and the subsequent information on the chemical components of this genus is not comprehensive enough. In order to conduct an in-depth study on the chemical composition and mechanism of action of anti-tumor components in plants of the genus Alangium, this article provides an overview of the species, resource distribution, anti-tumor components, and mechanisms of action of plants in the Alangium genus.

Methodology

Several search terms, such as Alangiaceae, cancer statistics, chemical composition, and antitumor, have been entered in consecutive order into various databases, including CNKI, PubMed, Google Scholar, Connected Paper, and chemical abstracts service (CAS). A total of more than 200 relevant references were found, out of which 96 references specifically focused on phytochemical and pharmacological studies of the genus Alangium. In addition to these references, several books were consulted to gather information on the traditional uses and botanical data of the genus Alangium. These include the Chinese Pharmacopoeia (2020 edition), the Chinese 119 Drug Dictionary (2006 edition), Quality standard of Chinese medicinal materials and ethnic medicinal materials in Guizhou Province (2003 edition) and the Chinese Flora.

Botany

Typically, plants belonging to Alangium Lam. are deciduous trees or shrubs, with occasional climbing varieties and very few spiny ones. The branches are cylindrical in shape, sometimes with a slight “zigzag” appearance. The leaves are arranged alternately on the stem, have a stalk, lack stipules, and are either completely smooth or divided into palm-like sections. They are usually asymmetrical on both sides of the base, with veins arranged in a feather-like pattern or having 3-7 main veins originating from the base in a palmate arrangement. The inflorescences of this plant are found in the axils of the leaves and arranged in a cymose pattern. They are usually sparsely clustered or solitary. The pedicels, or stalks of the flowers, are often segmented, and the bracts, which are small leaf-like structures, can be linear, subulate, or triangular in shape. The bracts fall off after a certain period of time. The flowers are bisexual and can be light white or yellowish in color. They are typically fragrant. The calyx, which is the outermost part of the flower, is small and has a bell-shaped tube that is fuzed with the ovary. It has 4-10 lobes with toothed or rounded ends. The petals, which are the innermost part of the flower, are also numbered between 4 and 10 and have a linear shape. In the bud stage, they are tightly connected to one another. They are arranged in a valvate manner, meaning they are regularly attached to each other at the base, although occasionally they may not be. After flowering, the upper part of the petals often curls outward. The stamens, which are the male reproductive parts of the flower, are as numerous as the petals or 2-4 times more. They alternate with the petals. The filaments, which are the stalks of the stamens, are flat and linear. The petals’ bases may be either detached or barely linked to them. The filaments’ inner surface is frequently slightly hairy. The anthers, which are the structures that produce pollen, are long and composed of two cells. They are divided longitudinally into lobes. The disc, which is a fleshy, is present. The ovary, the female reproductive organ of the flower, is situated beneath the receptacle and typically holds one or two carpels. The style, which is the stalk-like structure on top of the ovary, is positioned in the center of the disc. The stigma, which is the receptive surface for pollen, can be rounded or rod-shaped and may be undivided or divided into 2-4 lobes. The ovule, which contains the female gamete, is solitary and hangs down. It has two layers of protective covering. The fruits, called drupes, are elliptical, oval, or nearly spherical in shape. They have a prominent calyx, enamel, and disc at the top. The seeds are singular and have a large embryo and abundant endosperm. The shape of the cotyledons, which are the embryonic leaves, can vary from rectangular to nearly circular.⁸

There are approximately 30 species in this genus, which are found in Asia, Oceania, and Africa. These species can be categorized into two main groups: Alangium and Marlea (Roxb.) Baill. Among these species, 9 can be found in China, and the research discussed in this context specifically focuses on these 9 species (refer to Table 1, Figure 1).

Figure 1.

The geographical distribution of the genus Alangium in China.

Table 1.

The Genus Alangium and Its Botanical Classification in China.

Section	Species	Subspecies & Variety
Sect. 1 Alangium	Alangium salviifolium (Linn. f.) Wanger
Sect. 2 Marlea (Roxb.) Baill	Alangium alpinum (C. B. Clarke.) W.W.Smith
	Alamgium barbatum (R. Br.) Baill
	Alangium chinense (Lour.) Harm	Alangium chinense (Lour.) Harms subsp. Chinense Alangium chinense (Lour.) Harms subsp. strigosum Fang Alangium chinense (Lour.) Harms subsp. pauciflorum Fang Alangium chinense (Lour.) Harms subsp. triangulate (Wanger.) Fang
	Alangium faberi Oliv.	Alangium faberi Oliv. var. faberi Alangium faberi Oliv. var. platyphyllum Chun Alangium faberi Oliv. var. heterophyllum Yang Alangium faberi Oliv. var. perforatum (Levl.) Rehd.
	Alangium kurzu Craib in Kew Bull	Alangium kurzii Craib var. Kurzii Alangium kurzii Craib var. pachyphyllum Fang Alangium kurzii Craib var. umbellatum (Yang) Fang Alangium kurzii Craib var. handelii (Schnarf) Fang Alangium kurzii Craib var. laxifolium (Y. C. Wu) Fang
	Alangium kwangsiense Melch
	Alangium platanifolium (Sieb. et Zucc.) Harm
	Alangium yunnanense C. Y. Wu ex Fang

Traditional Use

This group of plants has been used for medicinal purposes for a long time. Various parts of the plant, including leaves, roots, flowers, and the entire plant itself, are known to have a wide range of healing properties. Alangium salviifolium, Alangium chinense, Alangium faberi, and Alangium platanifolium have been historically used for treating rheumatism and injuries. Alangium salviifolium can serve as an emetic and detoxifying agent, Alangium chinense is effective in stopping bleeding from external wounds, Alangium platanifolium can act as a pesticide, and Alangium faberi is known for its properties in clearing heat, aiding digestion, and detoxification.⁸

Phytochemistry

The chemical composition of Alangium Lam. is diverse. These compounds were isolated and purified using some conventional separation methods such as organic solvent gradient extraction, multistep Silica gel, macroporous resin, ODS, Sephadex LH-20 column chromatography, preparative thin-layer chromatography, preparative high-performance liquid chromatography, recrystallization. Until now, more than 300 chemical compounds have been detected from the genus Alangium. The classification of compounds is based on factors such as chemical structure, biological activity, origin, and synthesis pathways. It is worth noting that any classification system may have limitations, especially when dealing with the extensive structural diversity of natural products. However, reviews on natural products are usually organized by classification to ensure a logical and coherent presentation. In this review, we mainly summarized the three categories of components with anti-tumor activities, namely alkaloids, glycosides, and terpenoids. In addition, we have also attached the structure of these compounds. Some compounds with undetermined stereochemistry in literature, such as compounds 49 and 50, will be confirmed using appropriate method in our future research.

Alkaloids

Alkaloids are a group of natural drugs that were first developed from plants in the Alangium. Over 100 alkaloids have been extracted and identified from the genus Alangium, with 37 of them possessing anticancer properties. These alkaloids consist of 25 tetrahydroisoquinoline alkaloids (1-13, 16-21, 24-29), 4 indole alkaloids (32, 33, 35, 36), 2 pyridine alkaloids (23, 34), and 6 other alkaloids (14, 15, 29-31, 37). The majority of these alkaloids are found in three species of Alangium: Alangium salviifolium, Alangium bussyanum, and Alangium lamarckii. The main chemical structures are shown in Figure 2, and the chemical constituents in the genus Alangium are listed in Table 2.

Figure 2.

Structure of alkaloids 1-37 from the genus of Alangium.

Table 2.

Antitumor Components of Alkaloidal in the Genus Alangium.

NO.	Compound name	Plant	Dose	References
1	Tubulosine	Alangium bussyanum Alangium salviifiolium	A-549, 2.1 μM; SKOV-3, 0.4 μM	^9,10
2	Deoxytubulosine	Alangium bussyanum Alangium saluiifolium	A-549, 0.09 μM; SKOV-3, 0.003 μM	^9,10
3	9-demethyltubulosine	Alangium bussyanum Alangium longiﬂorum	A-549, 0.36 μM; MDA-MB-231, 0.19 μM MCF-7, 0.25 μM; KB, 0.29 μM	^9,11
4	Alangimarckine	Alangium salviifolium	A-549, 3.0 μM; SKOV-3, 0.2 μM	¹⁰
5	Tubulosatine	Alangium lamarckii	MCF-7, 2.42 μM; DLD-1, 4.52 μM	¹²
6	8-hydroxytubulosine	Alangium longiﬂorum	A-549, 0.21 μM; MDA-MB-231, 0.06 μM MCF-7, 0.12 μM; KB, 0.09 μM	¹¹
7	Deoxydesmethyltubulosine	Alangium bussyanum	/	⁹
8	O-methyltubulosine	Alangium bussyanum	CHO, 2 μM	^9,13
9	Δ1′,2′-deoxytubulosine	Alangium salviifolium	A-549, 12.51 μM; SKOV-3, 13.89 μM HeLa, 9.18 μM	¹⁴
10	Isotubulosine	Alangium lamarckii	PC-3, 5.26 μM; MCF-7, 5.47 μM HT-7, 20.61 μM; HL-60, 8.42 μM	^15,16
11	Protoemetinol	Alangium salviifolium	A-549, 0.3 μM; SKOV-3, 0.1 μM HeLa, 1.2 μM	¹⁰
12	Ankorine	Alangium salviifolium	A-549, 2.1 μM; SKOV-3, 3.6 μM HeLa, 5.3 μM	¹⁰
13	10-demethylprotoemetinol	Alangium bussyanum Alangium salviifolium Alangium lamarckii	A-549, 0.2 μM; SKOV-3, 0.06 μM HeLa, 0.01 μM	^9,10,17
14	Natalensine	Alangium salviifolium	A-549, 3.0 μM; SKOV-3, 3.7 μM HeLa, 1.3 μM	¹⁰
15	N-benzoyl-L-phenylalaninol	Alangium lamarckii	/	¹⁸
16	Cephaeline	Alangium salviifolium Alangium longiﬂorum	A-549, 3.0 μM; SKOV-3, 0.1 μM HeLa, 7.6 μM	^10,14
17	Emetine	Alangium longiﬂorum	A-549, 0.048 μM	¹⁹
18	10-O-demethylcephaeline	Alangium longiﬂorum	A-549, 0.013 μM	¹⁹
19	8-hydroxyl-cepheline	Alangium salviifolium	A-549, 3.25 μM; SKOV-3, 0.20 μM HeLa, 9.21 μM	¹⁴
20	Isocephaeline	Alangium salviifolium Alangium lamarckii	A-549, 2.7 μM; SKOV-3, 3.9 μM HeLa, 9.4 μM	^10,20
21	(−)10-O-demethylisocephaeline	Alangium longiﬂorum	A-549, 0.15 μM	¹⁹
22	Alangiifoliumine C	Alangium salviifolium	A-549, >10 μM; SKOV-3, 5.2 μM HeLa, >10 μM	¹⁰
23	Anabasine	Alangium chinense	U251, 792.0 μg/mL; SH-SY5Y, 661.2 μg/mL	^21,22
24	3-O-demethyl-2-O-methylisoalangiside	Alangium lamarckii	/	²³
25	3-O-demethyl-2-O-methylalangiside	Alangium longiﬂorum Alangium salviifolium	HepG2, 7.1 μM	^11,23
26	Alangiumkaloid A	Alangium salviifolium	MOLT-3, 13 μM; HepG2, 27.7 μM A-549, 76.5 μM; HuCCA-1, 58.6 μM	²³
27	Alangiumkaloid B	Alangium salviifolium	/	²³
28	Alangiifoliumine A	Alangium salviifolium	A-549, 12.50 μM; SKOV-3, 13.90 μM HeLa, 9.20 μM	¹⁰
29	Methyl pheophorbide a	Alangium longiﬂorum	H44, 0.50 μM AGS, 2.60 μM K562, 2.90 μM	^11,24
30	Pheophytin a	Alangium longiﬂorum	SCC9, 3.69 μM SCC9, 5.80 μM	^11,24
31	Uracil	Alangium chinense	/	²⁵
32	Alangiobussine	Alangium bussyanum	/	⁹
33	Alangiobussinine	Alangium bussyanum	/	⁹
34	Alangiumine A	Alangium chinense	GSC-3, 12.80 μM; GSC-18, 23.00 μM	²⁶
35	4,5-dimethoxycanthin-6-one	Alangium chinense	T98-G, 4.00 μM U-87, 4.00 μM U-251, 4.00 μM	^27,28
36	Javaniside	Alangium javanicum	/	²⁹
37	Adenosine	Alangium platanifolium	CHO-K1, 0.002 μM	^30,31

Glycosides

Up to this point, glycosides obtained from the genus Alangium account for the largest proportion. Researchers have found that 11 glycosides from this genus have anti-tumor effects. These consist of one lignan glycoside (38), three flavonol glucosides (39-41), one steroidal glucoside (42), three phenol glycosides (43, 46, 47), two megastigmane glycosides (44, 45), and additional glycoside (48). The structures of these glycosides can be seen in Figure 3, and their names, the plants from which they are sourced, and the references can be found in Table 3.

Figure 3.

Structure of glycosides 38-48 from the genus of Alangium.

Table 3.

Antitumor Components of Glycosides in the Genus Alangium.

NO.	Compound	Plant	Dose	References
38	Urolignoside	Alangium chinense	A-549, 15.29 μM; SK-MEL-2, 12.29 μM HCT-15, 28.14 μM	^6,32
39	Kaempferol 3-O-β-D-glucopyranoside	Alangium salviifolium	/	^33,34
40	Rutin	Alangium platanifolium	GLC4, 4.00 μM	^30,35
41	Kaempferol-3-O-rutinoside	Alangium platanifolium	/	^36,37
42	Daucosterol	Alangium platanifolium	/	^38,39
43	Salicin	Alangium chinense Alangium platanifolium Alangium salviifolium Alangium faberi	MCF-7, 16.6 mg/L Panc-1, 24.6 mg/L	^33,40–43
44	(6S, 9R)-roseoside	Alangium chinense	HeLa, 20.00 μg/mL	^44,45
45	Foliasalacioside B1	Alangium chinense	/	^44,46
46	Glucosyringic acid	Alangium chinense	/	^47,48
47	Coniferin	Alangium lamarckii	A-549, 16.33 μM	^49,50
48	Sweroside	Alangium lamarckii	/	^51,52

In their study, Itoh and colleagues³⁰ discovered rutin (40) for the first time in Alangium platanifolium. No other species within the Alangium genus have been found to possess this compound. Researchers, led by Hideaki,³⁶ extracted five flavonol glucosides from the leaves of Alangium platanifolium. In later investigations, Li and colleagues³⁷ found that one of these compounds, known as kaempferol-3-O-rutinoside (41), demonstrated anti-cancer properties. Zhu et al³⁸ isolated a steroidal compound known as daucosterol (42) from the root bark of Alangilum plantanifolium. Subsequently, it was discovered that daucosterol (42) possesses anti-lung cancer properties.³⁹

Researchers have identified a chemical compound known as salicin (43) in different plants from the Alangium. Researchers, such as Itoh et al,⁴⁰ extracted 43 from the leaves of Alangium platanifolium and Alangium chinense. Shi et al,⁵³ also found 43 in the stem bark of Alangium plantanifolium. Hung et al³³ isolated it from the leaves of Alangium salviifolium, while Liu et al⁴¹ were the first to extract it from Alangium faberi.

Terpenoids

The genus Alangium has 20 terpenoids with antitumor properties, including 11 sesquiterpenes (49-59), 2 megastigmane monoterpenes (67, 68), and 7 triterpenes (60-66). The structures, names, corresponding sources, and references of these compounds are summarized in Figure 4 and Table 4.

Figure 4.

Structure of terpenoids 49-68 from the genus of Alangium.

Table 4.

Antitumor Components of Terpenoids in the Genus Alangium.

NO.	Compound	Plant	Dose	References
49	(−)-7,8-dihydroxycalamenal	Alangium salviifolium	TYR, 172 μM	⁵⁴
50	Alangene A	Alangium salviifolium	CYP-19, 0.09 μM; MOLT-3, 7.9 μg/mL	⁵⁵
51	Alangene D	Alangium salviifolium	CYP-19, 2.91 μM; MOLT-3, 2.1 μg/mL	⁵⁵
52	Alangene E	Alangium salviifolium	CYP-19, 0.13 μM	⁵⁵
53	Alangene F	Alangium salviifolium	CYP-19, 0.30 μM	⁵⁵
54	Alangene G	Alangium salviifolium	CYP-19, 0.06 μM	⁵⁵
55	Mansonone G	Alangium salviifolium	CYP-19, 1.19 μM	^55,56
56	Mansonone E	Alangium salviifolium	CYP-19, 6.20 μM	^55,57
57	Mansonone H	Alangium salviifolium	CYP-19, 2.05 μM	⁵⁵
58	7-hydroxycadalene	Alangium chinense	MES-SA/MX2, 0.132 μM MES-SA, 0.01 μM	^28,58
59	Mansorin I	Alangium chinense	HCT-116, 11.1 μM HeLa, 3.95 μM	^44,59
60	Myriceric acid B	Alangium salviifolium	MOLT-3, 3.9 μM; HepG2, 22.1 μM A-549,49.7 μM; HuCCA-1, 30.0 μM	²³
61	Betulinic acid	Alangium lamarckii	HepG2, 16 μg/mL; SMMC-7721, 16 μg/mL	^60,61
62	Betulinaldehyde	Alangium lamarckii	A-549, 100 mg/kg	^60,62
63	Botulin	Alangium lamarckii	/	^60,63
64	Lupeol	Alangium lamarckii	Du145, 48 μM	^60,64
65	(23E)-coumaroylhederagenin	Alangium chinense	KB, 1.3 μM; HT29, 2.4 μM	^65,66
66	(23Z)-coumaroylhederagenin	Alangium chinense	KB, 1.6 μM; HT29, 3.6 μM	^65,66
67	3-oxo-α-ionol	Alangium chinense	/	^44,67
68	Vomifoliol	Alangium chinense	/	^44,68

Through searching an extensive literature indicates that the sesquiterpenes with antitumor activity in Alangium are mainly concentrated in Alangium salviifolium and Alangium chinense. Yagi et al⁵⁴ discovered a new type of cadinane-type sesquiterpenoid compound, (−)-7,8-dihydroxycalamenal (49), from Alangium salviifolium. Compared to the standard tyrosinase inhibitor β-arbutin (IC₅₀= 750 µM), this compound exhibits strong inhibitory activity against the enzyme tyrosinase (IC₅₀= 172 µM). 7 sesquiterpenoids (50-57) having antitumor activity were discovered by Phanruethai et al from the stems of Alangium salviifolium.⁵⁵ These substances exhibit potent aromatase inhibition but have limited cytotoxic effects. Among this group, alangene G (54) stands out as the most potent aromatase inhibitor, with an IC₅₀ value of 0.06 µM. Triterpenoids (60-66) with antitumor activity have been isolated from Alangium salviifolium, Alangium lamarckii, and Alangium chinense.

Other Compounds

Seventeen substances with antitumor properties have been identified in the Alangium, primarily from Alangium chinense. These substances include four flavonoids (72-75), four lignans (71, 81-83), two sterols (84, 85), five phenolic acids (76-80), and two straight-chain alkanes (69, 70). (See Figure 5 and Table 5 for details.)

Figure 5.

Structure of other compounds 69-85 from the genus of Alangium.

Table 5.

Antitumor Components of Other Compounds in the Genus Alangium.

NO.	Compound	Plant	Dose	References
69	Myristic acid	Alangium salviifolium	/	^69,70
70	Myricyl alcohol	Alangium salviifolium	/	^69,71
71	Lyoniresinol	Alangium premnifolium	/	^72,73
72	Hydnocarpin	Alangium chinense	/	^74,75
73	Kaempferol	Alangium salviifolium	/	^33,76
74	Quercetin	Alangium chinense	/	^72,77
75	Luteolin	Alangium chinense	/	^72,77
76	Vanillin	Alangium chinense	MCF-7, 45.01 μM; HepG2, 48.09 μM	^6,78
77	Gallic acid	Alangium chinense	/	^6,79
78	Gallincin	Alangium chinense	MCF-7, 81.077 μM	^6,80
79	Ethyl gallate	Alangium chinense	/	^6,81
80	Methyl caffeate	Alangium platanifolium	HeLa, 30.11 μM	^53,82
81	(+)-pinoresinol	Alangium kurzii	SKOV-3, 20 μM	^52,83
82	Syringaresinol	Alangium kurzii	/	^52,84
83	(+)-lariciresinol	Alangium kurzii	HepG2, 208 mg/L	^52,85
84	β-sitosterol	Alangium platanifolium	HCT-116, 140.0 μM	^38,86
85	Stigmasterol	Alangium platanifolium	/	^38,87

Kaempferol (73) was initially isolated from the leaves of Alangium salviifolium in 2009 by Hung et al,³³ and it was then discovered for the first time in Alangium faberi in 2022 by Liu et al⁴¹ Research shows that 73 has a certain inhibitory effect on the growth of breast cancer cells.⁷⁶

Mechanism of Action Against Tumor

With a deeper understanding of the anti-tumor effects and mechanisms of natural medicines, researchers have discovered that these medicines have regulatory effects on multiple signaling pathways. At present, the mechanisms through which anti-tumor effects are achieved include regulating the immune system, inhibiting tumor cell growth, inducing tumor cell differentiation, impeding tumor cell metastasis, initiating tumor cell apoptosis, inhibiting tumor angiogenesis, overcoming multidrug resistance in tumor cells, and suppressing telomerase activity.^88,89 Through extensive literature research, it has been found that the main chemical components of the Alangium primarily achieve anti-tumor effects by inhibiting tumor cell proliferation, suppressing tumor cell growth, promoting tumor cell apoptosis, and blocking the cell cycle (Figure 6).

Figure 6.

The mechanism of the genus Alangium (by Figdraw).

Inhibits the Growth and Proliferation of Tumor Cells

The most prominent characteristic of tumor cells is their abnormal proliferation, which continuously disrupts the normal cellular environment and ultimately leads to the death of healthy cells. Inhibiting the proliferation and growth of tumor cells is a commonly used method for treating cancer in clinical practice.

A substance known as 3-O-demethyl-2-O-methylalangisid (25), extracted from the stem of Alangium salviifolium, has been found to effectively inhibit the growth of HepG2 cancer cells. It exhibits an IC₅₀ value of 7.1 µM.²⁷ At the start, rutin (40) was identified as a flavonoid glycoside from Alangium platanifolium by Itoh et al³⁰ 40 can participate in the regulation of various molecular pathways such as the Akt/PI3K/mTOR signaling pathway, modulation of STAT signaling, modulation of Wnt/β-catenin signaling, modulation of mitogen-activated protein kinase (MAPK) signaling, targeting of apoptosis pathways and autophagy signaling molecules, and can also interact with microRNAs to inhibit tumor cell growth.³⁵ It has been found to inhibit the growth of HL-60 cells, and was commonly used in the treatment of leukemia.⁹⁰ It was also observed that 40 had an impact on GL-15 glioma cells over 72 h. The compound 40 showed the strongest ability to inhibit cell growth at concentrations of 50-100 µM. The inhibition of glioma cells depended on the concentration of the compound. Furthermore, it caused a decrease in P-ERK1/2 levels, resulting in a significant accumulation of tumor cells in the G2 phase. This effect also contributed to the anti-proliferative properties of compound 40.⁹¹

Betulinic acid (61), betulinaldehyde (62), and lupeol (64) are triterpenoids derived from Alangium lamarckii and possess anti-cancer properties. The proliferation of HepG2 and SMMC-7721 cells was suppressed by 61 in a manner that was influenced by the dosage and duration of treatment. Further investigations revealed that the suppression of HepG2 cells by 61 could be attributed to its ability to hinder the ROCK1/IP3/RAS signaling pathways.⁹² Compound 62 has the potential to be used as a drug for tumor immunotherapy, which acts as an activator of RORγt. Nude mice were injected with A549 cells under the skin, and the administration of 62 successfully inhibited the proliferation of tumor cells. This anti-tumor effect is likely achieved by blocking several signaling pathways that promote cell proliferation in A549 cells.⁶² Compound 64 inhibits the growth of cancer stem cells and chemoresistant Du145 cells.⁹³

Quercetin (74), a flavonoid found in Alangium chinense, has been shown to inhibit the growth of colon cancer cells in a dose-dependent manner. Meenu et al conducted a research study using the CCK-8 assay to investigate the effect of compound 74 on inhibiting cell growth in colon cancer cell lines in vitro. They discovered that 74 inhibits the growth of colon cancer cells by regulating the production of proteins associated with ageing, such as Sirtuin-6 and Klotho, and by inhibiting telomerase activity, which leads to shortened telomeres.⁹⁴

Pinoresinol (81), a lignan found in Alangium kurzii, has been discovered to inhibit the proliferation of SKOV-3 ovarian cancer cells by specifically targeting the Ras/MEK/ERK signaling pathway. This compound reduces the mitochondrial membrane potential of SKOV-3 cells and inhibits their invasive capacity. As a result, it suppresses tumor cell growth and exhibits anti-cancer properties.⁸³

Promotes Apoptosis of Tumor Cells

Apoptosis, which refers to programed cell death, occurs when the body actively adapts to a new environment. Regulating itself is a natural process employed by cells. This method is considered a more effective treatment, because it involves multiple signaling pathways, intricate mechanisms, and can target tumor development at any stage.

A compound called 4,5-dimethoxycanthin-6-one (35), which is an alkaloid found in Alangium chinense, has been discovered to inhibit the growth of leukemia, colon cancer, retinoblastoma, and breast cancer cells. Importantly, this compound has been found to be less harmful to normal human cells.⁹⁵ 35 has the potential to act as a novel inhibitor of LSD1, which could help manage glioblastoma and halt the proliferation of U251 and T98G cells. By targeting the LSD1-mediated AKT/mTOR and MAPK signaling pathways, this compound inhibits cell proliferation in glioblastoma, leading to cell cycle arrest and promoting apoptosis.²⁷ A glycoside called kaempferol-3-O-rutinoside (41), derived from Alangium platanifolium, has the ability to induce apoptosis in cancer cells. It achieves this by disrupting the cytoskeleton, impairing mitochondrial function, and causing an excessive influx of calcium.³⁷

Studies have shown that mansonones have a significant anti-tumor effect, with mansonone G (55) being particularly effective against HCT-116 and HT-29 cell lines in colorectal cancer (CRC) while causing less harm to normal cells. 55 triggers the production of reactive oxygen species (ROS) in both HCT-116 and HT-29 cells, which is linked to cell toxicity and apoptosis. The primary anti-tumor action of 55 involves reducing the expression of Bcl-2 and Bcl-xL proteins in CRC cell lines and increasing the expression of BAK protein in HT-29 cells. Furthermore, it affects the phosphorylation of ERK1/2 in HCT-116 cells and activates ERK1/2 phosphorylation in HT-29 cells. It also inhibits the AKT signaling pathway in CRC cell lines and regulates the ERK1/2 signaling pathway.⁵⁶ Mansonone E (56) is also a compound with a more pronounced anti-tumor effect in the mansonones. Even at concentrations as low as micrograms, 56 can significantly inhibit the proliferation of leukemia K562 cells. The inhibitory effect depends on both time and dosage. Its mechanism of action is to induce apoptosis in leukemia K562 cells through the activation of caspase-8 and caspase-3 pathways, and the Bcl-2 family proteins do not play a role in the regulation of apoptosis.⁹⁵ Studies have indicated that substances 55 and 56 have been extracted from the stem of Alangium salviifolium.⁵⁵

Blocking the Cell Cycle

The activity of tumor cell cycle proteins is abnormally activated, leading to uncontrolled proliferation. Inhibiting the activity of cell cycle proteins can halt the cell cycle and generate anti-tumor effects.

The tetrahydroisoquinoline alkaloid 8-hydroxytubulosine (6), which was discovered in Alangium longiflorum, primarily inhibits the growth of tumor cells by inducing cell cycle arrest.¹¹ Foliasalacioside B1 (45), a compound found in Alangium chinense, has been discovered to inhibit the G2/M phase of the cell cycle, thereby exhibiting anticancer properties.⁴⁶ Lupeol (64), a triterpenoid compound found in Alangium lamarckii, has been found to possess anti-cancer properties. It effectively inhibits the proliferation, movement, and infiltration of CNE2 cells, induces programed cell death, and arrests the cell cycle at the G1 phase.⁶⁴

Gallic acid (77), which is a type of phenolic acid, was separated from Alangium chinense.,. According to Pang, studies have found that this compound can inhibit the growth of tumor cells by blocking the H19-Wnt/β-catenin signaling pathway in osteosarcoma cells. It also has the ability to prevent tumor cell invasion and metastasis.⁷⁹

Other Mechanisms of Action

In addition, literature research has revealed that the chemical composition of the Alangium contains other mechanisms that exhibit anti-tumor effects, such as inhibiting tumor angiogenesis and regulating the immune system.

In 2019, the COVID-19 pandemic ravaged the entire country. Research has found that patients with lung adenocarcinoma (LUAD) are more susceptible to COVID-19. In light of this, researchers conducted in-depth studies and discovered that Emetine (17) n reduce the viability and proliferation of U2OS cells. It can also induce cell apoptosis by activating caspase-3 and caspase-7, effectively inhibiting the migration and invasion of U2OS cells.⁹⁶

Furthermore, salicin (43) has been extracted from various plants belonging to the Alangium genus. According to Muhammad, 43 has the ability to suppress the angiogenic activities of endothelial cells, including migration, lumen formation, and aortic budding. It also possesses antioxidant and anti-inflammatory properties, which enable it to inhibit tumor weight, tumor volume, levels of carcinoembryonic antigen, and tumor cholesterol content.⁴³

Conclusion and Outlook

This article presents a thorough examination of different aspects of Alangium Lam. plants, including their physical characteristics, geographical distribution, anti-tumor compounds, and mechanisms of action. There are approximately 30 species in this plant genus, with 9 main species found in China. These species are distributed throughout the country, except in Heilongjiang, Inner Mongolia, Xinjiang, Ningxia, and Qinghai. Various substances with significant anti-tumor effects, including alkaloids, glycosides, terpenoids, flavonoids, lignans, and steroids, have been extracted from plants within the Alangium. There are a total of 85 anti-tumor active ingredients, with alkaloids being the most abundant category. Out of these compounds, 37 anti-tumor active ingredients have been identified in Alangium, and many of them contain a central structure known as tetrahydroisoquinoline. This core structure can be further investigated as a potential focal point for studying anti-tumor activity. There are over 160 different types of glycoside compounds found in plants belonging to the Alangium genus. However, only 11 compounds with anti-tumor activity have been discovered so far. The next group of compounds is terpenoids. Among the Alangium genus, 20 compounds with anti-tumor activity have been isolated, including sesquiterpenoids and triterpenoids. Sesquiterpenoids are primarily isolated from Alangium salviifolium and Alangium chinense, while triterpenoids are mainly obtained from Alangium salviifolium, Alangium lamarckii, and Alangium chinense. These compounds primarily exert anti-tumor effects by inhibiting the growth and proliferation of tumor cells. Furthermore, there are 17 compounds with anti-tumor properties, which consist of 4 flavonoids, 4 lignans, 2 sterols, 5 phenolic acids, and 2 straight-chain alkanes. Some compounds, such as Rutin (40)、Salicin (43)、Lupeol (64)、Kaempferol (73)、Quercetin (74)、Luteolin (75)、Vanillin (76)、β-sitosterol (84) and Stigmasterol (85), have been found to be widely present in plants.

Recently, researchers have been focusing on traditional cancer therapy as a potential new treatment option. The Alangium genus, which is distributed globally, has a history of being used for medicinal purposes in various traditional medicine practices to treat cancer. The development of cancer is varied and intricate. The Alangium plant species contains numerous potent compounds and diverse extracts that can inhibit the growth of various types of tumors through immune system regulation, inhibition of tumor growth, promotion of tumor cell differentiation, prevention of tumor metastasis, initiation of tumor cell death, hindrance of tumor blood vessel formation, overcoming drug resistance in tumors, and suppression of telomerase activity. However, there is relatively little research on the mechanisms of new anti-tumor effects, such as the microenvironment, copper-induced cell death, and iron-induced cell death.

In summary, the Alangium genus is rich in chemical constituents and demonstrates significant anti-cancer properties that have the potential to reduce both mortality and morbidity through various mechanisms. This is in contrast to other plant genus such as Catharanthus roseus, which is mainly known for its anti-tumor effects associated with alkaloids. The main mechanism of the anti-tumor effect of these alkaloids is primarily through their action on the tumor microenvironment. Given the significant medical potential of this plant species, it is imperative to conduct comprehensive separation studies on its chemical compounds using bioactivity-guided methods. Future research should focus on investigating the pharmacological effects of these compounds in organisms, delving into the broader and deeper mechanisms underlying their biological activity. This will lay the groundwork for identifying potential lead compounds against tumors and for facilitating drug development.

Footnotes

Abbreviations

Acknowledgements

The authors express their gratitude to the editor and the anonymous reviewers for their t expert guidance and constructive feedback to enhancing our manuscript.

Author Contributions

Conception and design of the manuscript: C.S.; conducting literature search and analysis of the information: R.L., Q.D. and Y.K.; draft and revision of the manuscript: R.L. and Z.Z.; editing the manuscript: H.W. and H.Z.; finalization and approval of the revised manuscript for submission: C.S. and Z.Z. All authors have read and agreed to the published version of the manuscript.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

This research was funded by Natural Science Foundation of Shandong Province (No ZR2023MC009), Lin He's Academician Workstation of New Medicine and Clinical Translation in Jining Medical University (No JYHL2022ZD03), College Students’ Innovation and Entrepreneurship Program of Jining Medical University (cx2023069z).

ORCID iD

Chunmei Sai

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