Are there new therapeutic options for treating lung cancer based on herbal medicines and their metabolites?

Journal of Ethnopharmacology 138 (2011) 652–661

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Review

Are there new therapeutic options for treating lung cancer based on herbal medicines and their metabolites? Soo-Jin Jeong, Wonil Koh, Bonglee Kim, Sung-Hoon Kim ∗ Cancer Preventive Material Development Research Center, College of Oriental Medicine, Kyung Hee University, 130-701, Republic of Korea

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Article history: Received 21 June 2011 Received in revised form 10 October 2011 Accepted 11 October 2011 Available online 18 October 2011 Keywords: Herbal medicine Phytochemical Lung cancer Molecular targets Apoptosis Angiogenesis

a b s t r a c t Ethonopharmacological relevance: Lung cancer is one of the most lethal cancers in terms of mortality and incidence worldwide. Despite intensive research and investigation, treatment of lung cancer is still unsatisfactory due to adverse effects and multidrug resistance. Recently, herbal drugs have been recognized as one of attractive approaches for lung cancer therapy with little side effects. Furthermore, there are evidences that various herbal medicines have proven to be useful and effective in sensitizing conventional agents, prolonging survival time, preventing side effects of chemotherapy, and improving quality of life (QoL) in lung cancer patients. Aim and methods of the study: Nevertheless, the underlying molecular targets and efficacy of herbal medicines in lung cancer treatment still remain unclear. Thus, we reviewed traditionally used herbal medicines and their phytochemicals with antitumor activity against lung cancer from peer-reviewed papers through Scientific Database Medline, Scopus and Google scholar. Conclusions: We suggest that herbal medicines and phytochemicals can be useful anti-cancer agents for lung cancer treatment by targeting molecular signaling involved in the regulation of angiogenesis, metastasis and severe side effects, only provided quality control and reproducibility issues were solved. © 2011 Elsevier Ireland Ltd. All rights reserved.

Contents 1. 2.

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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Anti-lung cancer effects and molecular regulation of herbal medicines in vitro . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Apoptosis and herbal medicines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Inhibitory effects of herbal medicines on angiogenesis and metastasis in vitro . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Herbal medicines as multidrug resistance (MDR) reversal agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4. Reactive oxygen species (ROS) and lung cancer therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Anti-lung cancer activities of herbal medicines in vivo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical trials of herbal medicines for the treatment of lung cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Herbal medicines as combination therapy with conventional chemotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Herbal medicines for improved quality of life in lung cancer patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3. Herbal medicines for adverse effects of conventional intervention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Abbreviations: BBSKE, 1,2-[bis (1,2-benzisoselenazolone-3 (2H)-ketone)] ethane; bFGF, basic fibroblast growth factor; CAM, complementary and alternative medicine; COX, cyclooxygenase; CREB, cAMP response element-binding; CRP, clinical radiographic physiologic; DHA, dihydroartemisinin; DPPH, 1,1-diphenyl-2-hydrazyl; ECM, extracellular matrix; EGFR, epidermal growth factor receptor; ERK, extracellular signal-related kinase; FD, feiyanning decoction; GSP, grape seed proanthocyanidin; HUVEC, human umbilical vein endothelial cell; MDR, multidrug resistance; MK, monacolin K; MMP, matrix metalloproteinase; MRP, MDR-associated protein; NF-␬B, nuclear factor-kappaB; NP, navelbine and cisplatin; NSCLC, non-small cell lung cancer; PAI, plasminogen activator inhibitor; PARP, poly (ADP)-ribose polymerase; PDGF, platelet-derived growth factor; PFS, progression free survival; p-gp, p-glycoprotein; QoL, quality of life; RCT, randomized-controlled trial; ROS, reactive oxygen species; RTOG, Radiation Therapy Oncology Group; SCLC, small cell lung cancer; SENL, Supplement energy and nourish lung; SM, solamargine; TCS, trichosanthin; TGF, tumor growth factor; TIMP, tissue inhibitor of metalloproteinase; TNF, tumor necrosis factor; UA, ursolic acid; VEGF, vascular endothelial growth factor. ∗ Corresponding author at: Cancer Preventive Material Development Research Center, College of Oriental Medicine, Kyung Hee University, 1 Hoegi-dong, Dongdaemun-gu, Seoul 131-701, Republic of Korea. Tel.: +82 2 961 9233; fax: +82 2 964 1064. E-mail address: [email protected] (S.-H. Kim). 0378-8741/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.jep.2011.10.018

S.-J. Jeong et al. / Journal of Ethnopharmacology 138 (2011) 652–661

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4.4. Limitations and challenges of current clinical trials with herbal medicines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction Lung cancer, the leading one of cancer-related deaths worldwide, is divided into two major types such as small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). The most risk factor for lung cancer is cigarette smoking. Furthermore, lung cancer can be induced by chemical exposure to arsenic, beryllium, cadium, vinyl chloride, and nickel chromates. The occurrence of lung cancer in non-smokers is frequently attributed to a combination of genetic factors (Gorlova et al., 2007), radon gas (Catelinois et al., 2006), and air pollution (Kabir et al., 2007). Because lung cancer does not generally exhibit any significant symptoms until the cancer initiates metastasis to other organs, early diagnosis is a key factor for improving the survival of lung cancer patients. Therapeutic approaches to lung cancer, such as chemotherapy, radiotherapy, and surgery have been widely used. For treatment of SCLC, cisplatin, etoposide (Murray and Turrisi, 2006), and celecoxib (Aruajo et al., 2009) are generally utilized, whereas anthracycline, doxorubicin, epirubicin, topotecan, irinotecan, paclitaxel, and gemcitabine are applied either alone or in combination with others (Azim and Ganti, 2007). For treatment of NSCLC, cisplatin and carboplatin are often used in combination with other anti-cancer agents such as gemcitabine, paclitaxel, docetaxel, etoposide, or vinorelbine (Clegg et al., 2002). Nonetheless, because this standard chemotherapy often limited survival benefit due to severe toxicity (Broker and Giaccone, 2002), recent reports suggested that antitumor herbal medicines and their phytochemicals with little toxicity are attractive for lung cancer therapy. In traditional medicine, several herbal plants such as Platycodon grandiflorum (Campanulaceae), Morus alba (Moraceae), Prunus armenica (Rosaceae) and Rhus verniciflua (Anacardiaceae), Perilla frutescens (Labiatae), Stemona japonica (Stemonaceae), Tussilago farfara (Compositae) and Draba nemorosa (Brassicaceae) have been frequently used for lung diseases including cancer as folk remedies and medicines. Previously, 130 Chinese herbal medicines possessing anti-lung cancer effects were classified into five subgroups based on their action: (1) clearing heat and toxin, (2) resolving Dampness and Phlegm, (3) regulating blood and Qi, (4) reinforcing Qi, and (5) nourishing Yin (Liang et al., 2003) by their ethnopharmacological efficacies. In the current review, to support updated systemic information on the use of herbal medicines and their constituents for lung cancer treatment and prevention to cancer researchers, we discussed their ethnopharmacological effects focusing on angiogenesis, metastasis, apoptosis and clinical trial efficacy and finally suggested perspectives for future herbal medicine research with summarized table on family name, effective doses, constituents and molecular targets. We selected peerreviewed papers on herbal medicines and their phytochemicals for lung cancer treatment in vitro and in vivo shown through Scientific Database Medline, Scopus and Google scholar. The following keywords were used to search for the literature inside the databases: herb, phytochemical, plant extract, natural product and lung cancer. However, we excluded the papers on the antitumor effects of derivatives from herbal compounds.

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2. Anti-lung cancer effects and molecular regulation of herbal medicines in vitro It is important to understand their unique mechanisms of action to be developed as therapeutically useful agents for cancer. Investigation of the molecular mechanisms whereby herbal medicines exert anti-cancer activity has resulted in the development of many targeted therapeutic drugs for cancer treatment (Kukunoor et al., 2003). Molecular approaches provide new viewpoints for early diagnosis and screening of high-risk individuals, determination of prognosis, and identification of innovative treatments (Huber and Stratakis, 2004). In lung cancer therapy, angiogenesis- and metastasis-related factors such as VEGF and MMPs, along with cell proliferation- and survival-related factors such as AKT, NF-␬B, Ras, MAPKs, and EGFR, are importantly considered as target molecules for lung cancer therapy (Table 1). 2.1. Apoptosis and herbal medicines Apoptosis is characterized by a series of morphological alterations, including plasma and nuclear membrane blebbing, cell shrinkage, dissolution of nuclear lamina, and the biochemical process responsible for activation of apoptosis (Jacobson et al., 1994). More than 5000 research papers have been published on apoptosis in lung cancer. Among them, it is of interest that various herbal medicines and phytochemicals can induce apoptotic cell death in lung cancer cells. The fruit, bark, and roots of Toona sinensis (Meliaceae) has been used in Chinese medicine. Toona sinensis showed anti-diabetic activity by enhancement of lipolysis and glucose uptake in differentiated 3T3-L1 adipocytes (Yang et al., 2003). Toona sinensis leaf extract (TSL-1), a bioactive fraction, has shown anti-cancer effects against lung (Yang et al., 2010) and prostate cancer cells (Chen et al., 2009a). TSL-1 had the inhibitory effect of proliferation 24-h post-treatment (IC50 = 1.2 mg/ml) and mediated apoptosis at 0.5 or 1 mg/ml in H441 lung adenocarcinoma cells. TSL-1 induced apoptotic cell morphological changes, sub-G1 accumulation, and poly (ADP)-ribose polymerase (PARP) cleavage. Ocimum gratissimum (OG) (Lamiaceae), an aromatic, perennial herb, was traditionally used with its anti-bacterial and anti-diabetic activities and to treat gastrointestinal disorders in Taiwan. OG significantly decreased the cell viability. OG activated apoptosis signaling molecules such as caspase-3 and -9 at the concentrations of 500 or 800 ␮g/ml in A549 cells, suggesting that OG may be a beneficial candidate for lung carcinoma treatment (Chen et al., 2010a). Likewise, acetone extract of Bupleurum scorzonerifolium (Umbelliferae) (BS-AE) (Cheng et al., 2005), and Tianhua (TH-R) from Trichosanthes kirilowii Maxim (Cucurbitaceae) (Li et al., 2010a) and its constituent trichosanthin (TCS) (Li et al., 2010b) have been reported to possess anti-cancer activity by inducing apoptosis in A549 lung cancer cells. Many bioactive compounds from medicinal herbs also have been reported as potent apoptosis inducers in lung cancer cells. The flavonoid polyphenolic compound acacetin (5,7-dihydroxy4 -methoxyflavone) derived from Robinia pseudoacacia (Fabaceae) showed the anti-proliferation effect in A549 cells (IC50 = 9.46 ␮M). Acacetin induced apoptosis and cell cycle arrest via upregulation of p53 and p21/WAF1 proteins at the concentrations of 5 or 10 ␮M in A549 cells (Hsu et al., 2004). Dihydroartemisinin (DHA) is a artemisinin derivative from Artemisia annua (Asteraceae) used for

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Table 1 Herbal medicines and phytochemicals with antitumor activity in lung cancers. Compounds

Minimum dose/duration

Target molecules and pathway

Lung cancer cell lines

References

Other biological activities

Angelica keiskei

4-Hydroxyderricin

50 mg/kg × 2/2 weeks

↓CD4+ , CD8+ , NK-T cell (Tumorigenesis)

LLC, HUVEC (in vivo)

Kimura et al. (2004)

Angelica gigas

Decursin

50 mg/kg/13 days

↓VEGF, tumor growth (Tumorigenesis)

LLC (in vivo)

Lee et al. (2009)

Petroselinum crispum

Myristicin

10 mg/mouse/20 days

25-OCH(3)-PPD

1 ␮M/24 h

Artemisia annua

Dihydroartemisinin (DHA)

1 ␮g/ml/72 h

Glossogyne tenuifolia

Glossogin

12.5 ␮g/ml/48 h

N/A (in vivo) A549, H358, H838 (in vivo) ASTC-a-1, SPC-A-1, PC-14 (in vitro) A549 (in vitro)

Zheng et al. (1992)

Panax notoginseng

N/A (Tumorigenesis) ↓MDM2, E2F1, Cyclin D1, Cyclin E, cdc25c, cdk2, 4 ↑p21, p27 (Survival) ↑Caspase-3 ↓Survivin, p38 (Survival)

Anti-cancer (leukemia, neuroblastoma and colon cancer) Anti-inflammation, anti-oxidation, anti-bacteria, and regulation of lipid metabolisms Anti-cancer (prostate cancer), anti-oxidation and anti-neurotoxicity Anti-oxidation

Celastraceae

Tripterygium wilfordii

PG490 (triptolide)

10 ng/ml/24 h

Cucurbitaceae

Trichosanthes kirilowii

Trichosanthin

0.5 mg/ml/48 h

Robinia pseudoacacia

Acacetin

5 ␮M/48 h

Lonchocarpus utilis Lonchocarpus urucu

Deguelin

50 nmol/l/48 h

Quercus petraea

Proanthocyanidin

0.1% (w/w)/58 days

Cassia garrettiana

Cassigarol A

100 mg/kg

Cassia garrettiana

Piceatannol

50 mg/kg × 2/day

Apiaceae

Araliaceae

Asteraceae

Fabaceae

Fagaceae

Lauraceae

↑Cytochrome c, caspase-9, -3, Bad ↓Bcl-2, Bcl-xL (Survival) ↑Caspase-3, caspase-8, ERK2 (Survival)

↑IFN-␥ (Survival) ↑p53, p21, Fas, mFasL, sFasL (Survival) ↓mTOR, GSK3, AMPK, TSC2, MAPK, S6, P21, EGFR, CDK4, MEK1, VEGFR2, IGF-1R, AKT, p110␣, PDK1 ↑Caspase-7, 4EBP1, Stat3, Src, MAPK, Stat6 (Survival) ↑IGFBP-3, caspase-3 ↓VEGF (Tumorigenesis) ↓Plasmin (Multidrug resistance) ↑Survival time, survival rate ↓Tumor growth (Tumorigenesis)

Wang et al. (2009b)

Haemostasis and anti-cardiovascular disorders

Lu et al. (2009), Mu et al. (2008, 2007)

Anti-cancer, anti-malaria and sedative activities

Hsu et al. (2008)

Anti-cancer (breast, lung and liver cancer), anti-inflammation, and anti-oxidation

A549 (in vitro)

Frese et al. (2003)

A549 (in vitro) A549 (in vitro)

Li et al. (2010b)

Anti-rheumatoid arthritis and anti-autoimmune disorders Treatment of polycystic kidney disorders Inhibition of HIV-1 proliferation

Hsu et al. (2004)

Anti-cancer, anti-virus and narcodic activities

HBE, HBEC3, H1229, H460 (in vitro)

Kim et al. (2008)

Anti-cancer (colon, ovarian, prostate and gastric cancer)

A549, H1299 (in vivo) LLC, HUVEC (in vivo) LLC (in vivo)

Akhtar et al. (2009)

Anti-inflammation, anti-septic and haemostasis

Kimura et al. (2000a)

Anti-HIV, anti-histamine and anti-cancer (colon cancer)

Kimura et al. (2000b)

Anti-cancer (colon cancer) and anti-histamine

S.-J. Jeong et al. / Journal of Ethnopharmacology 138 (2011) 652–661

Medicinal plants (scientific names)

Family names

Table 1 (Continued) Medicinal plants (scientific names)

Compounds

Minimum dose/duration

Target molecules and pathway

Lung cancer cell lines

References

Other biological activities

Magnoliaceae

Magnolia officinalis

Honokiol

10 mg/kg/21 days

↓Tumor growth, CD31 (Tumorigenesis)

A549 (in vivo)

Jiang et al. (2008)

Anti-anxiety, anti-allergy, anti-asthma and anti-angiogenesis

Orchidaceae

Dendrobrium loddigesii

Moscatilin

1 ␮M/1 h

↓ERK1/2, Akt, eNOS (Angiogenesis s)

Tsai et al. (2010)

Anti-cancer (placenta, stomach and lung cancer)

Plumbaginaceae

Plumbago indica

Plumbagin

3 ␮M/48 h

Gomathinayagam et al. (2008)

Cure for lead poisoning

Polyclinidae

Ritterella tokioka

Ritterazine B

5 nM/24 h

Rheum palmatum

Emodin

60 ␮M/24 h

PC14 (in vitro) H1703, H5203 (in vitro)

Komiya et al. (2003) Ko et al. (2010)

Anti-cancer (leukemia)

Polygonaceae

↓EGFR/Neu, Akt, NF-␬B, survivin, cyclinB1, Cdc25B ↑JNK/p38, p53, p21CIP1/WAF (Survival) ↓CDK4/cyclin D (Survival) ↓ERCC1, ERK1/2 (Multidrug resistance)

HUVEC, A549 (in vitro) H460, A549 (in vitro)

Ranunculaceae

Thalictrum acutifolium

Acutiaporberine 0.003 ␮mol/ml/48 h

N/A

Hedyotis diffusa

Ursolic acid

PLA-801, 95-D (in vitro) A549 (in vitro)

Chen et al. (2002a,b)

Rubiaceae

Hsu et al. (2004)

Immunostimulant, anti-fever and anti-cancer (leukemia, prostate, colon and breast cancer)

Rutaceae

Phellodendron amurense Berberine

↓Bcl-2 ↑Bax, c-myc (Survival) 10 ␮M/48 h ↓CyclinD1, D2, E, cdk2, 4, 6, NF-␬B, Bcl-2, Bcl-xL ↑p21, Fas/APO-1, Fas ligand, Bax (Survival) 1000 parts per million (ppm)/14 days ↓AKT, CREB, MAPK (Tumorigenesis)

A549 (in vivo)

James et al. (2010)

Anti-oxidation, immunomodulation and anti-cancer (prostate cancer)

Solanaceae

Solanum incanum

Solamargine

3 ␮M/16 h

H441, H520, H661, H69 (in vitro)

Liang et al. (2008, 2007, 2004)

Anti-cancer (skin cancer) and anti-bacteria

Trilliaceae

Paris polyphylla

Saponin

20 mg//kg/14 days

LA795 (in vivo)

Man et al. (2009)

Anti-bacteria, anti-fungus anti-cancer (breast, liver, gastric and colon cancer)

Curcuma longa

EF24

0.8 ␮M/72 h

↑ERK1/2, JNK, p38 (Multidrug resistance)

A549 (in vitro)

Thomas et al. (2010)

Curcuma kwangsiensis

␤-Elemene

20 ␮g/ml/72 h

N/A (Survival)

NCI-H596, NCI-H69 (in vitro)

Li et al. (2010c)

Anti-cancer (leukemia, colon, liver, breast and prostate cancer), anti-virus, anti-arthritis, anti-amyloid, anti-oxidation, and anti-inflammation Anti-cancer (leukemia, brain, breast and liver cancer)

Zingiberaceae

↑TNF-␣, TNF-␤, caspase-3 cytochrome c, ↓Bcl-2, Bcl-xL ↑HER2, TOP2A (Metastasis) ↑TIMP-2 ↓MMP-2, MMP-9 (Metastasis)

Anti-inflammation, anti-bacteria, anti-obesity and anti-cancer (pancreatic, tongue and liver cancer)

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Family names

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malaria treatment (Posner et al., 1999). DHA mediated apoptosis in human lung cancer cells ASTC-a-1 (IC50 = ∼8 ␮g/ml) (Lu et al., 2009), PC-14 (IC50 = ∼43 ␮M) (Mu et al., 2008), and SPC-A-1 (Mu et al., 2007). PG490 (triptolide), a diterpene triepoxide from Tripterygium wilfordii (Celastraceae), had no significant effect on the induction of cell death in human lung cancer cell lines A549, NCI-H358, Calu1 and SkLu1 at 20 ng/ml. In contrast, PG490 significantly sensitized lung cancer to Apo2L/TRAIL-induced apoptosis (Frese et al., 2003). Acutiaporberine [a bisalkaloid from Thalictrum acutifolium (Ranunculaceae)], ritterazine B [one of the ritterazine analogues from Ritterella tokioka (Polyclinidae)], and ursolic acid [a pentacyclic triterpene from Hedyotis diffusa (Rubiaceae)] were reported to induce apoptosis in vitro. Acutiaporberine significantly downregulated anti-apoptotic Bcl-2 and upregulated pro-apoptotic Bax and c-myc in the highly metastatic human lung cancer 95-D cells (Chen et al., 2002a) and NSCLC PLA-801 (Chen et al., 2002b). Survival proteins including AKT, NF-␬B, Ras, and MAPKs, are known to play key roles in lung cancer progression and carcinogenesis. Asian ginseng extract (EAG) (Panax ginseng C.A. Meyer) had a significant cytotoxic effect against lung cancer cells LLC compared to other types of cancers such as cervical, breast and liver cancer cells, suggesting that lung cancer cells might be more susceptible to EAG treatment (Wong et al., 2010). EAG revealed the inhibitory effect on in vitro and in vivo growth of mouse LLC via modulation of ERK-p53 and NF-␬B signaling. The traditional Chinese herbal medicine feiyanning decoction (FD) markedly suppressed the proliferation of A549 cells, partly due to inhibition of NF-␬B activation induced by TNF-␣ (Wang et al., 2009a). Plumbagin from Plumbago indica decreased the viability of H460 cells. The viability of A549 cells was also decreased to by 17.6% at 15 ␮M. Plumbagin induced apotposis by inhibiting survival proteins AKT, NF-␬B, Bcl-2, and survivin in H460 cells (Gomathinayagam et al., 2008). Additionally, many other bioactive compounds from traditionally used herbs were reported to induce apoptosis in lung cancer cells; for instance, glossogin from Glossogyne tenuifolia (Asteraceae) (Hsu et al., 2008), a novel ginsenoside 25-OCH(3)-PPD from Panax notoginseng (Araliaceae) (Wang et al., 2009b), deguelin from Lonchocarpus utilis or Lonchocarpus urucu (Fabaceae) (Kim et al., 2008), and ␤-elemene from Curcuma kwangsiensis (Zingiberaceae) (Li et al., 2010c). 2.2. Inhibitory effects of herbal medicines on angiogenesis and metastasis in vitro Angiogenesis, the process involving the growth of new blood vessels from pre-existing vessels, contributes to the growth and spread of lung cancer (Carmeliet and Jain, 2000). Thus, blockage of angiogenesis is considered to be an important therapeutic target for lung cancer. Clinical trials over the last decade with anti-angiogenic modalities such as angiostatin, endostatin, solimastat, bevacizumab, and angiozyme-targeting vascular endothelial growth factor (VEGF) as a key factor of angiogenesis have shown survival benefits in patients with advanced stage malignancies (Ellis and Hicklin, 2008). VEFG is also closely associated with other indirect angiogenic factors such as basic fibroblast growth factor (bFGF), platelet-derived growth factor (PDGF), and tumor growth factor alpha (TGF-␣) (Glade Bender et al., 2004). Ganoderma lucidum (Ganodermataceae), a basidiomycete white rot fungus, is a medicinal herb prescribed for various diseases such as cancer, HIV, diabetes, asthma, ulcers, etc. in Korea, China and Japan. Many groups suggested the potential role of Ganoderma lucidum in the treatment of various cancers including prostate (Jiang et al., 2011), skin (Sun et al., 2011), ovarian (Zhao et al., 2011) and colon cancer (Jedinak et al., 2011). Cao et al. reported anti-tumor and anti-angiogenic activity of Ganoderma lucidum polysaccharides in vitro and in vivo (Cao and Lin, 2004, 2006).

Ganoderma lucidum polysaccharides reduced the growth of PG cells in Balb/c nude mice. Ganoderma lucidum polysaccharides also inhibited the proliferation of human umbilical vein endothelial cells (HUVECs) and inhibited the secretion of VEGF by lung cancer cell PG in hypoxic condition. Also, the serum from Ganoderma lucidum polysaccharides treated Balb/c mice also showed antiangiogenic effect by chick chorioallantoic membrane (CAM) assay. Overall, these data suggest that Ganoderma lucidum polysaccharides not only inhibited vascular cell proliferation in HUVECs, but also reduced the secretion of VEGF by human lung carcinoma PG cells. Interestingly, clinical study by Gao et al. (2005) suggest that the subgroups of advanced lung cancer patients might be responsive to Ganoderma lucidum polysaccharides in combination with chemo/radiotherapy by reversing the immunosuppressive effects of traditional cancer therapy. However, despite its antitumor activity against lung cancer, it is required to study its efficacy, safety, optimal concentration, and molecular targets including VEGF, alone or in combination with current cancer therapy for lung cancer by pharmacokinetic study in animals and humans in the future. Metastasis, the most characteristic aspect of malignant neoplasm, is the leading cause of death in cancer patients (Lee et al., 2008; Nonaka et al., 1993). Tumor metastasis is related to tumor cell dissociation, invasion, intravasation, and distribution to distant organs arrest in small vessels, adhesion to endothelial cells, extravasation, invasion of the target organ, and proliferation (Fidler, 2003; Weiss, 2000). It is well known that activation of matrix metalloproteinase (MMP), a proteolytic enzyme in the extracellular matrix (ECM), is closely associated with metastasis and cancer invasion. Of the MMP family, MMP-2 and -9 are mainly involved in the metastasis process (Curran and Murray, 2000). Lung is one of the most common sites of tumor metastasis along with liver and bone marrow (Murphy, 2001). Human NSCLC A549 cells are commonly utilized to evaluate in vitro anti-metastatic properties of anti-cancer candidates by invasion and migration assays, and analyses of the expression of metastasis-related molecules. Medicinal herb Scutellaria baicalensis was traditionally used for the treatment of febrifuge, hypertension, over-excitement, insomnia, chronic trachitis and cancer in Korea and Mongolia. Yang et al. reported anti-metastatic effect of Selaginella tamariscina (Selaginellaceae) extract (STE) in vitro on A549, a highly metastatic lung cancer cells. The expression of MMP-2 and -9, and plasminogen activator inhibitor-1 (PAI-1) whereas the expression of tissue inhibitor of metalloproteinase-2 (TIMP-2) was increased in A549 cells treated with STE (0-100 ␮g/ml). In vivo anti-metastatic effect of STE was also observed in LLC-bearing C57BL/6 mice (Yang et al., 2007). 2.3. Herbal medicines as multidrug resistance (MDR) reversal agents Multidrug resistance (MDR) is one of the important causes of chemotherapy failure against cancers. One of the underlying mechanisms of MDR is cellular overproduction of p-glycoprotein (p-gp), which acts as an efflux pump for various anticancer drugs (Hipfner et al., 1999). So far, a variety of compounds have been studied and developed as MDR reversal agents by interfering with p-gp function (Boesch et al., 1991; Koo et al., 2008; Pires et al., 2009; Pirker et al., 1990; Xu et al., 2008). Nevertheless, some MDR reversal agents induced altered pharmacokinetics and side effects (Sikic et al., 1997). Although many anti-cancer drugs such as docetaxel, gemcitabine, and vinorelbine have been developed for the treatment of NSCLC (Einhorn, 2008), NSCLC generally induces MDR due to the overexpression of MDR-associated proteins (MRPs), including pgp (Xu et al., 2000). Thus, to overcome MDR caused by anti-cancer agents, new MDR reversal agents are required to improve the therapeutic effect for lung cancer.

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Of herbal medicines, Stephania tetrandra (Menispermaceae)containing herbal formula, namely “Supplement energy and nourish lung” (SENL) (Xu et al., 2010), and Ganoderma lucidum (Ganodermataceae) (Sadava et al., 2009) showed MDR reversal effect in SW1573/2R 120, adriamycin (ADM)-resistant lung cancer cells and VPA MDR SCLC, respectively. Solamargine (SM), the major steroidal glycoalkaloid from Solanum incanum (Solanaceae) used for Chest pains, pleurist, pneumonia, tooth ache, sore throat in India, suppressed MRPs in lung cancer cells. SM enhanced the cytotoxicity against human lung cancer H661 and H69 cells to trastuzumab and epirubidin (Liang et al., 2008). Furthermore, SM sensitized apoptosis induction in tumor necrosis factor (TNF) and cisplatin-resistant lung cancer cells (Liang et al., 2004) and combination therapy of SM and epirubicin effectively promoted chemotherapy-induced apoptosis in A549 cells (Liang et al., 2007), strongly suggesting the potential of SM as a MDR reversal agent. Additional bioactive phytochemicals were reported as potent MDR reversal agents; a novel monoketone curcumin analog, EF24 from Curcuma longa (Zingiberaceae) (Thomas et al., 2010), emodin (1,3,8-trihydroxy-6methyl-anthraquinone) from Rheum palmatum (Polygonaceae) (Ko et al., 2010), and ␤-elemene from Curcuma kwangsiensis (Zingiberaceae) (Zhao et al., 2007).

2.4. Reactive oxygen species (ROS) and lung cancer therapy Increased ROS production and an altered redox signaling frequently mediate advanced cancer progression. Thus, targeting ROS signaling was also thought to be a striking method in recent cancer therapy including lung cancer (Trachootham et al., 2009). Especially, smoke-oxidative stress produces DNA damage and activates survival signaling cascades resulting in uncontrolled proliferation and transformation of lung epithelial cells (Faux et al., 2009). Several studies have provided evidences that several herbal extracts and their components have ROS-scavenging activity in lung cancer cells. Polygonum cuspidatum (Polygonaceae) was traditionally used in Korea to maintain oral health by reducing the viability of oral microorganisms and to treat arthritis and urinary diseases. Polygonum cuspidatum extract is constituted of alkaloids, phenolics and sterol/terpenes and has been shown various biological activities such as anti-inflammation (Ghanim et al., 2010), anti-oxidation (Li et al., 2011) and anti-cancer (Shin et al., 2011). The ethanol and ethyl acetate extracts of Polygonum cuspidatum showed significant scavenging effects on 1,1-diphenyl-2-hydrazyl (DPPH) and hydroxyl radicals in A549 and H1650 cells (Lin et al., 2010). Likewise, the ethyl acetate fraction (EAF) of wampee peel (Clausena lansium Skeels (Rutaceae)), a species of strongly scented evergreen trees in southeast Asia, exhibited higher anti-oxidant and anticancer activities than cisplatin in lung cancer cells A549 as well as gastric cancer cells SGC-7901 and liver cancer cells HepG2. EAF revealed 1,1-diphenyl-2-picryl hydrazyl (DPPH) radical scavenging activity, reducing power, and superoxide scavenging activity, suggesting the possibility of wampee peel as a natural anti-oxidant and pharmaceutical supplement (Prasad et al., 2009). Recently, Lawless et al. (2009) suggested in their review paper that histone deacetylase (HDAC) plays a role in regulating oxidative stress pathways and cancer progression in NSCLC. The authors suggested dietary HDAC inhibitors as therapeutic agents such as sulforaphane from Brassica oleracea (Brassicaceae), curcumin from Curcuma longa L. (Zingiberaceae) and epigallocatechin 3-gallate (EGCG) from Camellia sinensis (Theaceae) to target NSCLC as well as chronic obstructive pulmonary disease (COPD). However, further studies on the antitumor of herbal drugs via HDAC inhibition are required in the future.

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3. Anti-lung cancer activities of herbal medicines in vivo In vivo mouse xenograft or allograft model is a worthwhile tool in cancer biology to evaluate anti-cancer activity of novel drug(s). The anti-tumor activity is tested by measuring the inhibitory effect of tumor growth and survival time. Anti-tumorigenic activities of several herbal extracts were demonstrated against the growth of LLC allograft in syngenic mice or A549 lung cancer xenograft in immunodeficient mice. Selaginella tamariscina extract (STE) reduced tumor growth and weight by 53% and 72%, respectively, at 3 g/kg compared with untreated control on day 30 (P < 0.05). STE showed a significant in vivo anti-metastatic effect at 1 or 3 g/kg administration in LLC-bearing C57BL/6 mice (Yang et al., 2007). Also, intraperitoneal injection of aceton extract of Bupleurum scorzonerifolium (BS-AE) (100, 300 or 500 mg/kg) significantly suppressed tumor growth in a dose-dependent manner in A549 xenograft model compared with control (P < 0.001) (Cheng et al., 2005). In addition, ethanol extract of Ocimum sanctum L. (Lamiaceae) (EEOS), commonly known as ‘Holybasil’ in the Ayurvedic system of medicine (Singh et al., 1996), significantly inhibited cell adhesion, invasion and the activity of MMP-9 as well as significantly reduced tumor nodule formation and lung weight in LLC-bearing mice at a dose less than 100 mg/kg (Kim et al., 2010). Venkatesan et al. found that combination of Solanum trilobatum (Solanaceae) extract (300 mg/kg) with cisplatin (6 mg/kg) could effectively suppress benzo(a)pyrene-induced lung cancer in mice by protecting from ROS damage (Venkatesan et al., 2008). Bai et al. reported that the inhibitory effects of Shenqi extract [huangqi (Astragalus membranaceus (Leguminosae)) plus dangshen (Salvia miltiorrhiza Bunge (Labitae))] in combination with pacilitaxel were found on metastasis and angiogenesis compared with untreated control or administration of paclitaxel alone in a mouse Lewis lung carcinoma (LLC) model (P < 0.05). The survival time of Shenqi group was also significantly longer than other two groups (P < 0.05) (Bai et al., 2008). Pomegranate fruit extract (PFE) (0.2%, w/v in drinking water) also significantly inhibited lung tumorigenesis in A/J mice as a chemopreventive agent for human lung cancer treatment (Khan et al., 2007). A number of active herbal compounds also showed anti-lung cancer effects in vivo mouse models. Moscatilin from Dendrobium nobile (Orchidaceae) significantly suppressed tumor growth of A549 lung cancer cells in nude mice by intraperitoneal administration with moscatilin (100 mg/kg) compared with control. Interestingly, moscatilin led to a destruction of tumor vasculature which was evidenced by lower expression of CD31 staining, suggesting that moscatilin inhibits tumor growth via an antiangiogenic effect (Tsai et al., 2010). Rhizoma paridis saponins (RPS) induced the inhibition of tumor growth at 20 and 40 mg/kg administration, respectively (P < 0.05). RPS also inhibited lung metastasis by inducing apoptosis and up-regulation of TIMP-2 expression and down-regulation of MMP-2 and MMP-9 in murine lung adenocarcinoma (Man et al., 2009). Honokiol, a major bioactive compound from Magnolia officinalis (Magnoliaceae), showed the improved therapeutic effect by combined treatment with cisplatin in an A549 lung cancer mouse model. Treatment of honokiol (25 mg/kg) or cisplatin (5 mg/kg) individually resulted in the anti-tumor activity by measuring tumor volume and life span. Combined administration of honokiol and cisplatin had an advanced suppression of the tumor growth (Jiang et al., 2008). In the liver and small intestinal mucosa of female A/J mice, 65% inhibition of tumor multiplicity in the lung was observed by treatment with myristicin, a volatile aroma constituent of parsely leaf (Petroselinum crispum (Apiaceae)) oil, at 10 mg/mouse administration (Zheng et al., 1992). Surprisingly, xanthorrhizol, a natural sesquiterpenoid from Curcuma xanthorrhiza (Zingiberaceae) suppressed intraabdominal tumor mass formation by 91%. Furthermore, xanthorrhizol exerted anti-metastatic

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potential by targeting MMP-9, extracellular signal-related kinase (ERK), and cyclooxygenase 2 (COX-2) in a mouse lung metastasis model, strongly suggesting the anti-tumor potential of xanthorrhizol even at lower concentration (Choi et al., 2005). Dietary isoquinoline alkaloid component berberine or Phellodendron amurense (Rutaceae) extract (PAE), a Chinese herbal remedy with anti-tumor and anti-microbial activities, suppressed the phosphorylation of AKT, cAMP response element-binding (CREB), and MAPK in A 549 cells and also lung tumorigenesis in vivo (James et al., 2010). Grape seed proanthocyanidins (GSPs) from Quercus petraea (Fagaceae) inhibited the growth of A549 and H1299 in mice by targeting insulin-like growth factor binding protein 3, tumor cell proliferation, and angiogenic factors (Akhtar et al., 2009). Decursin from Korean Angelica gigas (Apiaceae) (Lee et al., 2009) and 4-hydroxyderricin from Angelica keiskei roots (Kimura et al., 2004) at 50 mg/kg exerted anti-tumorigenic activity in LLCbearing mice. Similarly, two active substances, cassigarol A (Kimura et al., 2000a) and piceatannol (Kimura et al., 2000b) from Cassia garrettiana (Lauraceae) heartwood, at 50 or 100 mg/kg revealed inhibitory effects on tumor growth and lung metastasis in LLCbearing mice.

4. Clinical trials of herbal medicines for the treatment of lung cancer The use of complementary and alternative medicine (CAM) modalities, including herbal medicine has increased in number especially among cancer patients (Boon et al., 2007; Xu et al., 2006). Recent cohort study with 453 cancer patients revealed that the percentage of patients using herbal medicines in combination with conventional treatment was as high as 77% (Richardson and White, 2000), mainly with the aims of reduction of therapy-associated toxicity, improvement of cancer-related symptoms, fostering of the immune system, and even direct anti-cancer effects (Gerber et al., 2006).

4.1. Herbal medicines as combination therapy with conventional chemotherapy In general, herbal medication was applied as an adjuvant therapy to conventional treatment to increase therapeutic benefit and quality of life (QoL), as well as decrease side effects or complications. In a recent randomized-controlled trial (RCT) with 63 in-patients with stage IIIb and IV NSCLC, Shengmai Injection (Ya’an Sanjiu Pharmaceutical Co., China) and Gujin Granule (Jiangyin Tianjiang Pharmaceutical Co., China) were administered intravenously and orally, respectively, while all groups were treated with navelbine and cisplatin (NP) chemotherapy. This combination therapy enhanced median survival time (P = 0.014) and response rate to 48.5% (16/33) compared to untreated control (32.2% = 9/28) in the control group (P = 0.0373). However, herbal medicine did not affect the 1-year survival rate, median time to progression, bone marrow inhibition occurrence, and mean cycles of chemotherapy applied (Chen et al., 2009b). In another clinical trial with Shenqi-fuzheng injection (Lizhu Co., China) among 232 NSCLC patients, herbal injection improved the response rate and QoL by using the QoL scale of European Organization for Research on Treatment of Cancer (QLQ-C30) (Lin and Li, 2007). Similarly, the clinical trial among sixty patients with advanced NSCLC showed that Yiqi Yangyin Jiedu Decoction significantly increased a Karnofsky (KPS) score and immunological parameters such as CD3+ , CD4+ , CD4+ /CD8+ , and CD8+ /CD28+ compared to untreated control, while all patients treated with NP or gemcitabine and cisplatin (GP) (Liu et al., 2008).

4.2. Herbal medicines for improved quality of life in lung cancer patients Recently QoL is regarded as a prognostic factor for long-time survival among NSCLC patients. In a randomized-controlled trial with an herbal formula Feiji Recipe, Feiji Recipe was found to enhance clinical therapeutic efficacy and alleviate side effects of chemotherapy in previous studies (Huang and Shi, 2007; You et al., 2006) by increasing higher scores in role, social, and economic status (P < 0.05 or P < 0.01) based on QLQ-C30 questionnaire (Tian et al., 2010). Similarly, in a clinical trial among 294 late NSCLC patients with TCM or Shenfu injection (Wu et al., 2006), based on Functional Assessment of Cancer Therapy-lung (FACT-L), herbal medicine was found to have positive effects on physical status when used alone as well as on emotional, functional, and additional concerned status when used with conventional chemotherapy (P < 0.05) (Lin et al., 2006). 4.3. Herbal medicines for adverse effects of conventional intervention One of the major risks of conventional treatment in lung cancer patients is radiation pneumonitis, possibly caused by radiotherapeutic intervention (Movsas et al., 1997) with symptoms of severe dyspnea, cough, fever, respiratory insufficiency, and/or cyanosis in severe cases (Graves et al., 2010). In a clinical trial with Dixiong Decoction among 46 NSCLC patients underwent by radiotherapy, based on the incidence of radiation pneumonitis after radiotherapy and QoL using the Watters clinical radiographic physiologic (CRP) dyspnea score, Radiation Therapy Oncology Group (RTOG) grading score, and KPS score, Dixiong Decoction significantly lowered the incidence of radiation pneumonitis (Treatment; 10.0%, Control; 26.3%, P = 0.0032) and improved the Watters CRP dyspnea score, RTOG grading score (P < 0.05), and KPS score (P < 0.01) (Dou et al., 2010). Likewise, there are many evidences on the beneficial efficacies by herbal medicines such as Liangxue Jiedu Huoxue Decoction (Xiao et al., 2010), Qingjin Runfei Decoction (Zhang et al., 2007), and Shenqi Fuzheng injection (Zheng et al., 2007). Irinotecan hydrochloride, a topoisomerase I inhibitor, isolated from Chinese tree Camptotheca acuminate (Cornaceae) is conventionally used to treat lung cancer in combination with other drugs (Matsuzaki et al., 1988; Oshita et al., 1997). However, adverse effects of irinotecan include leucopenia and diarrhea (Fukuoka et al., 1992). A randomized controlled trial with Hangeshashinto (TJ-14; Tsumura, Japan) among 44 irinotecan-treated NSCLC patients revealed that TJ-14 was shown to significantly improve the diarrhea grade (P = 0.044) and frequency of diarrhea grade 3 and 4 (P = 0.018) (Mori et al., 2003). 4.4. Limitations and challenges of current clinical trials with herbal medicines Current clinical investigation of herbal medicines also has limitations and difficulties. As noted in a recent review (Staud, 2011), traditional Chinese medicine (TCM), including herbal medicines, has its own unique feature such as holism and individualization. Under TCM theory, patients are diagnosed with presented symptoms rather than a disease itself and prescribed an individualized herbal formula to treat the symptoms accordingly. Although randomized-controlled trial (RCT) is a powerful tool to validate the clinical efficacy of medical regimens, application of individualized herbal medicine for RCT remains a challenge due to non-uniform batch administration (Xue et al., 2010). Similarly, the heterogeneity of herbal intervention induces some difficulties to conduct high-powered analysis of herbal medicines. Thus, in the future

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cancer research with herbal medicine and phytochemicals, we suggest that quality control for consistent batch and pharmacokinetic study should be performed with herbal medicines and their constituents known to exert antitumor activity against lung cancer. Thus, QoL of herbal medicines should be of specific concern in a sense that therapeutic efficacy may vary between different batches. Further, a lack of rigorous methodology, possible risk of bias, and a relatively small number of patients involved have been repeatedly pointed out in the previous literature on the application of herbal medicine to lung cancer patients (Chen et al., 2010b; Liu et al., 2005). Nevertheless, increasing evidences from recent basic and clinical studies support that herbal medicine may be beneficial and effective for the treatment of lung cancer patients by improvement of QoL, prevention of side effects due to conventional therapy, and/or immunologic parameters. However, new and specific methodologies must be developed to adequately address the challenges of current trials and to validate the possible credibility of herbal medicine (Xue et al., 2010). 5. Conclusions Despite remarkable advances in lung cancer treatment, lung cancer still ranks as one of leading cancer deaths all over the world. Recently molecular target therapy is so attractive, for instance, tyrosine kinase inhibitors such as gefitinib and erlotinib by targeting the epidermal growth factor receptor (EGFR) and its downstream mTOR signaling factors (Cataldo et al., 2011; Paez et al., 2004) and bevacizumab, a humanized monoclonal antibody that can bind to VEGF to improve response rates and progression free survival (PFS) in combination with carboplatin, paclitaxel, cisplatin and gemicitabin in phase II trials. However, Goel et al. (2008) demonstrated the limited benefit of such drugs in their recent review because the underlying molecular mechanisms responsible for anti-cancer activity can target a variety of genetic and environmental factors. A number of evidences from previous research papers suggested that Oriental medical therapies using medicinal herbs are effective in lung cancer treatment by regulating proliferation, apoptosis, angiogenesis, metastasis and MDR. They could target molecules involved in the biological processes in lung cancer cells without toxicity against normal lung epithelial cells. Although many various herbal formulae and plants have been traditionally used to treat lung diseases since ancient times as folk remedies and the standard lung cancer guidelines were for the first time published by the American College of Chest Physicians including complementary and alternative medicine in 2007, systemic review on the potential of medicinal herbs and their active compounds in lung cancer treatment was not performed so far. Thus, in the current review, we suggest the potential of herbal medicines and their phytochemicals that have been traditionally used for lung diseases including cancer as folk remedies by critical analyses and discussion with the data of in vitro or in vivo laboratory experimental models and clinical trials. Overall, we suggest that herbal medicines and phytochemicals can be potent anti-cancer agents for lung cancer treatment and prevention by regulating multi-molecular targets involved in angiogenesis, metastasis and severe side effects, only provided quality control and reproducibility issues were solved. Acknowledgement This work was supported by the Korea Science and Engineering Foundation (KOSEF) grant funded by the Korea government (MEST) (No. 2011-0006220).

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