Open access peer-reviewed chapter - ONLINE FIRST

Cytotoxicity and Antitumor Action of Lignans and Neolignans

Written By

Ana Laura Esquivel-Campos, Salud Pérez-Gutiérrez, Leonor Sánchez-Pérez, Nimsi Campos-Xolalpa and Julia Pérez-Ramos

Submitted: November 24th, 2021 Reviewed: December 20th, 2021 Published: March 4th, 2022

DOI: 10.5772/intechopen.102223

Secondary Metabolites - Trends and Reviews Edited by Ramasamy Vijayakumar

From the Edited Volume

Secondary Metabolites - Trends and Reviews [Working Title]

Dr. Ramasamy Vijayakumar and Dr. Suresh Selvapuram Sudalaimuthu Raja

Chapter metrics overview

45 Chapter Downloads

View Full Metrics


Lignans and neolignans are plant’s secondary metabolites, widely distributed in the plant kingdom, and have been identified in more than 70 plant families. These compounds are mainly localized in lignified tissues, seeds, and roots. Lignans and neolignans present a great variety of biological activities, such as antioxidant, anti-inflammatory, antineurodegenerative, antiviral, antimicrobial, and antitumor. By 2040, it is estimated that the number of new cancer cases per year will rise to 29.5 million; therefore, the development of new anticancer agents and adjuvants is essential. Lignans and neolignans have also indicated a reduction in the risk of cancer at different stages. The objective of this review is to search and analyze the cytotoxic and antitumor activity of lignans and neolignans that can be an important source of new antitumor drugs. We have made a comprehensive summary of 113 lignans and neolignans, obtained from 44 plants and divided between 34 families, which demonstrated cytotoxic activity in several human cancer cell lines evaluated through various in vitro studies and other in vivo models, by inducing mitochondrial apoptosis and cell cycle arrest, inhibiting NF-κβ activity and activation of metalloproteinases (MMPs), among other processes. Overall, 13 compounds, methoxypinoresinol, arctigenin, trachelogenin, 4-O-methylhonokiol, honokiol, bifidenone, (−)-trachelogeninit, deoxypodophyllotoxin, matairesinol, bejolghotin G, H, and I, and hedyotol-B, showed the best anticancer activity.


  • Neolignans
  • cytotoxic activity
  • cancer
  • natural products

1. Introduction

Cancer produces uncontrolled cell proliferation, and one of the treatments used to stop it is chemotherapy. However, although these therapies have advanced over the years, they not only destroy cancer cells but also healthy cells, causing adverse effects in people suffering from this disease. A great variety of tumors are the cause of death in the population; the World Health Organization (WHO) reports that cancer causes approximately 10 million deaths each year, with one out of every six deaths worldwide due to some type of cancer [1]. The main problem of this disease is that it is often detected at an advanced stage, and the lack of access to health services and the high cost of treatment are common, particularly in developing countries. The WHO suggests that 90% of the population in developed countries has access to treatment for this disease, while only 15% of the population in developing countries has access to treatment [2].

At present, the search for new chemotherapy drugs continues, with the purpose of having a wide range of compounds that help improve the quality of life of people with cancer. For many years, plants have played a very important role, as a source of compounds with biological activity. As a treatment alternative, multiple plant genera and species have demonstrated their cytotoxic potential in cancer cells and have been used in traditional medicine in many countries as anti-inflammatory and antirheumatic agents, among others, as well as antirhythmic and antitumor agents, since they inhibit cell proliferation and induce cytotoxicity in a large number of cell lines, as demonstrated through research [3].

Lignans are a group of secondary metabolites found in different plant and animal species. Lignans are biologically synthesized from the shikimic acid pathway [4] and through different reactions (Figure 1). Despite their structural variety, lignans are dimers of phenylpropanoid units that are linked via their β-carbon atoms [5]. Dimers of phenylpropanoid units that are coupled via other linkages are named neolignans [6]. The lignan family is classified into the following eight classes, based on how oxygen is incorporated into the skeleton and the cyclization pattern: furofuran, furan, dibenzylbutane, dibenzylbutyrolactone, aryltetralin, arylnaphthalene, dibenzocyclooctadiene, and dibenzylbutyrolactol. The neolignans have structural variety and are divided into more than 15 groups, some of them are: benzofuran, dihydrobenzofuran, diarylethane, benzodioxine, alkyl aryl ether, and bicycloctane derivatives, among others [7]. These metabolites present different biological activities, such as cytotoxicity; as an example, podophyllotoxin is used in cancer treatments today [8].

Figure 1.

Shikimic acid pathway for lignan and neolignan biosynthesis.

In this sense, Jiang and col. [9] have suggested that this behavior is not the same with all cell lines, where tested, and that it depends on the type of lignan for its cytotoxicity. Multiple lignans are being studied, particularly for their effectiveness against breast cancer. Because they bind to cells where there are estrogen deposits, they have been shown to be effective against breast cancer [10]. The cytotoxic activity of various lignans has also been studied on colon, pancreatic, throat, and oral cancers, among others, but the comparability of these studies depends on the type of assay with which the findings are reported. Therefore, the assay selection is of great importance in understanding the toxicity profile of lignans, as an approximation of their cytotoxic potential if used in humans.

The aim of this research was to present an overview of the anticancer activity of lignans in vitroand in vivostudies (Table 1), with the type of assay described in the international literature in the last 5 years, as well as their structures (Table 2).

1.3-(1, 3-benzodioxol-5- yl methyl)-4-[(3, 4-dimethoxyphenyl)methyl]dihydro-, (3S-cis)-2(3H)- furanone
2.4-[(R)-1, 3-benzodioxol-5-ylhydroxymethyl]-3-(1, 3-benzodioxol-5-ylmethyl)dihydro-, (3S, 4R)-2(3H)-furanone
4.Phenol, 4, 4′-(2R, 3S, 4S)-tetrahydro2-methoxy-3, 4-furandiyl]bis(methylene)]bis[2-methoxy
5.4, 4′-dihydroxy-3, 3′, 9-trimethoxy-9, 9′-epoxylignan
MTT assay
IC50 μM
> 40
3-(3′-methoxy-4′- hydroxylbenzyl)-γ-butyrolactone
MTT assayIC50 μM[12]
9.Sesamin (SE)MTT assayCytotoxicity %[13]
CCK-8 assay in
Cell apoptosis assay in EL4
lymphoma (EL4) induced in
BALB/c mice
% Viability (40 μM)
50 to 80 (48, 72 y 96 h)
SE Induced apoptosis by increased expression levels of apoptotic markers (Bax/Bcl-2) and cleaved-Caspase 3
SE decreased the size of tumor (10 mg/kg for 21 days)
10.MethoxypinoresinolMTT assay
IC50 μM
11.Erythro-austrobailignan-6 (EA6)MTT assay
4 T-1
Western blot
IC50 μM (24 h)
EA6 increased the levels of p38 MAPK and caspase-3, in 4 T-1 and MCF-7
12.Mappiodoinin A
13.Mappiodoinin B
14.Mappiodoinin C
16.Odoratisol A
18.Prunustosanan AI
MTT assayIC50 μM[9]
21.Noralashinol B
22.Noralashinol C
MTT assay
IC50 μM[17]
23.Arctigenin (ATN)MTT assayIC50μM[18]
SRB assay in MCF-7
Colony formation assay.
Cell cycle analysis by flow cytometry
At 200 μM arctigenin inhibited cell viability around 50%.
ATN induced autophagy in MCF-7cells.
The lignan might inhibit downstream effector molecules of the TOR resulting in a decreased expression of Erα in ER-positive MCF-7
Cell Count Reagent
Western blot.
JC-1 mitochondrial membrane potential
CC50 μM[20]
ATN induced the caspase-9-mediated apoptosis of glucose-starved PEL cells (BC3).
ATN induced mitochondrial disruption in glucose-starved BC3 cells by decreasing ATP levels and disrupting the mitochondrial membrane, and suppressed ERK and p38 MAPK signaling
24.Honokiol (HNK)CCK-8 assay
Apoptosis by annexin
Xenograft nude mice model
GI50 μM at 48 h
This compound induced apoptosis cell death
HNK had antitumour activity
MTT assayIC50 μg/mL[22]
KKU-213 L5
Apoptosis by Muse™ Cell Analyzer
Western blot
Flow cytometer analysis
24 (h)48 (h)
% apoptosis
50 μM70 μM
HNK increased apoptosis by decrease of intact caspase-3, whereas cleaved caspase-3 increased
The antitumor activity of dendritic cells (DC) is increased using a lysate derived from a cell line (KKU-2113 L5) treated with HNK
HNK increased antitumor activity of DCs stimulated with cell lysates derived from KKU-213 L5
26.Aloifol I
MTT assay
IC50 μM[23]
30.(−)-Trachelogenin (TA)MTT assay
Membrane integrity and viability by the exclusion of propidium iodide
IC50 μΜ
TA did not induce apoptosis, but it was induced by autophagic death mediated by the increase of LC3 activation. Also promoted changes in the expression of Beclin-1 levels
31.4-O-methylhonokiol (MH)MTT assay
IC50 μM
32.Bifidenone (BF)Sequoia Sciences Assay
Caspase-Glo 3/7 assay
LDH assay
Polymerization assay
Tubulin competition assay
IC50 μM
BF increased the levels of caspase (2.5-fold)
BF increased the level of LDH released
BF inhibits tubulin polymerization in a dose-dependent manner
BF interfered with mitosis by disrupting the microtubule dynamics necessary for cell division
IC50 μM
33.(+)-HinokininWST-8 Assay
PC50 μM
34.(−)-Deoxypodophyllotoxin (DPT)MTT assay
Annexin-V/propidium iodide (PI) assay
Acridine orange assay
IC50 nM
DPT induced apoptosis related with proteins
Annexin-V positive cells were increased in DPT-treated cells, compared with control group.
Formation of acidic vesicular organelles (AVOs) was significantly increased in DPT-treated cells in a dose-dependent manner
35.Lariciresinol (LA)CCK-8 assay
Flow cytometry
Immunofluorescence staining
Annexin V/PI double-staining assay
Mitochondrial membrane potential (ΔΨm)
IC50 μg/mL
208 after 48 h
LA exhibited an apoptosis-inducing effect
LA decreased Ki-67 expression and induced apoptosis
LA was a concentration- and time-dependent manner resulted in an
increasing percentage of apoptosis, which might result in the cytotoxic activity of LA on HepG2 cells
LA might induce HepG2 cell
apoptosis through the mitochondrial-mediated apoptosis pathway
MTT assay
IC50 μM[30]
38.Heilaohulignan C
39.Kadsuralignan I
40.Longipedunin B
MTT assayIC50 μM[31]
38 39 40
41.(−)-(7′S,8S,8′R)- 4,4′-dihydroxy-3,3′,5,5′-tetramethoxy-7′,9-epoxylignan-9′-ol-7-one
MMP-9 assayIC50 μM[32]
44.Oryzativol CEz-Cytox cell kit
MDA -MB -231
IC50 μM
45.(−)-AsarininMTT assay
Annexin V-FITC/PI Double Staining
IC50 μM
This compound might induce apoptotic cell death in human ovarian cancer cells
47.Dehydrodiconiferyl (DDI)
MTT assayIC50 μM[35]
Flow cytometry
DDI induced apoptosis
49.Dehydrodieugenol B
50.Methyldehydrodieugenol B (MEB)
MTT assayIC50 μg/mL[36]
Comet Assay CBMN on SKMEL-29100% of apoptosis25% of apoptosis
MEB increased DNA damage by cytokinesis
51.(−)-RabdosiinMTT assayIC50 μg/mL[37].
Flow Cytometry% of apoptosis
52.Kalshiolin ASRB assay
IC50 μg/mL
35.9 to 43.3
34.(−)-Deoxy podophyllotoxin
SRB assay
1.7 ng/mL3.7 μg/mL
54.Phengustifols ACCK-8 assay
IC50 μM
55.Hedyotol-BMTT assay
IC50 μM
56.Heilaohusus CMTT assay
IC50 μM[42]
57.Zijusesquilignan A
58.Zijusesquilignan B
59.Zijusesquilignan C
MTT assayIC50 μM[43]
60, 61.Crataegifin B (enantiomers)
MTT assayIC50 μM[44]
Flow cytometryCompound 61 at 25 μM induced apoptosis in Hep3B cell in 10.76%
63.Bejolghotin A
64.Bejolghotin B
65.Bejolghotin C
66.Bejolghotin G
67.Bejolghotin H
68.Bejolghotin I
MTT assayIC50 μM[45]
MTT assayIC50 μg/mL[46]
70.7-hydroxy- hinokinin
MTT assay
IC50 μM[47]
71.Cleistonkinin A
72.Cleistonkinin B
73.Cleistonkinin C
74.Cleistonkinin D
75.Cleistonkinin E
MTT assayIC50 μM[48]
76.Cleistonkiside A
77.Cleistonkiside B
78.Crataegusal A
79.Crataegusal A
MTT assay
IC50 μM[49]
80.Miliusin A
81.Miliusin B
82. Miliusin 7R,8S
83. Miliusin C
84.Miliusin D
85.Miliusin E
86.Miliusin F
MTT assayIC50 (μM)[50]
87.Pleiocarpumlignan BMTS assay
IC50 μM
88.Officinalioside (OFD)MTT assay
OFD showed cytotoxic effect at 50 μmol/L and 100 μmol/L[52]
MTT assayIC50 μM[53]
92.Schisphenlignan M
93.Schisphenlignan N
94.Gomisin G
95.Schisantherin D
96.Schisantherin A
97.Epigomisin O
98.(+)-omisin K3 (Schisanhenol)
99. Schisanhenol B
100.Gomisin A
MTT assay
IC50 μM
13.5 to >50
101.Glalignin B
102.Glalignin C
103.Glalignin E
104.Glaneolignin A
105.Dihydrodehydro diconiferyl alcohol
106.Tribulusamide A
MTT assay
IC50 μM[55]
107.Pinoresinol monomethyl ether-β-D-glucoside (PMG)MTT assay
IC50 μg/mL
10.1 (24 h) and 3.54(48 h)
>250 (24 and 48 h)
108.Methylcubebin (MB)
109.Cubebin (CB)
110.Dyhydrocubebin (DB)
111.Ethylcubebin (EB)
MTT assay
Transwell cell migration assay
MB and CB decreased cell proliferation at concentrations of 10 and 50 μg/mL
DB, EB, and MB decreased cell migration
2-furanyl] phenoxy]-1,3-propanediol (MFP)
MTT assay
Flow cytometry
IC50 μM
MFP induced dose-dependent apoptosis in MCF-7 cells

Table 1.

Anticancer activity of lignans and neolignan isolated of different plants.

Abbreviations: PC50: Preferential cytotoxicity mean Concentration; IC50 Inhibitory mean Concentration; CC50: cytotoxic effects; GI50:Growth inhibition; LDH deshidrogenase lac tate; MTT: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; SRB: Sulforhodamine B; CCK-8: The Cell Counting Kit 8 assay; CBMNCyt: cytokinesis block micronucleus; MMP-9: Matrix metalloproteinase 9; LC3: a process that involved the bulk degradation of cytoplasmic components (positive structures are prominent in autophagy-deficient); MAPK: protein kinase; ERK: extracellular signal-regulated kinase; MYCN: proto-oncogene; MYCN2: human neuroblastoma cell with MYCN amplification; pCNA nuclear antigen of cell proliferation; STATs: Signal transducers and activators of transcription; JC-1: mitochondrial membrane assay.

Human cancer cell lines: A2780, SKOV3, OVCAR-8: ovarian; A549, NCI-H460: lung; BGC-823, SGC7901: gastric cancer; Caco-2, HCC-2998, HCT-16, HCT-116, HCT-8, SW480, SW620: colon cancer; HeLa: human cervical uterine cancer; KB, KBVIN: papillomavirus; Bcap-37: endocervical adenocarcinoma; Hep3B, HepG2, SMMC 7721: hepatocellular carcinoma; KKU-213 L5: cholangiocarcinoma; HEp-2: laryngeal cancer; HL-60: promyelocytic leukemia; SN-1: leukemia; HN22: head and neck squamous cell carcinoma; TNBC, MCF-10A, MCF-7, MDA-MB-468, MDA-MB-453, MDAMB-231, SK-BR-3: breast cancer; NB: neuroblastoma; SKMEL-147: wild-type human melanoma; SKMEL-29: human melanoma carrying the B-Raf mutation-V600E; SKMEL-2, A375: malignant melanoma skin; M14, UACC-62: melanoma; OC2, SCC-25, OSCC: squamous cell carcinoma; Lu carcinoma; MIA-PaCa2, CAPAN-1, KLM-1 PANC-1: pancreatic cancer; PC-3: prostate cancer; SF-295, U251: glioblastoma; ACHN: renal cancer; U2OS: osteosarcoma; BCBL1: lymphoma cells; muscular cancer cell lines 4 T-1.

Table 2.

Lignans and neolignans structures.


2. Discussion

Lignans act as antioxidants and play an important role in protection against herbivores, pathogenic fungi, and bacteria [59]. These lignans have positive effects on different diseases, such as cancer and type 2 diabetes.

The lignans present in the feed diet might be metabolized by the gut microbiota through deglycosylations, p-dehydroxylations, and m-demethylations, but there is no enantiomeric inversion, producing phytoestrogens (molecules with an estrogen-like effect), but there is not enantiomeric inversion; these metabolites are called “mammalian lignans or enterolignans” [60], for example, aglycones of enterolactone and enterodiol, formed from matairesinol and secoisolariciresinol, respectively. Both of these aglycones have antitumor effects against breast, colon, and lung cancer [61].

In this review, we found 112 lignans and norlignans with cytotoxic activity, isolated from plants of 34 families, such as Magnolicea, Lauraceae, and Sauracea, among others. We found that 13 of these lignans have a high activity on several human cancer cell lines.

Only cytotoxicity activity was determined in 92 of these lignans and this effect was evaluated by MTT assay. The antitumor effect of sesamine and honokiol was determined on tumors induced with lymphoma cells and squamous cells carcinoma respectively.

In the treatment of cancer, there are used compounds that produce cell death in two ways: apoptosis and direct toxicity, then the new therapies are focused on substances to induce apoptotic cancer cell death [62]. In this review, we found 16 lignans that promote cell death by apoptosis.

The apoptotic cell death could occur by the disruption of the mitochondrial membrane, which is a crucial signaling pathway in the induction of apoptosis diminishing the levels of ATP, inhibiting ERK and p38 MAPK signaling. Bcl-2 (antiapoptotic protein) protein family control apoptosis by regulating mitochondrial membrane permeability while Bax is an inducer of apoptosis. Caspase-9 is activated, promoting the cleavage of caspase-3 and PARP, which contributes to apoptosis and ultimately cell death. Lignans 23 y 35 induced apoptosis by this route [29, 20].

MMP-9 is an overexpressed proteolytic enzyme in cancer cells that acts as a precursor to the action of other endopeptidases. This enzyme is a new target for cancer therapy owing to its pivotal role in metastatic tumors. Compounds 41, 42, and 43 inhibit the overexpression of MMP-9 [32].

In vitrotest flow cytometry is used for the investigation and diagnosis of diseases such as cancer. In the different studies reported in this review, this technique was used to find out: the percentage of viable cancer cells, the characteristics of the cells such as size and shape, tumor markers, cell cycle analysis, and type of cell death [63]. In Table 1, it is shown that compounds 35, 47, 51, 61, and 112 induced apoptotic death of cancer cells by this technique.

Tubulin and its assembly product, microtubules, are among the most successful targets in cancer chemotherapy. It is currently known that podophyllotoxin and its commercial derivatives Etoposide and Teniposide exert their mechanism of action in cancer cells by altering Topoisomerase II and tubulin [64]. Williams et al. (2017) found that Bifidenone lignan also acts at the microtubule level of NCI-H460 cells, causing the inhibition of tubulin polymerization and therefore the arrest of the G2 / M phase of the cell cycle [32].

Arctigenin (ATN) is a dibenzylbutirolactone lignan isolated from the fruit of Arctium lappa and exhibited a cytotoxic effect on different breast cancer cell lines (MDA-MB-231, MDA-MB-435S, MDA-MB-453, and MDA-MB-468). In ER-positive MCF-7 cells, ATN inhibited downstream effector molecules of the target of rapamycin (TOR), decreasing the expression of estrogen receptor-α (Erα) and inducing autophagy.

Another way for cell death: Autophagy is a self-degradative process, which involves the enzymatic breakdown of different cytoplasmatic components. This process promotes the elimination of damaged or harmful components [65].

In vitro, this lignan inhibited the migration and invasion of MDA-MB-231 by downregulation of MMP-2, MMP-9, and heparinase expression [66].

(−)-Trachelogenin (TA) belongs to the dibenzylbutyrolactone lignan class and has been isolated from different plants, such as Trachelospermi caulis, T. asiaticum, T. Jasminoides, and Combretum fruticosum. This lignan has different pharmacological activities, such as anti-inflammatory [67], antidepressant, and anticancer effects [68]. TA did not induce apoptosis but induced autophagic death, mediated by increased LC3; its possible mechanism of induced autophagic cell death involves cytoplasmic vacuolization and formation of autophagosomes mediated by increasing LC3 activation, promoting changes in the expression of Beclin-1 levels [24].

4-O-methylhonokiol (MH) is a neolignan, a type of phenolic compound. It is found in the bark of Magnolia grandiflora, Magnolia virginianaflowers, and Magnolia officinalis. MH induced cytotoxicity on human oral carcinoma cells (OSCC PE/CA-PJ41). Its anticancer activity is due to its capacity to induce ROS-mediated alteration of MMP, mitochondrial apoptosis, and cell cycle arrest [25], and to inhibit neuroinflammation, amyloidogenesis, and memory impairment [69]. MH protected against diabetic cardiomyopathy in type 2 diabetic mice [70]. It also inhibited NkKB activity on human colon cancer cells and cell cycle arrest, and induced apoptosis [71]. Additionally, MH induced apoptosis on oral squamous cancer cells (OSCC) via Sp1 [72].

Deoxypodophyllotoxin (DPT) was isolated from plants of the genus Podophyllum and has also been obtained from other species, such as Athriscus sylvestris, Juniperus oblonga,and Cupressus macrocarpa. DPT presented high toxicity and some side effects, so its use is limited [73]. In vitro, DPT reduced the cell proliferation of NB cells, MDA-MB-231, and A549 lines, induced apoptosis and cell cycle arrest, reduced the expression of pCNA, and increased intracellular free calcium levels that promoted NB cell death.

Matairesinol (MT) was isolated from Juniperus oblongaand exhibited anti-inflammatory [74] and cytotoxic activity against neuroblastoma cell lines, with and without tetracycline-inducible MYCN over-expression, and induced apoptosis and cell cycle arrest [39]. MT ameliorated experimental autoimmune uveitis [75] and showed angiogenic activity in vivo and in vitro. This compound also inhibited the proliferation of human umbilical vein endothelial cells (HUVECs) [76].

Other lignans with significant anticancer activity are: methoxypinoresinol, which is a furanoid lignan isolated from the leaves of Calotropis gigantea; honokiol was isolated from Magnolia officinalis; trachelogenin isolated from Combretum fruticosum; bifidenone, which is isolated from Beilschmiediasp.; hedyotol-B, which was isolated from the stems of Herpetospermum pedunculosum; bejolghotin G, H, and I, which were isolated from the leaves and twigs of Cinnamomum bejolghota. These compounds have been isolated recently, and they are the subject of few pharmacological studies.

The most studied cancer cell lines were lung, hepatocellular carcinoma, colon, and breast. The cell lines diversity was colon cancer, breast cancer, human melanoma, and pancreatic cancer. These cell lines had the highest number of reports.

The lignans and neolignans with middle activity in lung cancer cells were: 12−20, 63−68, 112, colon cancer cells: 12−20, 63−68, 80−85,112, hepatocellular carcinoma cells: 12−20, 69, 70, 80−85, 112, and breast cancer cells: 11, 51, 63–68, 107,112.

In this review, we found that the less studied cancer cells were ovarian, gastric, endocervical adenocarcinoma cells, cholangiocarcinoma, laryngeal, leukemia, neuroblastoma, pancreatic cancer, prostate cancer, renal cancer, and osteosarcoma.

This review shows that various lignans and neolignans could be promising candidates for the treatment of different types of cancer.


Conflict of interest

The authors declare that they have no competing interests.


  1. 1. Ferlay J, Colombet M, Soerjomataram I, Mathers C, Parkin DM, Piñeros M, et al. Estimating the global cancer incidence and mortality in 2018: GLOBOCAN. International Journal of Cancer. 2018;144:1941-1953. DOI: 10.1002/ijc.31937
  2. 2. World Health Organization. Assessing national capacity for the prevention and control of noncommunicable diseases: Report of the 2019 global survey. 2020; Available from:[Accessed: November 16, 2021]
  3. 3. Ji N, Jiang L, Deng P, Xu H, Chen F, Liu J, et al. Synergistic effect of honokiol and 5-fluorouracil on apoptosis of oral squamous cell carcinoma cells. Journal of Oral. 2017;46:201-207. DOI: 10.1111/jop.12481
  4. 4. Talapatra SK, Talapatra B. Shikimic acid pathway. In: Chemistry of Plant Natural Products. 1st ed. Berlin, Heidelberg: Springer; 2014. pp. 625-674. DOI: 10.1007/978-3-642-45410-3_13
  5. 5. Suzuki S, Umezawa T. Biosynthesis of lignans and norlignans. Journal of Wood Science. 2007;53(4):273-284. DOI: 10.1007/s10086-007-0892-x
  6. 6. Moss GP. Nomenclature of lignans and neolignans (IUPAC Recommendations 2000). Pure and Applied Chemistry. 2000;72:1493-1523. DOI: 10.1351/pac200072081493
  7. 7. Ríos JL, Giner RM, Prieto JM. New findings on the bioactivity of lignans. Studies in Natural Products Chemistry. 2002;26:183-292. DOI: 10.1016/S1572-5995(02)80008-4
  8. 8. Dar AA, Arumugam N. Lignans of sesame: purification methods, biological activities and biosynthesis–A review. Bioorganic Chemistry. 2013;50:1-10. DOI: 10.1016/j.bioorg.2013.06.009
  9. 9. Jiang ZH, Liu YP, Huang ZH, Wang TT, Feng XY, Yue H, et al. Cytotoxic dihydrobenzofuran neolignans fromMappianthus iodoies. Bioorganic Chemistry. 2017;75:260-264. DOI: 10.1016/j.bioorg.2017.10.003
  10. 10. Sung MK, Lautens M, Thompson LU. Mammalian lignans inhibit the growth of estrogen-independent human colon tumor cells. Anticancer Research. 1998;18:1405-1408 PMID: 9673348
  11. 11. Lei JP, Yuan JJ, Pi SH, Wang R, Tan R, Ma CY, et al. Flavones and lignans from the stems of wikstroemia scytophylla Diels. Pharmacognosy Magazine. 2017;13:488. DOI: 10.4103/pm.pm_275_16
  12. 12. Li DQ, Wang D, Zhou L, Li LZ, Liu QB, Wu YY, et al. Antioxidant and cytotoxic lignans from the roots ofBupleurum chinense. Journal of Asian Natural Products Research. 2017;19:519-527. DOI: 10.1080/10286020.2016.1234456
  13. 13. Bodede O, Shaik S, Singh M, Moodley R. Phytochemical analysis with antioxidant and cytotoxicity studies of the bioactive principles from Zanthoxylum capense (Small knobwood). Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry-Anti-Cancer Agents). 2017;17:627-634. DOI: 10.2174/1871520616666160627091939
  14. 14. Meng Z, Liu H, Zhang J, Zheng Z, Wang Z, Zhang L, et al. Sesamin promotes apoptosis and pyroptosis via autophagy to enhance antitumour effects on murine T-cell lymphoma. Journal of Pharmacological Sciences. 2021;147:260-270. DOI: 10.1016/j.jphs.2021.08.001
  15. 15. Dang PH, Awale S, Nhan NT. Phytochemical and cytotoxic studies on the leaves ofCalotropis gigantea. Bioorganic & Medicinal Chemistry Letters. 2016;27:2902-2906. DOI: 10.1016/j.bmcl.2017.04.087
  16. 16. Han JH, Jeong HJ, Lee HN, Kwon YJ, Shin HM, Choi Y, et al. Erythro-austrobailignan-6 down-regulates HER2/EGFR/integrinβ3 expression via p38 activation in breast. cancer. Phytomedicine. 2017;24:24-30. DOI: 10.1016/j.phymed.2016.11.009
  17. 17. Zhang RF, Feng X, Su GZ, Yin X, Yang XY, Zhao YF, et al. Noralashinol B, a norlignan with cytotoxicity from stem barks ofSyringa pinnatifolia. Journal of Asian Natural Products Research. 2017;19:416-422. DOI: 10.1080/10286020.2017.1307188
  18. 18. Feng T, Cao W, Shen W, Zhang L, Gu X, Guo Y, et al. Arctigenin inhibits STAT3 and exhibits anticancer potential in human triple-negative breast cancer therapy. Oncotarget. 2017;8:329. DOI: 10.18632/oncotarget.13393
  19. 19. Maxwell T, Lee KS, Kim S, Nam KS. Arctigenin inhibits the activation of the mTOR pathway, resulting in autophagic cell death and decreased ER expression in ER-positive human breast cancer cells. International Journal of Oncology. 2018;52:1339-1349. DOI: 10.3892/ijo.2018.4271
  20. 20. Baba Y, Shigemi Z, Hara N, Moriguchi M, Ikeda M, Watanabe T, et al. Arctigenin induces the apoptosis of primary effusion lymphoma cells under conditions of glucose deprivation. International Journal of Oncology. 2018;52:505-517. DOI: 10.3892/ijo.2017.4215
  21. 21. Huang KJ, Kuo CH, Chen SH, Lin CY, Lee YR. Honokiol inhibits in vitro and in vivo growth of oral squamous cell carcinoma through induction of apoptosis, cell cycle arrest and autophagy. Journal of Cellular and Molecular Medicine. 2018;22:1894-1908. DOI: 10.1111/jcmm.13474
  22. 22. Jiraviriyakul A, Songjang W, Kaewthet P, Tanawatkitichai P, Bayan P, Pongcharoen S. Honokiol-enhanced cytotoxic T lymphocyte activity against cholangiocarcinoma cells mediated by dendritic cells pulsed with damage-associated molecular patterns. World Journal of Gastroenterology. 2019;25:3941. DOI: 10.3748/wjg.v25.i29.3941
  23. 23. Yang M, Zhang Y, Chen L, Chen Y. A new (propylphenyl) bibenzyl derivative fromDendrobium williamsonii. Natural Product Research. 2018;32:1699-1705. DOI: 10.1080/14786419.2017.1396599
  24. 24. Moura AF, Lima KSB, Sousa TS, Marinho-Filho JDB, Pessoa C, Silveira ER, et al. In vitro antitumor effect of a lignan isolated fromCombretum fruticosum, trachelogenin, in HCT-116 human colon cancer cells. Toxicology In Vitro. 2018;47:129-136. DOI: 10.1016/j.tiv.2017.11.014
  25. 25. Xiao S, Chen F, Gao C. Antitumor activity of 4-O-Methylhonokiol in human oral cancer cells is mediated via ROS generation, disruption of mitochondrial potential, cell cycle arrest and modulation of Bcl-2/Bax proteins. Journal of BUON. 2017;22:1577-1581 PMID: 29332355
  26. 26. Williams RB, Martin SM, Lawrence JA, Norman VL, O’Neil-Johnson M, Eldridge GR, et al. Isolation and identification of the novel tubulin polymerization inhibitor bifidenone. Journal of Natural Products. 2017;80:616-624. DOI: 10.1021/acs.jnatprod.6b00893
  27. 27. Dibwe DF, Sun S, Ueda JY, Balachandran C, Matsumoto K, Awale S. Discovery of potential antiausterity agents from the Japanese cypressChamaecyparis obtusa. Bioorganic & Medicinal Chemistry Letters. 2017;27:4898-4903. DOI: 10.1016/j.bmcl.2017.09.034
  28. 28. Kim SH, Son KM, Kim KY, Yu SN, Park SG, Kim YW, et al. Deoxypodophyllotoxin induces cytoprotective autophagy against apoptosis via inhibition of PI3K/AKT/mTOR pathway in osteosarcoma U2OS cells. Pharmacological Reports. 2017;69:878-884. DOI: 10.1016/j.pharep.2017.04.007
  29. 29. Ma ZJ, Lu L, Yang JJ, Wang XX, Su G, Wang ZL, et al. Lariciresinol induces apoptosis in HepG2 cells via mitochondrial-mediated apoptosis pathway. European Journal of Pharmacology. 2018;821:1-10. DOI: 10.1016/j.ejphar.2017.12.027
  30. 30. Gigliarelli G, Zadra C, Cossignani L, Robles Zepeda RE, Rascón-Valenzuela LA, Velázquez-Contreras CA, et al. Two new lignans from the resin ofBursera microphyllaA. gray and their cytotoxic activity. Natural Product Research. 2018;32:2646-2651. DOI: 10.1080/14786419.2017.1375922
  31. 31. Liu Y, Yang Y, Tasneem S, Hussain N, Daniyal M, Yuan H, et al. Lignans from Tujia ethnomedicine Heilaohu: Chemical characterization and evaluation of their cytotoxicity and antioxidant activities. Molecules. 2018;23:2147. DOI: 10.3390/molecules23092147
  32. 32. Zhu Y, Huang RZ, Wang CG, Ouyang XL, Jing XT, Liang D, et al. New inhibitors of matrix metalloproteinases 9 (MMP-9): Lignans from Selaginella moellendorffii. Fitoterapia. 2018;130:281-289. DOI: 10.1016/j.fitote.2018.09.008
  33. 33. Lee TK, Lee D, Yu JS, Jo MS, Baek SC, Shin MS, et al. Biological evaluation of a new lignan from the roots of rice (Oryza sativa). Chemistry & Biodiversity. 2018;15(11):e1800333. DOI: 10.1002/cbdv.201800333
  34. 34. Jeong M, Kim HM, Lee JS, Choi JH, Jang DS. (−)-Asarinin from the roots of asarum sieboldii induces apoptotic cell death via caspase activation in human ovarian cancer cells. Molecules. 2018;23:1849. DOI: 10.3390/molecules23081849
  35. 35. Lou LL, Yaoaz GD, Wang J, Zhao WY, Wang XB, Huang XX, et al. Enantiomeric neolignans fromPicrasma quassioidesexhibit distinctive cytotoxicity on hepatic carcinoma cells through ROS generation and apoptosis induction. Bioorganic & Medicinal Chemistry Letters. 2018;28:1263-1268. DOI: 10.1016/j.bmcl.2018.03.043
  36. 36. de Sousa FS, Nunes EA, Gomes KS, Cerchiaro G, Lago JHG. Genotoxic and cytotoxic effects of neolignans isolated fromNectandra leucantha(Lauraceae). Toxicology In Vitro. 2019;55:116-123. DOI: 10.1016/j.tiv.2018.12.011
  37. 37. Flegkas A, Milosević Ifantis T, Barda C, Samara P, Tsitsilonis O, Skaltsa H. Antiproliferative activity of (−)-rabdosiin isolated fromOcimum sanctumL. Medicine. 2019;6:37. DOI: 10.3390/medicines6010037
  38. 38. Wang GK, Jin WF, Zhang N, Wang G, Cheng YY, Morris-Natschke SL, et al. Kalshiolin A, new lignan fromKalimeris shimadai. Journal of Asian Natural Products Research. 2020;22:489-495. DOI: 10.1080/10286020.2019.1592164
  39. 39. Qiao Y, Sunada NK, Hatada AE, Lange I, Khutsishvili M, Alizade V, et al. Potential anti-neuroblastoma agents from Juniperus oblonga. Biochemical and Biophysical Research Communications. 2019;516:733-738. DOI: 10.1016/j.bbrc.2019.06.123
  40. 40. Han J, Chen X, Liu W, Cui H, Yuan T. Triterpenoid saponin and lignan glycosides from the traditional medicine Elaeagnus angustifolia flowers and their cytotoxic activities. Molecules. 2020;25:462. DOI: 10.3390/molecules25030462
  41. 41. Ma Y, Wang H, Wang R, Meng F, Dong Z, Wang G, et al. Cytotoxic lignans from the stems of Herpetospermum pedunculosum. Phytochemistry. 2019;164:102-110. DOI: 10.1016/j.phytochem.2019.05.004
  42. 42. Yang Y, Liu Y, Daniyal M, Yu H, Xie Q, Li B, et al. New lignans from roots of Kadsura coccinea. Fitoterapia. 2019;139:104368. DOI: 10.1016/j.fitote.2019.104368
  43. 43. Tran HNK, Cao TQ, Kim JA, Woo MH, Min BS. Anti-inflammatory and cytotoxic activities of constituents isolated from the fruits ofZiziphus jujubavar.inermisRehder. Fitoterapia. 2019;137:104261. DOI: 10.1016/j.fitote.2019.104261
  44. 44. Guo R, Lv TM, Shang XY, Yao GD, Lin B, Wang XB, et al. Racemic neolignans fromCrataegus pinnatifida: Chiral resolution, configurational assignment, and cytotoxic activities against human hepatoma cells. Fitoterapia. 2019;137:104287. DOI: 10.1016/j.fitote.2019.104287
  45. 45. Rao L, You YX, Su Y, Fan Y, Liu Y, He Q, et al. Lignans and neolignans with antioxidant and human cancer cell proliferation inhibitory activities fromCinnamomum bejolghotaconfirm its functional food property. Journal of Agricultural and Food Chemistry. 2020;68:8825-8835. DOI: 10.1021/acs.jafc.0c02885
  46. 46. Al-Sayed E, Ke TY, Hwang TL, Chen SR, Korinek M, Chen SL, et al. Cytotoxic and anti-inflammatory effects of lignans and diterpenes from Cupressus macrocarpa. Bioorganic & Medicinal Chemistry Letters. 2020;30:127127. DOI: 10.1016/j.bmcl.2020.127127
  47. 47. Zhang L, Wang XL, Wang B, Zhang LT, Gao HM, Shen T, et al. Lignans from Euphorbia hirta L. Natural Product Research. 2020:36:1478-6427. DOI: 10.1080/14786419.2020.1761358
  48. 48. Nguyen LH, Vu VN, Thi DP, Tran VH, Litaudon M, Roussi F, et al. Cytotoxic lignans from fruits of Cleistanthus tonkinensis. Fitoterapia. 2020;140:104432. DOI: 10.1016/j.fitote.2019.104432
  49. 49. Shang XY, Guo R, Yu XQ, Lin B, Huang XX, Yao GD, et al. Enantiomeric 8-O-4′-type neolignans from Crataegus pinnatifida exhibit cytotoxic effect via apoptosis and autophagy in Hep3B cells. Bioorganic Chemistry. 2020;104:104267. DOI: 10.1016/j.bioorg.2020.104267
  50. 50. Pootaeng-On Y, Charoensuksai P, Wongprayoon P, Jiajaroen S, Chainok K, Rayanil K. Miliusins; cytotoxic neolignans from the leaves ofMiliusa sessilis. Phytochemistry. 2020;176:112417. DOI: 10.1016/j.phytochem.2020.112417
  51. 51. Su XM, Liang Q, Zhang XM, Yao ZY, Xu WH. Four new chemical constituents fromPiper pleiocarpum. Fitoterapia. 2020;143:104544. DOI: 10.1016/j.fitote.2020.104544
  52. 52. Wang X, Zhao Y, Dong X, Wu X, Yu HY, Zhang LH, et al. Amides and lignans fromSolanum lyratum. Phytochemistry Letters. 2021;45:25-29. DOI: 10.1016/j.phytol.2021.07.002
  53. 53. Tra NT, Van Tuyen N, Van Cuong P, Ha NTT, Anh LTT, Son NT. Chemical constituents from the leaves of Styrax argentifolius HL Li and their biological activities. Phytochemistry Letters. 2021;41:70-73. DOI: 10.1016/j.phytol.2020.11.003
  54. 54. Huang S, Liu Y, Li Y, Fan H, Huang W, Deng C, et al. Dibenzocyclooctadiene lignans from the root bark ofSchisandra sphenanthera. Phytochemistry Letters. 2021;45:137-141. DOI: 10.1016/j.phytol.2021.08.015
  55. 55. Gao XX, Gao YN, Wang DD, Hu GS, Yan T, Jia JM, et al. Six novel lignanoids with complex structures fromSigesbeckia glabrescensMakino with their cytotoxic activities. Fitoterapia. 2021;148:104799. DOI: 10.1016/j.fitote.2020.104799
  56. 56. Atabaki V, Pourahmad J, Hosseinabadi T. Phytochemical compounds fromJurinea macrocephalasubsp.elbursensisand their cytotoxicity evaluation. South African Journal of Botany. 2021;137:399-405. DOI: 10.1016/j.sajb.2020.11.011
  57. 57. Gusson-Zanetoni JP, Monteiro da Silva JSG, Picão TB, Cardin LT, Prates J, Sousa SO, et al. Effect ofPiper cubebatotal extract and isolated lignans on head and neck cancer cell lines and normal fibroblasts. Journal of Pharmacological Sciences. 2021;148:93-102. DOI: 10.1016/j.jphs.2021.09.002
  58. 58. Kaunda JS, Qin XJ, Zhu HT, Wang D, Yang CR, Zhang YJ. Previously undescribed pyridyl-steroidal glycoalkaloids and 23S, 26R-hydroxylated spirostanoid saponin from the fruits of Solanum violaceum ortega and their bioactivities. Phytochemistry. 2021;184:112656. DOI: 10.1016/j.phytochem.2021.112656
  59. 59. Harmatha J, Dinan L. Biological activities of lignans and stilbenoids associated with plant-insectchemical interactions. Phytochemistry Reviews. 2003;2:321-330. DOI: 10.1023/B:PHYT.0000045494.98645.a3
  60. 60. Tsao R. Chemistry and biochemistry of dietary polyphenols. Nutrients. 2010;2:1231-1246. DOI: 10.3390/nu2121231
  61. 61. Kirsch V, Bakuradze T, Richling E. Toxicological testing of syringaresinol and enterolignans. Current Research in Toxicology. 2020;1:104-110. DOI: 10.1016/j.crtox.2020.09.002
  62. 62. Gerl R, Vaux DL. Apoptosis in the development and treatment of cancer. Carcinogenesis. 2005;2005(26):263-270. DOI: 10.1093/carcin/bgh283
  63. 63. Henry CM, Hollville E, Martin SJ. Measuring apoptosis by microscopy and flow cytometry. Methods. 2013;61:90-97. DOI: 10.1016/j.ymeth.2013.01.008
  64. 64. Guerram M, Jiang ZZ, Zhang LY. Podophyllotoxin, a medicinal agent of plant origin: Past, present and future. Chinese Journal of Natural Medicines. 2012;10:161-169. DOI: 10.3724/SP.J.1009.2012.00161
  65. 65. Glick D, Barth S, Macleod KF. Autophagy: Cellular and molecular mechanisms. The Journal of Pathology. 2010;221(1):3-12. DOI: 10.1002/path.2697
  66. 66. Lou C, Zhu Z, Zhao Y, Zhu R, Zhao H. Arctigenin, a lignan from Arctium lappa L., inhibits metastasis of human breast cancer cells through the downregulation of MMP-2/−9 and heparanase in MDA-MB-231 cells. Oncology Reports. 2017;37:179-184. DOI: 10.3892/or.2016.5269
  67. 67. Shin HS, Bae MJ, Jung SY, See HJ, Kim YT, Do JR, et al. Enhancing effect of trachelogenin fromTrachelospermi caulisextract on intestinal barrier function. Biological and Pharmaceutical Bulletin. 2015;38:1707-1713. DOI: 10.1248/bpb.b15-00332
  68. 68. Kuehnl S, Schroecksnadel S, Temml V, Gostner JM, Schennach H, Schuster D, et al. Lignans from Carthamus tinctorius suppress tryptophan breakdown via indoleamine 2, 3-dioxygenase. Phytomedicine. 2013;20:1190-1195. DOI: 10.1016/j.phymed.2013.06.006
  69. 69. Lee YJ, Choi DY, Choi IS, Kim KH, Kim YH, Kim HM, et al. Inhibitory effect of 4-O-methylhonokiol on lipopolysaccharide-induced neuroinflammation, amyloidogenesis and memory impairment via inhibition of nuclear factor-kappaB in vitro and in vivo models. Journal of Neuroinflammation. 2012;9:1-19. DOI: 10.1186/1742-2094-9-35
  70. 70. Zheng Z, Ma T, Guo H, Kim KS, Kim KT, Bi L, et al. 4-O-methylhonokiol protects against diabetic cardiomyopathy in type 2 diabetic mice by activation of AMPK-mediated cardiac lipid metabolism improvement. Journal of Cellular and Molecular Medicine. 2019;23:5771-5781. DOI: 10.1111/jcmm.14493
  71. 71. Oh JH, Ban JO, Cho MC, Jo M, Jung JK, Ahn B, et al. 4-O-methylhonokiol inhibits colon tumor growth via p21-mediated suppression of NF-κB activity. The Journal of Nutritional Biochemistry. 2012;23:706-715. DOI: 10.1016/j.jnutbio.2011.03.013
  72. 72. Cho JH, Lee RH, Jeon YJ, Shin JC, Park SM, Choi NJ, et al. Role of transcription factor Sp1 in the 4-O-methylhonokiol-mediated apoptotic effect on oral squamous cancer cells and xenograft. The International Journal of Biochemistry & Cell Biology. 2015;64:287-297. DOI: 10.1016/j.biocel.2015.05.007
  73. 73. Hu S, Zhou Q, Wu WR, Duan YX, Gao ZY, Li YW, et al. Anticancer effect of deoxypodophyllotoxin induces apoptosis of human prostate cancer cells. Oncology Letters. 2016;12:2918-2923. DOI: 10.3892/ol.2016.4943
  74. 74. Kuehnl S, Schroecksnadel S, Temml V, Gostner JM, Schennach H, Schuster D, et al. Lignans from Carthamus tinctorius suppress tryptophan breakdown via indoleamine 2, 3-dioxygenase. Phytomedicine. 2013;20:190-1195. DOI: 10.1016/j.phymed.2013.06.006
  75. 75. Li X, Gao Q, Yang L, Han M, Zhou C, Mu H. Matairesinol ameliorates experimental autoimmune uveitis by suppression of IRBP-specific Th17 cells. Journal of Neuroimmunology. 2020;345:577286. DOI: 10.1016/j.jneuroim.2020.577286
  76. 76. Lee B, Kim KH, Jung HJ, Kwon HJ. Matairesinol inhibits angiogenesis via suppression of mitochondrial reactive oxygen species. Biochemical and Biophysical Research Communications. 2012;421:76-80. DOI: 10.1016/j.bbrc.2012.03.114

Written By

Ana Laura Esquivel-Campos, Salud Pérez-Gutiérrez, Leonor Sánchez-Pérez, Nimsi Campos-Xolalpa and Julia Pérez-Ramos

Submitted: November 24th, 2021 Reviewed: December 20th, 2021 Published: March 4th, 2022