Anti-genotoxicity of galangin as a cancer chemopreventive agent candidate

doi:10.1016/S1383-5742(01)00054-0

Mutation Research/Reviews in Mutation Research

Volume 488, Issue 2, May 2001, Pages 135-150

https://doi.org/10.1016/S1383-5742(01)00054-0 Get rights and content

Abstract

Flavonoids are polyphenolic compounds that are present in plants. They have been shown to possess a variety of biological activities at non-toxic concentrations in organisms. Galangin, a member of the flavonol class of flavonoid, is present in high concentrations in medicinal plants (e.g. Alpinia officinarum) and propolis, a natural beehive product. Results from in vitro and in vivo studies indicate that galangin with anti-oxidative and free radical scavenging activities is capable of modulating enzyme activities and suppressing the genotoxicity of chemicals. These activities will be discussed in this review. Based on our review, galangin may be a promising candidate for cancer chemoprevention.

Section snippets

Galangin as cancer chemopreventive agent

The practice of disease prevention is the most cost effective means for improving human health. Therefore, different approaches have been actively used, e.g. sanitation, vaccination and life style modification. With increased awareness of our environment, it becomes clear that environmental mutagens and carcinogens (e.g. automobile exhaust, food-borne toxicants, cigarette smoke) can cause a variety of health problems but exposure to them is often unavoidable. Therefore, recently there is

Anti-genotoxic activity against alkylating agents

The collected reports on the anti-genotoxicity of galangin in the literature are organized in Table 1. Several plant flavonoids have been shown to suppress the induction of mutation in Salmonella typhimurium strain TA100 by the direct-acting N-methyl-N′-nitro-N-nitrosoguanidine (MNNG) [18]. Among the flavonoids tested, the most effective ones are the isoflavone (biochanin A), the flavanone and its glycoside (naringenin, naringin), and the flavonol and its glycosides (morin, fisetin, kaempferol,

Genotoxicity

While glycoside derivatives are not mutagenic, aglycones have moderate mutagenic activity toward S. typhimurium TA98 and TA100 [44]. With the finding of mutagenic activities, natural flavonoids in vegetables and fruits were tested for their carcinogenic activities in rodent. Quercetin is mutagenic but non-carcinogenic in rats, mice and hamsters, even when the concentration of quercetin reaches 10% in the diet [45]. The National Toxicology Program (NTP) showed that quercetin administration to

Effects of galangin on carcinogen metabolism

Epidemiological studies have shown that frequent consumption of fruits and vegetables is associated with low risks of various cancers [58], [59]. This protective effect has been attributed in part to flavonoids, which are ubiquitously present in plant-derived foods and are important constituents of the human diet [8], [60]. Studies in vitro and in vivo have shown that some flavonoids modulate the metabolism and disposition of xenobiotics and can contribute to cancer prevention [42], [59]. The

The structure–activity relationship (SAR) of galangin

Galangin is a flavonol derivative that does not have any hydroxyl group in the B-ring, but has a 2,3-double bond with a 3-hydroxyl group in the C-ring and 5,7-dihydroxyl groups in the A-ring. Galangin is the most lipophilic compound among similar flavonol compounds such as quercetin, kaempferol, morin and myricetin, etc. [16]. Addition of a 3- or 5-hydroxy group into 7-hydroxyflavone enhances the inhibitory potentials relative to 7-hydroxyflavone. Apigenin which has 2,3-double bond in the

Conclusions

Flavonoids are generally non-toxic and show a variety of beneficial biological activities. Therefore, flavonoids are considered as possible chemopreventive agents against various diseases. However, only a few clinical studies have been conducted on their cancer chemopreventive activities. A prospective study involving about 10,000 men and women aged 15–99 years was carried out in Finland [128]. After 24 years of follow-up, a reduction in the risk of lung cancer by about 50% was found in the

Acknowledgements

This work was supported by Korea Research Foundation Grant (KRF-99-041-F00310F6190). Preparation of this manuscript is partially supported by a fellowship from the Faculty Research Abroad Program (1999), Kangwon National University, South Korea.

References (132)

G.J. Kelloff
Perspectives on cancer chemoprevention research and drug development
Adv. Cancer Res.
(1999)
I. Shureiqi et al.
Chemoprevention: general perspective
Crit. Rev. Oncol. Hematol.
(2000)
G.J. Kelloff et al.
Cancer chemoprevention: progress and promise
Eur. J. Cancer
(1999)
J. Peterson et al.
Flavonoids: dietary occurrence and biochemical activity
Nutr. Res.
(1998)
B. Stavric
Antimutagens and anticarcinogens in foods
Food Chem. Toxicol.
(1994)
P.C. Hollman et al.
Dietary flavonoids: intake, health effects and bioavailability
Food Chem. Toxicol.
(1999)
H. Shih et al.
Differential effects of flavonoid compounds on tumor promoter-induced activation of the human CYP1A2 enhancer
Arch. Biochem. Biophys.
(2000)
M.Y. Heo et al.
Anticlastogenic effect of flavonoids against mutagen-induced micronuclei in mice
Mutat. Res.
(1992)
K. Shimoi et al.
Radioprotective effects of antioxidative plant flavonoids in mice
Mutat. Res.
(1996)
M.Y. Heo et al.
Anticlastogenic effects of galangin against bleomycin-induced chromosomal aberrations in mouse spleen lymphocytes
Mutat. Res.
(1994)

N. Umezawa et al.

Participation of reactive oxygen species in phototoxicity induced by quinolone antibacterial agents

Arch. Biochem. Biophys.

(1997)

L. Ebringer et al.

Antimutagens reduce ofloxacin-induced bleaching in Euglena gracilis

Mutat. Res.

(1996)

S.M. Kuo

Antiproliferative potency of structurally distinct dietary flavonoids on human colon cancer cells

Cancer Lett.

(1996)

M.H. Castillo et al.

The effects of the bioflavonoid quercetin on squamous cell carcinoma of head and neck origin

Am. J. Surg.

(1989)

M. Yoshida et al.

The effect of quercetin on cell cycle progression and growth of human gastric cancer cells

FEBS Lett.

(1990)

S.M. Kuo et al.

Effect of antiproliferative flavonoids on ascorbic acid accumulation in human colon adenocarcinoma cells

Cancer Lett.

(1997)

J. Levy et al.

Tyrosine protein kinase activity in the DMBA-induced rat mammary tumor: inhibition by quercetin

Biochem. Biophys. Res. Commun.

(1984)

T. Akiyama et al.

Genistein a specific inhibitor of tyrosine-specific protein kinases

J. Biol. Chem.

(1987)

P.C. Ferriola et al.

Protein kinase C inhibition by plant flavonoids. Kinetic mechanisms and structure–activity relationships

Biochem. Pharmacol.

(1989)

F.V. So et al.

Inhibition of proliferation of estrogen receptor-positive MCF-7 human breast cancer cells by flavonoids in the presence and absence of excess estrogen

Cancer Lett.

(1997)

J.T. MacGregor et al.

Mutagenicity of plant flavonoids: structural requirements for mutagenic activity in Salmonella typhimurium

Mutat. Res.

(1978)

J.H. Carver et al.

Genetic effects of the flavonols quercetin, kaempferol, and galangin on Chinese hamster ovary cells in vitro

Mutat. Res.

(1983)

J.P. Brown et al.

Mutagenicity of plant flavonols in the Salmonella/mammalian microsome test: activation of flavonol glycosides by mixed glycosidases from rat cecal bacteria and other sources

Mutat. Res.

(1979)

S. Ogawa et al.

Enhancement of the mutagenicity of 2-acetylaminofluorene by flavonoids and the structural requirements

Mutat. Res.

(1987)

J.T. MacGregor et al.

In vivo exposure to plant flavonols. Influence on frequencies of micronuclei in mouse erythrocytes and sister-chromatid exchange in rabbit lymphocytes

Mutat. Res.

(1983)

N. Yamashita et al.

Mechanism of oxidative DNA damage induced by quercetin in the presence of Cu(II)

Mutat. Res.

(1999)

S.C. Sahu et al.

Lipid peroxidation and DNA damage induced by morin and naringenin in isolated rat liver nuclei

Food Chem. Toxicol.

(1997)

I.B. Tsyrlov et al.

Isozyme- and species-specific susceptibility of cDNA-expressed CYP1A P450s to different flavonoids

Biochim. Biophys. Acta

(1994)

B. Havsteen

Flavonoids, a class of natural products of high pharmacological potency

Biochem. Pharmacol.

(1983)

T. Prestera et al.

The electrophile counterattack response: protection against neoplasia and toxicity

Adv. Enzyme Regulat.

(1993)

Y. Uda et al.

Induction of the anticarcinogenic marker enzyme, quinone reductase, in murine hepatoma cells in vitro by flavonoids

Cancer Lett.

(1997)

K.D. Meisheri et al.

Enzymatic and non-enzymatic sulfation mechanisms in the biological actions of minoxidil

Biochem. Pharmacol.

(1993)

G.A. LeBlanc

Hepatic vectorial transport of xenobiotics

Chem. Biol. Interact.

(1994)

E. Chieli et al.

Effects of flavonols on P-glycoprotein activity in cultured rat hepatocytes

Life Sci.

(1995)

J. Critchfield et al.

Modulation of adriamycin accumulation and efflux by flavonoids in HCT-15 colon cells. Activation of P-glycoprotein as a putative mechanism

Biochem. Pharmacol.

(1994)

M. Oshima et al.

Suppression of intestinal polyposis in Apc delta-716 knockout mice by inhibition of cyclooxygenase 2 (COX-2)

Cell

(1996)

B. Fisher et al.

Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study

J. Natl. Cancer Instit.

(1998)

O.P. Heinonen et al.

Prostate cancer and supplementation with α-tocopherol and β-carotene: incidence and mortality in a controlled trial

J. Natl. Cancer Instit.

(1998)

E. Middleton Jr., C. Kandaswami, The impact of plant flavonoids on mammalian biology: implications for immunity,...

J. Kuhnau

The flavonoids, a class of semi-essential food components: their role in human nutrition

World Rev. Nutr. Diet

(1976)

M.G.L. Hertog et al.

Intake of potentially anticarcinogenic flavonoids and their determinants in adults in The Netherlands

Nutr. Cancer

(1993)

Y.K. Park et al.

Survey of some components of propolis which were collected by Apis mellifera in Brazil

Arch. Biol. Technol.

(1995)

M.E. Wall et al.

Plant antimutagenic agents. 2. Flavonoids

J. Natl. Prod.

(1988)

M.Y. Heo et al.

Anticlastogenic effects of galangin against mitomycin C-induced micronuclei in reticulocytes of mice

Mutat. Res.

(1996)

M.R. Cholbi et al.

Inhibitory effects of phenolic compounds on CCl₄-induced microsomal lipid peroxidation

Experientia

(1991)

Y. Imamura et al.

Inhibitory effects of flavonoids on rabbit heart carbonyl reductase

J. Biochem. Tokyo

(2000)

A.R. Francis et al.

Modulating effect of plant flavonoids on the mutagenicity of N-methyl-N-nitro-N-nitrosoguanidine

Carcinogenesis

(1989)

S.J. Sohn et al.

Inhibition of N-methyl-N-nitrosourea-induced sister-chromatid exchange and DNA methylation by galangin

Yakhak Hoeji

(1995)

S.J. Sohn et al.

Antigenotoxicity of galangin against N-methyl-N-nitrosourea

Mutat. Res.

(1998)

L.W. Wattenerg et al.

Inhibition of carcinogenic action of benzo[a]pyrene by flavones

Cancer Res.

(1970)

Cited by (203)

Ursolic acid inhibits glioblastoma through suppressing TGFβ-mediated epithelial-mesenchymal transition (EMT) and angiogenesis
2024, Heliyon
Found in many fruits and plants, Ursolic acid (UA), a pentacyclic triterpene that occurs naturally, is recognized for its anti-cancer effects, especially in combating glioblastoma. However, the intricate molecular mechanisms underpinning its anti-tumor actions are still not fully understood, despite the recognition of these effects. By examining the functions of epithelial-mesenchymal transition (EMT) and angiogenesis, crucial for glioblastoma progression, and their regulation through Transforming Growth Factor Beta (TGFβ) – a key marker for glioblastoma, our research aims to fill this knowledge gap. This study explores how ursolic acid can block the progression of glioblastoma by precisely targeting TGFβ-triggered EMT and angiogenesis. The findings show that UA successfully blocks the spread, movement, and invasion of glioblastoma cells. Accompanying this, there is a significant reduction in the expression of TGFβ and crucial EMT indicators like snail and vimentin. Furthermore, UA shows a reduction in angiogenesis that depends on the dosage, highlighted by decreased vascular endothelial growth factor (VEGF) in human umbilical vein endothelial cells (HUVECs). Interestingly, increased TGFβ expression in U87 and U251 glioblastoma cell lines was found to weaken UA's anti-tumor properties, shedding more light on TGFβ′s critical function in glioblastoma's pathology. Supporting these laboratory results, UA also showed considerable inhibition of tumor growth in a glioblastoma xenograft mouse model. Overall, our research emphasizes Ursolic acid's promise as a new treatment for glioblastoma and clarifies its action mechanism, mainly by inhibiting TGFβ signaling and thereby EMT and angiogenesis.
Small-molecule agents for treating skin diseases
2024, European Journal of Medicinal Chemistry
Skin diseases are a class of common and frequently occurring diseases that significantly impact daily lives. Currently, the limited effective therapeutic drugs are far from meeting the clinical needs; most drugs typically only provide symptomatic relief rather than a cure. Developing small-molecule drugs with improved efficacy holds paramount importance for treating skin diseases. This review aimed to systematically introduce the pathogenesis of common skin diseases in daily life, list related drugs applied in the clinic, and summarize the clinical research status of candidate drugs and the latest research progress of candidate compounds in the drug discovery stage. Also, it statistically analyzed the number of publications and global attention trends for the involved skin diseases. This review might provide practical information for researchers engaged in dermatological drugs and further increase research attention to this disease area.
Unveiling the therapeutic potential of natural-based anticancer compounds inducing non-canonical cell death mechanisms
2023, Pathology Research and Practice
In the Mid-19^th century, Rudolf Virchow considered necrosis to be a prominent form of cell death; since then, pathologists have recognized necrosis as both a cause and a consequence of disease. About a century later, the mechanism of apoptosis, another form of cell death, was discovered, and we now know that this process is regulated by several molecular mechanisms that "programme" the cell to die. However, discoveries on cell death mechanisms are not limited to these, and recent studies have allowed the identification of novel cell death pathways that can be molecularly distinguished from necrotic and apoptotic cell death mechanisms. Moreover, the main goal of current cancer therapy is to discover and develop drugs that target apoptosis. However, resistance to chemotherapeutic agents targeting apoptosis is mainly responsible for the failure of clinical therapy and adverse side effects of the chemotherapeutic agents currently in use pose a major threat to the well-being and lives of patients. Therefore, the development of natural-based anticancer drugs with low cellular and organismal side effects is of great interest. In this comprehensive review, we thoroughly examine and discuss natural anticancer compounds that specifically target non-canonical cell death mechanisms.
Targeting the NRF2/KEAP1 pathway in cervical and endometrial cancers
2023, European Journal of Pharmacology
Cervical and endometrial cancers are among the most dangerous gynaecological malignancies, with high fatality and recurrence rates due to frequent diagnosis at an advanced stage and chemoresistance onset.
The NRF2/KEAP1 signalling pathway plays an important role in protecting cells against oxidative damage due to increased reactive oxygen species (ROS) levels. NRF2, activated by ROS, induces the expression of antioxidant enzymes such as heme oxygenase, catalase, glutathione peroxidase and superoxide dismutase which neutralize ROS, protecting cells against oxidative stress damage. However, activation of NRF2/KEAP1 signalling in cancer cells results in chemoresistance, inactivating drug-mediated oxidative stress and protecting cancer cells from drug-induced cell death. We review the literature on the role of the NRF2/KEAP1 pathway in cervical and endometrial cancers, with a focus on the expression of its components and downstream genes. We also examine the role of the NRF2/KEAP1 pathway in chemotherapy resistance and how this pathway can be modulated by natural and synthetic modulators.
Potential of natural products in osteosarcoma treatment: Focus on molecular mechanisms
2021, Biomedicine and Pharmacotherapy
Osteosarcoma is the most frequent type of bone cancer found in children and adolescents, and commonly arises in the metaphyseal region of tubular long bones. Standard therapeutic approaches, such as surgery, chemotherapy, and radiation therapy, are used in the management of osteosarcoma. In recent years, the mortality rate of osteosarcoma has decreased due to advances in treatment methods. Today, the scientific community is investigating the use of different naturally derived active principles against various types of cancer. Natural bioactive compounds can function against cancer cells in two ways. Firstly they can act as classical cytotoxic compounds by non-specifically affecting macromolecules, such as DNA, enzymes, and microtubules, which are also expressed in normal proliferating cells, but to a greater extent by cancer cells. Secondly, they can act against oncogenic signal transduction pathways, many of which are activated in cancer cells. Some bioactive plant-derived agents are gaining increasing attention because of their anti-cancer properties. Moreover, some naturally-derived compounds can significantly promote the effectiveness of standard chemotherapy drugs, and in certain cases are able to ameliorate drug-induced adverse effects caused by chemotherapy. In the present review we summarize the effects of various naturally-occurring bioactive compounds against osteosarcoma.
Alpinia officinarum water extract inhibits the atopic dermatitis-like responses in NC/Nga mice by regulation of inflammatory chemokine production
2021, Biomedicine and Pharmacotherapy
Alpinia officinarum (AO) has been traditionally used in Asia as an herbal medicine to treat inflammatory and internal diseases. However, the therapeutic effect of AO on atopic dermatitis (AD) is unclear. Therefore, we examined whether Alpinia officinarum water extract (AOWex) affects AD in vivo and in vitro. Oral administration of AOWex to NC/Nga mice with Dermatophagoies farina extract (DfE)-induced AD-like symptoms significantly reduced the severity of clinical dermatitis, epidermal thickness, and mast cell infiltration into the skin and ear tissue. Decreased total serum IgE, macrophage-derived chemokine (MDC), and regulated on activation, normal T-cell expressed and secreted (RANTES) levels were observed in DfE-induced NC/Nga mice in the AOWex-treated group. These effects were confirmed in vitro using HaCaT cells. Treatment with AOWex inhibited the expression of proinflammatory chemokines such as MDC, RANTES, IP-10 and I-TAC in interferon-γ and tumor necrosis factor-α-stimulated HaCaT cells. The anti-inflammatory effects of AOWex were due to its inhibitory action on MAPK phosphorylation (ERK and JNK), NF-κB, and STAT1. Furthermore, galangin, protocatechuic acid, and epicatechin from AOWex were identified as candidate anti-AD compounds. These results suggest that AOWex exerts therapeutic effects against AD by alleviating AD-like skin lesions, suppressing inflammatory mediators, and inhibiting major signaling molecules.

View all citing articles on Scopus

View full text

ReviewAnti-genotoxicity of galangin as a cancer chemopreventive agent candidate

Abstract

Section snippets

Galangin as cancer chemopreventive agent

Anti-genotoxic activity against alkylating agents

Genotoxicity

Effects of galangin on carcinogen metabolism

The structure–activity relationship (SAR) of galangin

Conclusions

Acknowledgements

Adv. Cancer Res.

Crit. Rev. Oncol. Hematol.

Eur. J. Cancer

Nutr. Res.

Food Chem. Toxicol.

Food Chem. Toxicol.

Arch. Biochem. Biophys.

Mutat. Res.

Mutat. Res.

Mutat. Res.

Arch. Biochem. Biophys.

Mutat. Res.

Cancer Lett.

Am. J. Surg.

FEBS Lett.

Cancer Lett.

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

Biochem. Pharmacol.

Cancer Lett.

Mutat. Res.

Mutat. Res.

Mutat. Res.

Mutat. Res.

Mutat. Res.

Mutat. Res.

Food Chem. Toxicol.

Biochim. Biophys. Acta

Biochem. Pharmacol.

Adv. Enzyme Regulat.

Cancer Lett.

Biochem. Pharmacol.

Chem. Biol. Interact.

Life Sci.

Biochem. Pharmacol.

Cell

Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study

J. Natl. Cancer Instit.

Prostate cancer and supplementation with α-tocopherol and β-carotene: incidence and mortality in a controlled trial

J. Natl. Cancer Instit.

The flavonoids, a class of semi-essential food components: their role in human nutrition

World Rev. Nutr. Diet

Intake of potentially anticarcinogenic flavonoids and their determinants in adults in The Netherlands

Nutr. Cancer

Survey of some components of propolis which were collected by Apis mellifera in Brazil

Arch. Biol. Technol.

Plant antimutagenic agents. 2. Flavonoids

J. Natl. Prod.

Anticlastogenic effects of galangin against mitomycin C-induced micronuclei in reticulocytes of mice

Mutat. Res.

Inhibitory effects of phenolic compounds on CCl4-induced microsomal lipid peroxidation

Experientia

Inhibitory effects of flavonoids on rabbit heart carbonyl reductase

J. Biochem. Tokyo

Modulating effect of plant flavonoids on the mutagenicity of N-methyl-N-nitro-N-nitrosoguanidine

Carcinogenesis

Inhibition of N-methyl-N-nitrosourea-induced sister-chromatid exchange and DNA methylation by galangin

Yakhak Hoeji

Antigenotoxicity of galangin against N-methyl-N-nitrosourea

Mutat. Res.

Inhibition of carcinogenic action of benzo[a]pyrene by flavones

Cancer Res.

Review
Anti-genotoxicity of galangin as a cancer chemopreventive agent candidate

Inhibitory effects of phenolic compounds on CCl₄-induced microsomal lipid peroxidation