Alkaloids Isolated from Natural Herbs as the Anti-cancer Agents

17 Pages·2013·0.14 MB·English

Quinones derived from plant secondary metabolites as anti-cancer agents

Jin-Jian Lu1,#, Jiao-Ling Bao1,#, Guo-Sheng Wu1, Wen-Shan Xu1, Ming-Qing Huang2, Xiu-Ping
Chen1,*, Yi-Tao Wang1,*

1 State Key Laboratory of Quality Research in Chinese Medicine (University of Macau), Institute
of Chinese Medical Sciences, University of Macau, Macao SAR, China
2 College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou, China

# These authors contributed equally to this review.
* Corresponding authors:
Xiu-Ping Chen ([email protected])
Yi-Tao Wang ([email protected])
State Key Laboratory of Quality Research in Chinese Medicine (University of Macau)
Institute of Chinese Medical Sciences
University of Macau
Av. Padre Toma's Pereira S.J., Taipa
Macao SAR, 999078, PR China
Tel.: [phone]
Fax: [phone]
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Abstract
Quinones are plant-derived secondary metabolites that present some anti-proliferation and
anti-metastasis effects in various cancer types both in vitro and in vivo. This review focuses on the
anti-cancer prospects of plant-derived quinones, namely, aloe-emodin, juglone, β-lapachol,
plumbagin, shikonin, and thymoquinone. We intend to summarize their anti-cancer effects and
investigate the mechanism of actions to promote the research and development of anti-cancer
agents from quinones.
Key words: quinone, plant, secondary metabolites, tumor

ABBREVIATIONS
5-FU: 5-fluorouracil; AR, androgen receptor; Bcl-2: B-cell lymphoma 2; CDK2: cyclin-dependent
kinase 2; COX-2: cyclooxygenase-2; DR-5: death receptor-5; EGFR: epidermal growth factor
receptor; FAK: focal adhesion kinase; GSH: glutathione; HER-2: human epidermal growth factor
receptor-2; IGF-1, insulin-like growth factor 1; JNK, c-Jun N-terminal kinase; MDR: multi-drug
resistance; MMP: matrix metalloproteinase; NF-κB: nuclear factor κ-light-chain-enhancer of
activated B cells; p38 MAPK: p38 mitogen-activated protein kinase; PKC, protein kinase C;
PPAR-γ, peroxisome proliferator-activated receptor γ; PTEN, phosphatase and tensin homolog;
ROS: reactive oxygen species; STAT3, the signal transducer and activator of transcription 3; TopI:
topoisomerase I; TopII: topoisomerase II; TRAIL: TNF-related apoptosis-inducing ligand
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INTRODUCTION
Quinones, a type of plant-derived secondary metabolites, is a class of compounds with
the quinone structure and can be mainly divided into four types, namely,
benzoquinone, naphthoquinone, phenanthrenequinone, and anthraquinone, according
to the number of benzene rings in the structural skeleton and fused [1]. Quinones are widely
distributed in the plant kingdom and mainly exist in higher plants, such as those from the
Polygonaceaee, Rubiaceae, Leguminosae, Rhamnaceae, Labiatae, and Boraginaceae families,
among others [1]. Moreover, a number of quinones present significant biological activities, such
as the purgative effect of quinones isolated from Rheum officinale, as well as the anti-bacterial and
anti-cancer activities of juglone and plumbagin isolated from Juglandiphyllum and sundew,
respectively [1-4].
This review focuses on the progress of natural plant-derived quinones, such as aloe-emodin,
juglone, β-lapachol, plumbagin, shikonin, and thymoquinone (Fig. 1), with anti-cancer activities
and intends to investigate, as well as summarize, its mechanism of actions to promote further
anti-cancer drug discovery from quinones.

ALOE-EMODIN
Aloe-emodin is a bioactive hydroxyanthraquinone that exists in several traditional medical plants,
such as R. palmatum L., and displays laxative, anti-fungal, anti-viral, and hepatoprotective effects
[5-8]. Aloe-emodin also has specific in vitro and in vivo anti-cancer activities in various human
carcinoma cells, including leukemia, lung cancer, colon cancer, neuroectodermal tumor,
nasopharyngeal carcinoma, and hepatocellular carcinoma [9-14]. Aloe-emodin-induced cancer cell
proliferative inhibition is caused by prolonged G , S, or G /M phase cell cycle arrest or apoptosis
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depending on the cell types and treatment procedure [12, 15-19]. This quinone remarkably inhibits
chorioallantoic membrane angiogenesis at low concentrations and inhibits tubule formation of
endothelial cells on matrigel [13, 20]. Aloe-emodin also suppresses cancer cell migration, invasion,
and metastasis [21, 22], in addition to its potential anti-proliferative effects when combined with
cisplatin, doxorubicin, 5-fluorouracil (5-FU), and the tyrosine kinase inhibitor STI571 [23].
Aloe-emodin induces DNA damage and inhibits DNA repair gene expression in cancer cells
probably related to the induction of reactive oxygen species (ROS) [11, 24]. This molecule
downregulates cyclin A, cyclin-dependent kinase 2 (CDK2), protein kinase C (PKC), and c-Myc
as well as upregulates cyclin B1, CDK1, p53, p21, and p27 [15, 16, 18, 19]. The p38
mitogen-activated protein kinase (p38 MAPK) pathway, p53 pathway, c-Jun N-terminal kinase
(JNK) activation [25], Fas/death-receptor, and caspase activation are mechanistically involved in
aloe-emodin-induced apoptosis [19, 26, 27]. Aloe-emodin also performs the following activities:
decreases the levels of urokinase; reduces protein and mRNA expressions of focal adhesion kinase
(FAK) [20]; suppresses the expression of matrix metalloproteinase 2 (MMP-2), MMP-9 [12, 21,
22]; and restrains nuclear translocation as well as DNA binding of nuclear factor
κ-light-chain-enhancer of activated B cells (NF-κB) [13].
Other natural hydroxyanthraquinones, such as emodin and rhein, also have anti-cancer activities
and mechanisms similar to aloe-emodin [28-32].

JUGLONE
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Juglone is a naturally occurring naphthoquinone isolated from walnut trees and has various
biological activities, such as anti-fungal, anti-viral, and anti-bacterial activities. This quinone also
lowers the blood glucose and is a potent anti-cancer agent that inhibits proliferation, mediates G
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phase cell cycle arrest, and induces apoptosis, among others [33-37]. Juglone inhibits intestinal
carcinogenesis induced by azoxymethane in rats and might be a promising chemopreventive agent
in human intestinal neoplasia [38]. This quinone also shows potent immunostimulating activities
in tumorous tissues [39]. Treatment of cells with juglone synergistically enhances the cytotoxicity
of etoposide when etoposide treatment precedes juglone exposure [40]. However, most of the data
reported are based on in vitro cellular toxicity assays. Concrete information based on mouse
models of cancer is insufficient, and there is a dearth of clinical evidence.
The anti-cancer effects of juglone can be attributed to the induction of oxidative stress,
depletion of glutathione, and damage of cell membrane, and so on, leading to cell death by both
apoptosis and necrosis [4, 41-45]. Juglone is also an inhibitor of peptidyl-prolyl isomerase Pin1
that is overexpressed in many human cancer tissues [46, 47]. This quinone also markedly
suppresses the expression of activator protein-2α and the human epidermal growth factor
receptor-2 promoter activity [48], downregulates p53 protein level [49], alters the levels of B-cell
lymphoma 2 (Bcl-2) and Bax [41, 42, 50], activates PARP [41], and induces subsequent caspase
activation [41, 45, 51].

β-LAPACHONE
β-Lapachone is a natural naphthoquinone derived from Tabebuia avellanedae (Bignoniaceae) [52].
This molecule exhibits a wide spectrum of pharmacological activities, including anti-fungal,
anti-bacterial anti-trypanocidal, and anti-cancer activities [53-55]. β-lapachone, a potent
anti-cancer agent, can selectively induce cell death in several human cancer cells without killing
non-transformed cells [27]. This quinone also delays cell cycle progression at the G /S transition.
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The in vivo anti-cancer effect of β-Lapachone has been demonstrated in animal xenografts [56-59].
The combination of β-lapachone and radiotherapy has potential for the treatment of human
cancers. Thus, β-Lapachone is currently in multiple phase II clinical trials for use in monotherapy
and in combination with other drugs [60].
β-lapachone inhibits the activity of topoisomerase I (Topo I) through a mechanism in contrast to
that of typical topoisomerase inhibitors [61]. This quinone induces topoisomerase II (Topo II)
α-mediated DNA breaks, instead of Topo I-mediated DNA breaks [62]. β-lapachone also inhibits
eukaryotic DNA polymerase-α [63], activates the Mre11p-Tel1p checkpoint pathway by inducing
DNA double strand breaks [64], activates MAPKs [65], and induces caspase activation [66],
among others. NAD(P)H:quinone oxidoreductase (NQO1) is an intracellular target for
β-lapachone in tumor cells [67]. NQO1 catalyses the reduction of β-lapachone and causes a futile
cycling between its quinone and hydroquinone forms. This cycle results in a severe loss in reduced
NAD(P)H [67] and a concomitant rise in cytosolic Ca2+, finally inducing apoptosis [68]. The
metabolism of β-lapachone by NQO1 also leads to ROS generation, DNA breaks, and γ-H2AX
foci formation [69, 70]. β-lapachone sensitizes cells to radiation by interrupting the involvement
of NQO1 in radiation-induced activation of NF-κB [71] and inhibiting sub-lethal radiation damage
repair [72].
Lapachol, among the analogs and derivatives of β-lapachone studied and is present in T.
avellanedae along with β-lapachone, shows a number of pharmacologic properties [52] and has
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highly significant activity against tumors [73]. However, further studies on lapachol as an
anti-neoplastic were terminated in 1970 because of its toxicity [74].

PLUMBAGIN
Plumbagin, an organic yellow dye, was originally isolated from the roots and aerial parts of
Dyerophytum africanum, Plumbago pearsonii, and in roots of P. auriculata [75]. Multiple
pharmacologic properties of plumbagin, such as anti-inflammatory, analgesic, anti-oxidant,
anti-cancer, anti-bacterial, and anti-fungal activities, have been documented in various cellular and
animal models [3, 76]. The anti-cancer effect of this quinone has been gradually confirmed in the
past decade. Plumbagin significantly inhibits cancer cell proliferation in in vitro cell models in
dose- and time- dependent manners with IC at micromolar level depending on the type of cells
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and duration of treatment [77-79]. The inhibitory effect of plumbagin on tumor growth in in vivo
animal models was also observed in solid tumor and Ehrlich ascites model [80], C57BL/6J mice
bearing B16F1 melanoma [36], and hormone-refractory prostate cancer [81]. Moreover,
plumbagin suppresses tumor angiogenesis and tumor growth in human colon carcinoma, as well as
in prostate cancer xenograft mouse models [82], in addition to its enhancement of radiation
induced cytogenetic in mouse Ehrlich ascites carcinoma in vivo [83]. Interestingly, plumbagin
inhibits ultraviolet radiation-induced development of squamous cell carcinomas suggesting that
this quinone may be a novel agent for the prevention of skin cancer [84].
Plumbagin induces cell cycle arrest at G /M phase in cancer cell lines by regulating p53, p21,
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cyclinB1, Cdc25B, cyclin A, Cdc2, Cdc25C, and Chk2, among others [85-88]. The inhibitory
effect of this molecule on cancer cell proliferation can be attributed mainly to apoptosis [77-79, 89,
90] mediated by induction of intracellular ROS formation [77, 89-92], upregulation of p53 [90],
inactivation of NF-κB [78], downregulation of cyclooxygenase-2 (COX-2) [79], activation of JNK
[87], among others, and subsequent activation of caspases and Bcl-2 family proteins. Plumbagin
induced ROS generation might be mainly from mitochondria since plumbagin was identified as a
NOX4 inhibitor of NAD(P)H oxidase [93]. ROS mediated inhibition of Topo II is another
important mechanism contributing to plumbagin-induced apoptosis [94]. Plumbagin is a potent
inhibitor of the NF-κB activation pathway that leads to the suppression of NF-κB-regulated gene
products, such as IAP, Bcl-2, Bcl-xL, survivin, cyclinD1, COX-2, and MMP-9, among others [95].
This molecule also inhibits the invasion and migration of breast, as well as gastric, cancer cells by
downregulating the expression of chemokine receptor CXCR4 mediated by NF-κB inhibition [96].
In addition, plumbagin is a substrate for the multidrug resistance (MDR) linked ATP binding
cassette drug transporter ABCG [97], suggesting its potential role in MDR.

SHIKONIN
Shikonin, a naphthoquinone pigment, is an active component isolated from the roots of Chinese
herbal plant Lithospermum erythrorhizon. This medicinal plant has been broadly used to treat
burns, sore throats, measles, carbuncles, macular eruptions, and allergic disease in China for
thousands of years [98]. In addition to its well-established anti-inflammatory and anti-oxidant
activities, recent studies have focused on the anti-cancer effects of shikonin, which includes
inhibition of cell proliferation, induction of apoptosis, and retardation of invasion, among others.
The values of IC for anti-proliferation vary depending upon the cancer cell type and treatment
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time, and approximately at micromolar levels. The anti-cancer effects of shikonin were also
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determined in both allografts and xenografts animal models in vivo [99].
ROS generation, inactivation of NF-κB, regulation of epidermal growth factor receptor and
insulin-like growth factor 1, and activation of caspases may be involved in the anti-cancer
mechanisms of shikonin [32, 100-107]. This quinone inhibits Topo I/II activity and results in DNA
damage in cancer cells [108]. Shikonin also has anti-cancer effects as an anti-estrogen agent by
reversing NQO1 expression [109, 110] and acts as a selective estrogen enzyme modulator by
downregulating the expression of steroid sulfatase, important for the biosynthesis of estrogen
[111]. In addition, pyuvate kinase-M2 and proteasome are also inhibited by shikonin or its analogs
[112].

THYMOQUINONE
Thymoquinone is an active ingredient isolated from Nigella sativa and has been investigated for
its anti-oxidant, anti-inflammatory, and anti-cancer activities in both in vitro and in vivo models
since its first extraction in 1960s [113-115]. The anti-cancer effects of thymoquinone are mediated
through different modes of action, including anti-proliferation, apoptosis induction, cell cycle
arrest, anti-metastasis, and anti-angiogenesis [113, 116, 117]. The anti-tumor effects of
thymoquinone have also been investigated in tumor xenograft mice models for colon, prostate,
pancreatic, and lung cancer, among others [113, 118]. Thymoquinone greatly inhibits
doxorubicin-resistant human breast cancer MCF-7/DOX cell proliferation [119] without exhibiting
cytotoxicity to normal human intestinal FHs74Int cells [117]. The combination of thymoquinone
and conventional chemotherapeutic drugs, such as 5-FU, gemcitabine, cisplatin, oxaliplatin, and
doxorubicin, could produce greater therapeutic effect in vitro and/or in vivo in different cancer
types [113, 120-122]. Sub-toxic doses of thymoquinone sensitize PEL cells to TNF-related
apoptosis-inducing ligand via upregulation of death receptor-5 (DR-5) [123].
This quinone exhibits anti-cancer activity through the modulation of multiple molecular targets,
including F-actin, α and β tubulin, p53, p73, phosphatase and tensin homolog, the signal
transducer and activator of transcription 3, NF-κB, peroxisome proliferator-activated receptor γ,
polo-like kinase 1, polo-box domain, androgen receptor, E2F-1, Bcl-2, focal adhesion kinase, and
MMPs among others [113, 118, 119, 121, 123-130]. Thymoquinone also generates ROS, induces
DNA damage, and inhibits telomerase activity [117, 131]. Most recently, thymoquinone treatment
has been demonstrated to inhibit strongly CXCL12-mediated chemotaxis in multiple myeloma
cells, but not normal peripheral blood mononuclear cells, and significantly downregulate CXCR4
expression and CXCL12-mediated CXCR4/CD45 association [132].

SUMMARY
We summarized the recent progress of several anti-cancer quinones from plant-derived secondary
metabolites as well as the characteristics of these quinones. Based on previous studies, sources of
the anti-cancer quinones derived from plant secondary metabolites are fewer than alkaloids,
terpenoids, and flavone. Certain quinone antibiotics, such as mitomycins, have also been used in
clinical treatments of malignant diseases [133]. However, there are few plant-derived quinones
that have entered clinical trials thus far. One promising compound, salvicine, synthesized by the
structural modification of a natural product isolated from Salvia prionitis lance, has already
entered phase II clinical trial in China [60, 134, 135]. Therefore, obtaining promising anti-cancer
quinones from plants is possible, but appropriate structural modification is also necessary.
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Given that oxidative damage appears to be a common characteristic of quinones to achieve the
anti-cancer effects [25, 41, 117], more than one type of cellular molecule, especially those
sensitive to oxidative stress such as enzyme with thiol [107, 136], will be targeted after quinone
treatment. These anti-cancer quinones have multiple molecular targets, and the mechanisms still
require further clarification. Thus, we propose that more high-throughput technologies, such as
proteomics, high content screening, and biochip, among others, [137-139] be employed to explore
the anti-cancer mechanisms of quinones. The toxicity and characteristics of drug
metabolism of these quinones should also be studied urgently to develop successfully anti-cancer
agents.

ACKNOWLEDGEMENTS
This study was supported by the Research Fund of University of Macau
(UL016/09Y4/CMS/WYT01/ICMS and MYRG208(Y2-L4)-ICMS11-WYT).

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