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FEATURE ARTICLE Recent Highlights of Experimental Research for Inhibiting Tumor Growth by Using Chinese Medicine HE Xi-ran (何曦冉), HAN Shu-yan (韩淑燕), and LI Ping-ping (李萍萍) ABSTRACT To give an overview of contemporary experimental research using Chinese medicine (CM) for the treatment of cancer. As an integral part of mainstream medicine in the People's Republic of China, CM emphasizes improvements in holistic physical condition instead of merely killing tumor cells, which is consistent with the current medical model that advocates patient-oriented treatment. Great progress has been made in experimental research, and the principle aspects include anti-tumor angiogenesis, inducing apoptosis and differentiation, reversing multidrug resistance, and improving immune function. As a current hot topic in cancer research, tumor microenvironment (TME) highlights the mutual and interdependent interaction between tumor cells and their surrounding tissues, and the CM treatment concept bears a striking resemblance to it. To date, primary points of TME include Prof. LI Ping-ping extracellular matrix remodeling, inflammation, hypoxia, and angiogenesis, but trials using CM with a focus on TME are rare. Despite considerable recent development, experimental research on CM for solving cancer issues appears insufficient. Greater efforts in this field are urgently needed. KEYWORDS Chinese medicine, tumor, experimental research, highlights
Cancer has garnered unprecedented attention in recent years, as it is regarded as a fatal threat to human health worldwide. According to Siegel, et al,(1) one in four deaths was due to cancer in the United States in 2013. With dramatic advances and the transition of treatment concepts toward oncology, not only are researchers concerned with studying tumor cells but they also focus on the tumor microenvironment (TME), which plays an indispensable role in tumor growth and prognosis.(2) With a history of over 2000 years, Chinese medicine (CM) has evolved into a unique system of diagnosing and treating cancer, representing a holistic approach that attempts to bring the body into harmony. To date, it has been acknowledged that CM holds irreplaceable status in complementary and alternative medicine (CAM), which appears far more influential and prevalent than previously considered, and is an efficacious option for cancer treatment.(3,4) Correspondingly, experimental research related to these above aspects has also attained remarkable achievements. Considerable progress has been made in the past several decades with respect to our understanding of anti-tumor angiogenesis, induction of apoptosis and differentiation, reversal of multiple
drug resistance, regulation of immune function, and improvement of TME when treated with CM.(5-9) Herein, we summarize existing literature that documents in vitro and in vivo experimental research of CM applied to cancer, especially paying scrupulous attention to TME.
Anti-Angiogenic Function of CM Angiogenesis is a pivotal aspect of tumor growth, invasion, and metastasis. Therefore, antiangiogenesis has been proposed as a mainstay in cancer therapy for decades. (10) Much experimental research has demonstrated that CM activates the anti-angiogenesis functions of numerous cancer celltypes, while simultaneously trying to unravel the underlying molecular mechanisms. Wang, et al (6) elucidated that Trametes robiniophila Murr extract inhibited the proliferation of human umbilical vein
© The Chinese Journal of Integrated Traditional and Western Medicine Press and Springer-Verlag Berlin Heidelberg 2015 Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Integration of Traditional Chinese and Western Medicine, Peking University School of Oncology, Peking University Cancer Hospital & Institute, Beijing (100142), China Correspondence to: Prof. LI Ping-ping, Tel: 86-013910768927, E-mail:
[email protected] DOI: 10.1007/s11655-015-2318-8
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endothelial cells (HUVECs) and mouse mammary 4T1 tumor cells, accompanied by a decrease in motility and tube formation of HUVECs, in a dose-dependent manner in vitro . In addition, western blot analysis showed that this CM extract could downregulate the expression of phosphorylated extracellular signalregulated kinase (ERK), transcription factor p65, c-Jun N-terminal kinase (JNK), signal transducer and activator of transcription 3 (STAT3), and vascular endothelial growth factor (VEGF), which are all crucial molecules in angiogenesis. In addition, chick embryo chorioallantoic membrane (CAM) and rat aortic ring assays were suppressed in the presence of Huaier extract.(6) Zhang, et al(11) demonstrated that norcantharidin (NCTD; a reagent isolated from blister beetles) also blocked VEGF-induced cell proliferation, migration, invasion, and capillary tube formation in primary HUVECs. Furthermore, NCTD suppressed the angiogenesis of colon cancer cells (LOVO) in vivo , as well as vascular endothelial growth factor receptor-2 (VEGFR2)/ mitogen activated protein kinase (MEK)/ ERK pathway kinases. In addition to these various extracts from herbs or animals, compounds/decoctions that constitute different types of herbs and/or animals have also displayed undoubted effectiveness for inhibiting tumor angiogenesis. For instance, Yu, et al(12) showed that Erxian Decoction (二仙汤, EXD; composed of Epimedium , Curculigo , Angelica , Morinda , Cortex Phellodendri , Anemarrhena , etc.) inhibited vessel formation in zebra-fish embryos by reducing VEGF mRNA and hypoxia-inducible factor 1α (HIF-1α) protein levels. Additionally, when treating mammalian endothelial cells in vitro , EXD appears efficacious for suppressing proliferation, migration, and tube formation in HUVECs, along with causing HUVEC apoptosis and increasing the proportion of cells in the G0/ G1 phase.(13) Moreover, Xu, et al(14) concluded that Taohong Siwu Decoction Ⅱ (桃红四物汤, THSWD Ⅱ) can reduce the blood vessel index of CAM and absorbency of HUVECs in a dose-dependent manner and block the expression of kinase insert domain containing receptor/ fetal liver kinase 1 (KDR/ Flk-1) and microvessel density (MVD) of B16 melanoma in mice.
Apoptosis/Autophagy-inducing Functions of CM Apoptosis, namely, type Ⅰ programmed cell death (PCD), is critical for the development and survival of living organisms. During tumorigenesis and
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invasion, apoptosis can be suppressed by immune response, gene regulation, signal transduction, etc. The induction of apoptosis is an elementary mechanism and a primary target for most anti-tumor therapies, including CM. (15,16) Zhang, et al (17) reported that an arenobufagin monomer (a bufadienolide from toad venom) has potent mitochondria-mediated apoptosisinducing action in hepatocellular carcinoma cells, by means of increasing the Bax/Bcl-2 expression ratio and blocking the phosphoinositide 3-kinase/ protein kinase B/mammalian target of rapamycin (PI3K/Akt/ mTOR) pathway.We searched PubMed and China Journals Full-text Database and obtained abundant studies focusing on the induction of apoptosis by CM. For example, Li, et al (18) demonstrated that Lichong decoction (理冲汤, composed of Astragalus , Codonopsis , yam, Trichosanthes kirilowii , Anemarrhena asphodeloides , Scirpus fluviatilis , zedoary, chicken's gizzard membrane, etc.) decreased Bcl-2 mRNA and increased Bax mRNA expression level in myoma cells, thereby inducing apoptosis. Deng, et al(19) illuminated that Teng-Long-Bu-ZhongTang (藤龙补中汤, TLBZT; composed of Solanum nigrum Duchesnea , Rhizoma Atractylodis, Wolfiporia extensa, Semen coicis , Viscum album , Scutellaria barbata , etc.) induced apoptosis and senescence of CT26 carcinoma fells, with caspase-3, caspase-8, and caspase-9 activation and PARP cleavage, while it downregulated XIAP and survivin levels. In addition, it is worth mentioning that autophagy (type Ⅱ PCD) resulting from "excessive self-eating" has aroused pervasive interest in CM research of late. Lin, et al(20) showed that baicalin (a monomer extracted from Scutellaria baicalensis Georg) enhanced the protein expression of Atg 5/7/12, beclin-1, and LC3-Ⅱ in human bladder cancer T24 cells, while suppressing phospho-AKT (Ser473) and the enzymatic activity of AKT. In brief, baicalin triggered autophagy through the AKT signaling pathway in T24 cells.
Inducing Differentiation Using CM Current studies support the theory that several compounds or active ingredients from CM can induce re-differentiation of malignant cells to normal or near normal ones, rather than killing them. These compounds include compound Muji granules (复方木 鸡颗粒), Ganoderma compounds, Compound Yangyin decoction (复方养阴方), Zhenggan decoction (正肝方), Xufukang decoction (血富康方), Oldenlandia , bufalin, tanshinone, baicalin, matrine, Ginseng saponins, and
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Pueraria flavonoids. Lai, et al(21) illustrated that the serum containing Xiaochaihu decoction (小柴胡汤) induced re-differentiation of hepatocellular carcinoma SMMC-7721 cells to normal cells, accompanied by a reduction in lactate dehydrogenase (LDH) activity.
Reversing Multidrug Resistance Using CM Cancer chemotherapy is efficacious as an antitumor therapy ever since the 1940s, yet it tends to induce multi-drug resistance (MDR) leading to treatment failure, which is regarded as a bottleneck in current oncology research. At present, many studies have explored novel reversal agents possessing higher efficiency and lower toxicity than CM, and some progress has been made. Yang, et al (22) demonstrated that extracts from Curcuma wenyujin and Chrysanthemum indicum modulated the MDR phenotype and function of P-glycoprotein in MCF-7/adriamycin (ADR) and A549/taxol cells, as well as sensitizing these resistant cancer cells at non-toxic concentrations to doxorubicin and docetaxel.(22) Han, et al(23) showed that Marsdenia tenacissima extract [MTE; trade name: Xiaoaiping injection (消癌平注射液)] combined with gefitinib could overcome the resistance of non-smallcell lung cancer cells to gefitinib. MTE followed by MTE plus gefitinib (M→M+G) treatment significantly reduced the phosphorylation of EGFR downstream signaling molecules, accompanied by weakening of c-Met phosphorylation in H460 and H1975 cells. Moreover, there are many theses reporting reversion of MDR when treated with CM decoction. For example, Sui, et al(24) reported that Jianpi Jiedu recipe (健脾解毒方, JJR; composed of Astragalus , Atractylodes , Codonopsis , Akebia , Semen coicis , Mucuna macrocarpa Wallich , and Polyporus ) combined with chemotherapeutic drugs can reverse drug-resistance in HCT8 cells, and it increased sensitivity to vincristine/cisplatin/5-fluorouracil/pirarubicin (VCR/DDP/5-Fu/THP) via reducing MDR1 expression and P-glycoprotein levels. Additionally, inductively coupled plasma-mass spectrometry (ICP-MS) results show that JJR raised the concentration of drugs in HCT8/V cells. Sui H, et al(25) also expounded that Zuojin Pill (左金丸, ZJP; comprised of Rhizoma Coptidis and Evodia ) significantly sensitized HCT116/ oxaliplatin (L-OHP), SGC7901/DDP, and Bel/Fu MDR cells to chemotherapy. When ZJP was combined with chemotherapeutic drugs, drug resistance in HCT116/ L-OHP cells could be reversed, and the sensitivity of HCT116/L-OHP cells to L-OHP, DDP, 5-Fu, and MMC increased in vitro . Furthermore, ICP-MS revealed that
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ZJP increased the concentration of chemotherapeutic drugs in HCT116/L-OHP cells in a dose-dependent manner.
Immunomodulatory Functions of CM Cancer patients always have low immune function due to anti-tumor treatments, such as chemoradiotherapy. CM for the regulation of the immune system has become a hot topic for quite some time, and its mechanisms include strengthening "qi" and eliminating evil to promote immune function, thereby achieving the goals of coexistence with tumors and elevating the quality of life, rather than just killing malignant cells. Aikemu, et al(26) certified that abnormal Savda Munziq (ASMq; a traditional Uyghur medicine) can enhance concentrations of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-2 in Kunming mice transplanted with sarcoma 180 cells, thereby dramatically improving immunity function. Wang, et al(27) reported that Shenqi Fuzheng injection (参 芪扶正注射液, SFI; composed of Codonopsis and Astragalus ) notably lifted the counts of peripheral white blood cells and bone marrow cells, promoted T cell and B cell proliferation activity, together with splenic nature killer cells and peritoneal macrophage phagocytosis, and improved IL-2 levels in serum. Lin, et al(28) elaborated that extracts from Hedyotis diffusa Willd (HDW) attenuated spleen and liver weights and raised the percentage of CD11b cell-surface markers in murine WEHI-3 leukemia; HDW appears to act, to some extent, as an immune-modulator.
Influence of CM on TME To date, experimental research on CM when applied as anti-tumor treatments have shown tremendous progress. The distinct dominance of CM is the holistic regulation of relative balance status, thus improving disease resistance in hosts. This core ideology underlying CM reflects the relationship between tumor growth and the TME. Exuberant proliferation can be regarded as a prominent characteristic of tumor cells, for which they must continuously remold the external environment to accommodate their own vigorous growth. This principle works throughout cancer development and progression, and this modifying of outer tissues is also referred to as TME. Similar to the normal extracellular environment, TME is a complex micro-ecological system containing fibroblasts, immune cells, endothelial
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cells, extracellular matrix (ECM), proteases, cytokines, etc. These above constituents play non-substitutable and complicated roles in tumor growth, vascularization, and metastasis. (29) At present, TME has obtained worldwide acknowledgement as an essential functional unit supporting cancer development and recurrence. Malignant cells are resulted from many intricate factors, and the CM possesses unique properties, as it includes whole organism regulation and multiple treatment targets. Hence, numerous previous studies exploring mechanisms only from a single factor in CM research have encountered unprecedented challenges, as their approach does not accurately reflect actual conditions. From a regulation of the whole perspective, emerging studies are exploring CM for treating neoplasms; namely, the seed and soil concept.(30) A tumor and its microenvironment should be regarded as an indivisible ensemble, and the CM philosophy reflects this sentiment; remolding TME to inhibit tumor growth and compelling malignant cells to return to a non-malignant state. Currently, studies on the TME have investigated ECM remodeling, inflammation, hypoxia, angiogenesis, etc. Research investigating the relationship between CM and TME for treating malignant disease is still in its infancy, but studies are recently emerging. To follow are brief elaborations of these recent studies.
Effectiveness of CM for ECM Remodeling In most solid tumors, cancer-associated fibroblasts (CAFs) are typically most abundant in the stroma and can result in ECM remodeling through autocrine signaling. Various proteins in the ECM maintain close contact with malignant cells, via integrins and other receptors on the cell surface, thereby influencing biological processes, such as proliferation, apoptosis, metastasis, and differentiation. Studies have identified specific molecules, such as tenascin-C (TNC), fibronectin (FN), and matrix metalloproteinases (MMPs), which are upregulated in the majority of tumors and are considered fundamental components involved in ECM remodeling.(31,32) Palumbo Jr, et al(33) showed that in LNCaP prostate tumor cells, the ECM secreted by stromal cells contains key tumor promoters, which assist the proliferation and migration of malignant cells, as well as inhibit apoptosis. Liao, et al(34) reported that in U-2 OS human osteosarcoma cells, crude extract from Corni Fructus (CECF) significantly inhibited MMP-2/9 activity, decreased focal adhesion kinase
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(FAK) protein levels, as well as protein kinase C (PKC), salt overly sensitive 1 (SOS1), mitogen-activated protein kinase kinase 7 (MKK7), mitogen-activated protein kinase kinase kinase 3 (MEKK3), and growth factor receptor-bound protein 2 (GRB2). CECF may also possess potent migration and invasion inhibiting properties in cancer cells.
Effectiveness of CM on Inflammatory TME Regarded as self-defense protection from invasive pathogens, chronic inflammation may increase the risk of tumor progression, according to many recent studies. For instance, chronic reflux esophagitis is a high-risk factors leading to esophagus cancer, and Helicobacter pylori is tightly related to gastric carcinoma. Existing research has demonstrated that tumor-associated macrophages (TAMs) are the foremost cellular components of cancer-related inflammation, and they also secrete multiple cellular factors such as epidermal growth factor (EGF) and VEGF.(35) In transgenic mouse models of breast cancer, TAMs promoted cancerization and increased the risk of metastasis via the Wnt-signaling pathway.(36) Killian, et al(37) expounded that curcumin inhibited the expression levels of pro-inflammatory factors in breast and prostate cancer, such as chemokine ligand 1/2 (CXCL1/2), and nuclear factor-κB (NFκB). Huang, et al(38) showed that the aqueous extract of Centipeda minima (ACM) distinctly improved the activities of catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx) in RAW264.7 macrophages, and reduced the levels of malondialdehyde (MDA), inducible nitric oxide synthase (iNOS), and cyclooxygenase (COX)-2, thus supporting the hypothesis that ACM exhibits antiinflammatory activity.
Effectiveness of CM for Hypoxia The exuberant proliferation and vigorous metabolism of malignant cells demand a greater energy supply compared with normal cells; therefore, this often results in hypoxia, which is a common and specific phenomenon in cancer cells. As an adaption to this hypoxia, angiogenesis and glycolysis are correspondingly aggravated.(39) Nevertheless, although hypoxia inhibits tumor growth to some extent, it contributes to invasion and metastasis. Therefore, it can be regarded as an independent risk factor for poor prognosis.(40) Research has demonstrated that hypoxia can induce HIF, cadherins, VEGF, platelet-
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derived growth factor (PDGF), and fibroblast growth factor (FGF), thereby modulating cellular metabolism, angiogenesis, proliferation, apoptosis, and tissue remodeling.(41) Park, et al(42) presented that in anaplastic thyroid cancer cells, Pulsatilla koreana extract (PKE) can reduce HIF-1α and VEGF, and suppress HUVEC tube formation. Li, et al(43) reported the serum containing Changweiqing (肠胃清, CWQ; comprised of Astragalus , Atractylodes , Polyporus , Akebia quinata , Salvia chinensis , Ampelopsis brevipedunculata , and Coix lachrymajobi ) decreased expression of HIF-1α, VEGF, and MMP-2/9 in colon cancer cells, thereby attenuating risks of invasion and metastasis.
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6. Wang X, Zhang N, Huo Q, Yang Q. Anti-angiogenic and antitumor activities of Huaier aqueous extract. Oncol Rep 2012;28:1167-1175. 7. Zhong ZF, Hoi PM, Wu GS, Xu ZT, Tan W, Chen XP, et al. Anti-angiogenic effect of furanodiene on HUVECs in vitro and on zebrafish in vivo . J Ethnopharmacol 2012;141:721-727. 8. Yang L, Wei DD, Chen Z, Wang JS, Kong LY. Reversal effects of traditional Chinese herbs on multidrug resistance in cancer cells. Nat Prod Res 2011;25:1885-1889. 9. Reid-Adam J, Yang N, Song Y, Cravedi P, Li XM, Heeger P. Immunosuppressive effects of the traditional Chinese herb Qu Mai on human alloreactive T cells. Am J Transplant 2013;13:1159-1167. 10. Welti J, Loges S, Dimmeler S, Carmeliet P. Recent
Conclusions and Perspectives To date, CM has become an indispensable element of cancer research and has achieved a high degree of efficacy in clinical practice, especially with respect to cancer treatment and controlling metastasis.(44) As Robert A. Gatenby(45) said, finding a "cure" for cancer may likely lead to resistance and recurrence, but trying to control the disease may prove better than striving to cure it, a concept that is consistent with CM. Overall regulation to balance the relationship between cancer and the TME and seamlessly combining CM and the latest scientific research are important goals.
molecular discoveries in angiogenesis and antiangiogenic therapies in cancer. J Clin Invest 2013;123:3190-3200. 11. Zhang L, Ji Q, Liu X, Chen X, Chen Z, Qiu Y, et al. Norcantharidin inhibits tumor angiogenesis via blocking VEGFR2/MEK/ERK signaling pathways. Cancer Sci 2013;104:604-610. 12. Yu X, Tong Y, Kwok HF, Sze SC, Zhong L, Lau CB, et al. Anti-angiogenic activity of Erxian Decoction, a traditional Chinese herbal formula, in zebrafish. Biol Pharm Bull 2012;35:2119-2127. 13. Yu X, Tong Y, Huang W, Ge W. Erxian decoction, a traditional chinese herbal formula, inhibits angiogenesis in human umbilical vein endothelial cells. Biol Pharm Bull 2013;36:754-763.
CM has a long history and has exhibited unique advantages through the ages. Experimental research in CM also shows great potential and broad applications in day-to-day life. We strongly believe CM will generate future developments and contribute to overall human health.
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