Antitumor Activities of Kushen: Literature Review

Sun, Mingyu; Cao, Hongyan; Sun, Lin; Dong, Shu; Bian, Yanqin; Han, Jun; Zhang, Lijun; Ren, Shuang; Hu, Yiyang; Liu, Chenghai; Xu, Lieming; Liu, Ping

doi:https://doi.org/10.1155/2012/373219

Evidence-Based Complementary and Alternative Medicine

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Complementary and Alternative Medicine and Cancer Survivorship

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Volume 2012 | Article ID 373219 | https://doi.org/10.1155/2012/373219

Antitumor Activities of Kushen: Literature Review

Mingyu Sun,^1,2,3Hongyan Cao,¹Lin Sun,⁴Shu Dong,¹Yanqin Bian,¹Jun Han,⁵Lijun Zhang,¹Shuang Ren,¹Yiyang Hu,^1,2,3Chenghai Liu,^1,2,3Lieming Xu,^1,2,3and Ping Liu^1,2,3

Academic Editor: Francesca Borrelli

Received04 Jan 2012

Revised30 May 2012

Accepted07 Jun 2012

Published28 Aug 2012

Abstract

To discover and develop novel natural compounds with therapeutic selectivity or that can preferentially kill cancer cells without significant toxicity to normal cells is an important area in cancer chemotherapy. Kushen, the dried roots of Sophora flavescens Aiton, has a long history of use in traditional Chinese medicine to treat inflammatory diseases and cancer. Kushen alkaloids (KS-As) and kushen flavonoids (KS-Fs) are well-characterized components in kushen. KS-As containing oxymatrine, matrine, and total alkaloids have been developed in China as anticancer drugs. More potent antitumor activities were identified in KS-Fs than in KS-As in vitro and in vivo. KS-Fs may be developed as novel antitumor agents.

1. Introduction

To discover and develop novel natural compounds with therapeutic selectivity or that can preferentially kill cancer cells without significant toxicity to normal cells is an important area in cancer chemotherapy. Because of their wide range of biological activities and low toxicity in animal models, some natural products have been used as alternative treatments for cancers. Many anticancer drugs are derived from naturally occurring compounds. Vinca alkaloids (e.g., vinblastine, vincristine) and taxol are examples of such compounds.

The traditional Chinese medicine kushen is the dried roots of Sophora flavescens Aiton (Leguminosae). It was first described in the Chinese book Shen Nong Ben Cao Jing in 200 A.D. as a treatment for solid tumors, inflammation, and other diseases [1]. The traditional use of kushen includes the decoction or powder of dried plant roots. It is commonly used for the treatment of viral hepatitis, cancer, enteritis, viral myocarditis, arrhythmia, and skin diseases (e.g., colpitis, psoriasis, eczema) [2].

The known chemical components of kushen include alkaloids (3.3%), flavonoids (1.5%), alkylxanthones, quinones, triterpene glycosides, fatty acids, and essential oils [2, 3]. Kushen alkaloids (KS-As) and kushen flavonoids (KS-Fs) are well-characterized components in kushen. KS-As have been developed as anticancer drugs in China. More potent antitumor activities have been identified in KS-Fs than in KS-As [4].

2. KS-As

KS-As have been well studied and are considered to be the major active components of kushen as demonstrated in experimental animal models [5–8] and clinical studies [9–14]. The bioactivities of kushen (including antitumor, anti-viral and anti-inflammatory activities) have been shown in the KS-As fraction [6].

KS-As containing oxymatrine, matrine (Figure 1), and total alkaloids were approved for the treatment of cancer patients by the Chinese State Food and Drug Administration (SFDA) in 1992. Multiple KS-As products have been used widely in China for the treatment of cancers and hepatitis. The SFDA-approved KS drugs for oncology are all KS-As used as single agents or in combination with chemotherapy or radiotherapy. Few studies focused on the efficacy of KS-As in animal models and clinical trials before 1992, when KS-As was first approved.

Several clinical studies reported that KS-As were efficacious in the treatment of various types of solid tumors (including lung, liver, and gastrointestinal tract). The treatment responses were comparable to, or better than, that of chemotherapy drug-treated patients (Table 1) [11, 14–32]. KS-As demonstrates a good safety profile in cancer patients, such as reduced toxicity in the bone marrow when used in combination with chemotherapy agents [33]. Long-term survival data for KS-As-treated cancer patients remains to be demonstrated with well-controlled clinical studies and large patient cohorts.

3. Matrine and Oxymatrine

Matrine and oxymatrine (Figure 1) are the two major alkaloid components found in the roots of Sophora species. They are obtained primarily from Sophora japonica (kushen), Sophora subprostrata (shandougen), and from the overground portion of Sophora alopecuroides. The matrines were first isolated and identified in 1958; they are unique tetracyclo-quinolizindine alkaloids found only in Sophora species thus far [52–56].

In vitro studies have demonstrated that matrine and oxymatrine weakly inhibit the growth of various human tumor cell lines with a half-maximal inhibitory concentration (IC₅₀) of 1.0–4.0 mg/mL [57–61].

In vivo studies have shown that KS-As, oxymatrine, and matrine inhibit the growth of murine tumors, including H22, hepatoma, S180, sarcoma, and MA737 breast cancer cells [58, 60, 62, 63]. In a human xenograft tumor model using the SGC-7901 cell line, matrine enhanced the inhibition of 5-fluorouracil in the tumor [33].

Matrine can also inhibit the invasiveness and metastasis of the human malignant melanoma cell line A375 and cervical cancer HeLa cells, as well as induce differentiation of leukemia K-562 cells [64–66]. In addition, matrine-induced autophagy in rat C6 glioma cells has been observed by electron microscopy [67].

The antitumor response of KS-As was further demonstrated in several clinical studies in various types of cancers, including stomach, esophagus, liver, colon, lung, cervix, ovary, and breast cancers, as a single agent [9–14] or in combination with chemotherapy [15–18] or radiotherapy [68]. It has been reported that matrine exerts its antitumor effects by inhibiting the proliferation and inducing the apoptosis of gastric and cervical cancer cells as well as leukemic and glioma cells [34, 67–70].

Several in vitro and in vivo studies have tried to elucidate the mechanism of action of matrine. Matrine promotes apoptosis in leukemic [35], breast cancer [36], nonsmall-cell lung cancer [37], hepatocarcinoma, and gastric cancer cells [38] by a mitochondrial-mediated pathway [39]. Beclin 1 is involved in matrine-induced autophagy, and the pro-apoptotic mechanism of matrine may be related to its upregulation of Bax expression [39]. Recent evidence indicates that matrine also has appreciable effects in modulating the immune response by reducing the invasion and metastasis of HCC cells [40, 41, 71].

Tissue homeostasis requires a balance between the division, differentiation and death of cells. A tumor is a type of “cell cycle disorder” that has the abnormal interface of division, differentiation and death [42]. As a “biological modifier” of cells, matrine can reverse the abnormal biologic behavior of tumor cells and recover the balance between the division, differentiation, and death of cells.

Matrine can also inhibit the invasiveness and metastasis of the human malignant melanoma cell line A375 [43]. Some studies reported that matrine reduced the adhesion and migration of HeLa cells [72]. The mechanisms of action of matrine against cancer cell proliferation and invasion are associated with epidermal growth factorvascular endothelial growth factor vascular endothelial growth factor receptor 1 Akt–nuclear factor-kappa B (EGF/VEGF—VEGFR1—Akt—NF-κB) signaling [36] (Table 2).

Matrine displays synergistic effects with the anticancer agents celecoxib (cyclooxygenase-2 inhibitor), trichostatin A (histone deacetylase inhibitor) and rosiglitazone against the tumor proliferation and VEGF secretion. Matrine may have broad therapeutic and/or adjuvant therapeutic applications in the treatment of human nonsmall-cell lung cancer, breast cancer, and hepatoma [36, 37] (Table 2).

Some studies have also reported upon the anticancer activity of oxymatrine in human gastric cancer cells, pancreatic cancer, and human breast cancer cells [73–75]. Oxymatrine can induce the apoptosis death of human pancreatic cancer cells, which might be attributed to the regulation of Bcl-2 and IAP families, release of mitochondrial cytochrome C, and activation of caspase-3 [74] (Table 2).

Compound kushen injection (CKI), commonly known as Yanshu injection, is extracted from two herbs, kushen (Radix Sophorae Flavescentis) and Baituling (Rhizoma Smilacis Glabrae), with the primary components being oxymatrine and matrine [75]. CKI has been used extensively alone or in combination with chemotherapy or radiotherapy for many years in China. Clinical studies have shown that CKI attenuates the side effects of chemotherapy and radiotherapy by improving the quality of life and regulating the immune function of cancer patients, as well as synergizing the therapeutic effects of chemotherapy and radiotherapy (Table 1) [15–32, 76]. It has been demonstrated that CKI suppresses the growth of tumor cells by inducing apoptosis and inhibiting the migration, invasion, and adhesion, of such cells [77].

Cancer stem cells (CSCs) play an important part in the initiation, relapse and metastasis of cancer. A specific agent has not been found to target CSCs because they are resistant to most conventional therapies and proliferate indefinitely. In one study, CKI suppressed the size of the side population (SP; ~90%) and downregulated the main genes of the Wnt signaling pathway in MCF-7 SP cells. CKI suppressed tumor growth by downregulating the Wnt/b-catenin pathway, whereas cisplatin activated the Wnt/b-catenin pathway and could spare SP cells. These data suggested that CKI may serve as a novel drug targeting CSCs, but further studies are recommended [44].

4. KS-Fs

The antitumor effects of some flavonoid compounds (Figure 1) have been demonstrated in vitro and in vivo [78–82]. Surprisingly, the antitumor activities of KS-Fs were more potent than those of KS-As, which have been considered to be the major active components in the plant [83]. KS-Fs such as kurarinone, 2′-methoxykurarinone, and sophoraflavanone G (lavandulyl flavanones isolated from S. flavescens) (Figure 1) can inhibit cell proliferation in A549, NCI-H460 (nonsmall-cell lung), SK-OV-3 (ovary), SK-MEL-2 (skin), XF498 (central nerve system), HCT-15 (colon) HL-60 (myeloid leukemia) and SPC-A-1 (lung) cells with IC₅₀ values between 2 μg/mL and 36 μg/mL [80, 82, 83].

Antitumor efficacies were confirmed in mice models of H22, S180 and Lewis lung tumors as well as nude mice models of human H460 and Eca-109 xenografted tumors [45, 83]. Moreover, KS-Fs and kurarinone enhanced the antitumor activities of Taxol in vitro and in vivo [83, 84]. The oral or intravenous maximum tolerated dose of KS-Fs was >2.8 g/kg or 750 mg/kg, respectively, appreciably more than the oral median lethal dose of KS-As (≤1.18 g/kg). Adverse reactions were not observed. In addition, peripheral blood cell counts were not significantly affected in normal mice treated with KS-Fs at 200 mg/kg/day for 2 weeks [45, 83].

Kuraridin, sophora flavanone G, kurarinone, kushenol F, and norkurarinol have extremely strong tyrosinase inhibitory activity [45–49]. Kurarinol, kuraridinol, and trifolirhizin markedly inhibited (>50%) melanin synthesis [48, 49].

The mechanism of action of KS-Fs and kurarinone involves inhibition of tumor necrosis alpha one (TNFαl)-induced NF-κB activation and enhance apoptosis [45, 50, 51]. The apoptosis-inducing effect was enhanced in the presence of taxol. In H460 xenograft mice treated with kurarinone, downregulation of Bcl-2 and upregulation of caspase 8 and caspase 3 in tumors were observed [45]. KS-Fs and kurarinone induce apoptosis in tumors by acting on multiple cellular targets, including inhibition of NF-κB activation and multiple receptor tyrosine kinase activities [45]. Kurarinone and kuraridin attenuate NF-κB activation by inhibition of IκBα proteolysis and p65 nuclear translocation, as well as phosphorylation of extracellular signal-regulated kinase (ERK)1/2, c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinases [45, 51]. Constitutive NF-κB and RSK2 activities are important hallmarks of human cancers (including hematopoietic malignancies and solid tumors), so prenylated flavanones represent an attractive class of natural inhibitors of the ERK/RSK2 signaling pathway for cancer therapy [85] (Table 2).

Fifty-six flavonoids have been identified from KS-Fs. Twenty-one of the KS-Fs have been found to have antitumor activities. Studies have demonstrated that more potent antitumor activities are observed in KS-Fs instead of KS-As fractions. KS-Fs were more than 10-fold more potent than KS-As in the cell proliferation assay. Further evaluation of the safety and efficacy of KS-Fs in clinical oncology settings is warranted. KS-Fs could be developed as botanical drugs for solid tumors, and kurarinone could be used as a marker compound. Additional structural modifications of KS-Fs compounds could also generate more potent drug candidates.

5. Conclusions and Future Perspectives

This paper summarized the antitumor efficacy and mechanism of action of kushen and its constituents in vitro and in vivo. Many Patents of kushen extracts have been applied in USA, China and other countries (Table 3). These results strengthen the hypothesis that kushen (or its components) alone or combination with chemotherapy agents could modulate various molecular pathways in tumors or be used to treat cancer. Studies described here and elsewhere highlight the use of flavonoids of kushen as novel chemoprevention agents for cancer intervention. It is expected that future studies with kushen will help to define various molecular mechanisms and targets for the inhibition and apoptosis of tumor cells. The number of multicenter, large sample, randomized, double-blind, controlled chemoprevention clinical trials with kushen are very limited. Extensive clinical research is warranted to evaluate further the safety and chemoprevention efficacy of kushen alone or in combination with chemotherapy agents.

Acknowledgments

This work was supported by the National Natural Science Foundation (Grant no. 30701070), Scientific and Technological Project of Shanghai (11DZ1971702), Wang Bao-En Hepatic Fibrosis Research Fund (20100048), Shanghai Rising-Star Program (08QA1406200), Xinglin Scholars Program of Shanghai University of Traditional Chinese Medicine, E-institute of Shanghai Municipal Education Commission (Project E03008), Innovative Research Team in Universities, Shanghai Municipal Education Commission, Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, and Key Disciplines of Liver and Gall Bladder Diseases of State Administration of Traditional Chinese Medicine of the People’s Republic of China.

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Copyright © 2012 Mingyu Sun et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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