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REVIEW ARTICLE
Year : 2014  |  Volume : 10  |  Issue : 5  |  Page : 8-13

Research advances on TCM anti-tumor effects and the molecular mechanisms


1 Shanghai Jiao Tong University School of Medicine, Shanghai, China
2 Sbarro Institute for Cancer Research and Molecular Medicine, Center of Biotechnology, College of Science and Technology, Temple University, Philadelphia, Pennsylvania, USA

Date of Web Publication30-Aug-2014

Correspondence Address:
Jack Jia
Sbarro Institute for Cancer Research and Molecular Medicine, Center of Biotechnology, College of Science and Technology, Temple University, Philadelphia, Pennsylvania
USA
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.139744

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 > Abstract 

With unceasingly deep researches on tumor cytology and molecular biology in recent years, it has been recognized that tumor is not only the outcome of occurrence and progress of cell proliferative disorders and abnormal differentiation, but also closely related to abnormality of apoptosis. Since traditional Chinese medicine (TCM) is easy to obtain and exhibits significant antitumor effects accompanied with less toxic and side effects, it has already become a hotspot for cancer researches. This article is to overview TCM's antitumor effects and to summarize the underlying molecular mechanisms.

Keywords: Antitumor, apoptosis, cell cycle, molecular mechanism, TCM


How to cite this article:
Qiu X, Jia J. Research advances on TCM anti-tumor effects and the molecular mechanisms. J Can Res Ther 2014;10, Suppl S1:8-13

How to cite this URL:
Qiu X, Jia J. Research advances on TCM anti-tumor effects and the molecular mechanisms. J Can Res Ther [serial online] 2014 [cited 2019 Aug 22];10:8-13. Available from: http://www.cancerjournal.net/text.asp?2014/10/5/8/139744


 > Introduction Top


Nowadays, with high morbidity and mortality of malignant tumors, prevention and treatment of malignant tumors has already become a difficult and important issue for biologists and clinicians. Current surgical modalities include preventive treatment, minimally invasive treatment and individualized treatment, which are evolved from extensive surgical excision to tissue and function preservation treatment. Medical treatment has been developed to molecular targeted therapy and biological therapy from nonspecific cytotoxic drugs and large dose drugs-induced killer treatment to tumor cells of different phases. Moreover, radiotherapy has also evolved to combination therapy, which has less damage to normal tissues and favorably enhances the efficacy. It is found that long-term using of chemotherapeutic drugs lead to drug resistance, thus generating more toxic and side effects. In addition, long-term application of chemotherapeutic drugs cost high expenses. All these factors dramatically decrease life qualities of patients. In recent years, development and application of natural medicines has become a research hotspot. Compared with western medicines, traditional Chinese medicine (TCM) has lots of advantages, such as wide range of sources, low costs and fewer side effects. Therefore, through researches on a single drug or compound mixture of TCM, biological active ingredients can be extracted so as to obtain new antitumor drugs, which has already become a new avenue for cancer treatment. [1]

Modern research results prove that common cancer inhibition mechanisms of TCM include the followings: (1) inducing tumor cell apoptosis; [2],[3] (2) inhibiting tumor angiogenesis; [4],[5] (3) enhancing body immunity, downregulating immunosuppressive molecules and influencing the manifestation of immunosuppressive effects; [6],[7] (4) affecting telomerase activity [8],[9] and many others. [10],[11] In this article, we will expound molecular mechanisms of TCM antitumor effects separately.

Pathway of TCM induced tumor cell apoptosis

Caspase protein plays a key role in the process of cell apoptosis. Xiao D et al., [12] confirmed that allicin could induce apoptosis of prostate cancer DU-145 and PC-3 cell lines through enhancing the activities of caspase-3 protein and caspase-9 protein. They also found that the activity of caspase protein is inhibited and consequently the apoptosis of prostate cancer cell lines is also inhibited after treated with caspase3, or caspase-9-specific inhibitor, zVAD-fmk and zLEHD-fmk. Artesunate, a derivative from of artemisinin, widely used in malaria, has been demonstrated recently that it has antitumor effect. Wang Y and his colleagues reported that artesunate could induce apoptosis through caspase-dependent mitochondrial pathway. [13] When A549 human lung adenocarcinoma cells are treated by artesunate, cell growth and proliferation was inhibited, and apoptosis was induced in a dose-dependent manner. [14]

At present, there are two widely accepted classical pathways of cell apoptosis: mitochondrial pathway and death receptor pathway. [15],[16],[17] Mitochondria play a key role in the process of cell apoptosis as it can regulate tumor cell apoptosis and participate in the whole process of apoptosis. [18] Therefore, in the two pathways of cell apoptosis, mitochondrial pathway occupies an important position. During cell apoptosis, the related apoptosis pathway is reflected in the aspects of modification of mitochondrial transmembrane voltage and increase of caspase activity induced by the openness of mitrochondrial outer membrane permeability (MOMP). [19] Green R et al., found that Bax can transfer to mitochondrial outer membrane along cytoplasm and thus enhances the permeability of mitochondrial membrane. [20] Therefore, when the level of Bax increases and transmembrane voltage steps down, proteins located in mitochondria such as apoptosis-inducing factor (AIF) and cytochrome can be released and endonuclease activity is stimulated so that a series of reactions are brought about and cell apoptosis is induced. [19] It has been reported that bufalin could downregulate the expressions of B-cell lymphoma 2 (Bcl-2) and survivin and increase the Bcl-2 associated X protein (Bax)/Bcl-2 rat. [21] Meanwhile, both the reductions of the expression of Second Mitochondria-derived Activator of Caspases (Smac)/Direct IAP-Binding protein with Low PI (DIABLO) protein and mitochondrial transmembrane voltage bring about release of mitochondria and activation of Caspase-3 protein. [22] These facts indicate that bufalin can induce the apoptosis of HL-60 leukemia cell and the mechanism may be closely related to mitochondrial pathway.

Research about death receptor and ligand is also a hotspot in the aspect of inducing tumor cell apoptosis. Death receptor is composed of various molecules with its extracellular domain rich in cysteine sequence, while intracytoplasm sequence is also characterized with death zone or death domain. At present, the widely known death receptors include FasL, CAR1, NGFR, DR4, TNFRK, CARK and DR5. Ligands connected with these death receptors belong to tumor necrosis factor (TNF) gene superfamily, including FasL, TNF, Apo-2L and Apo3L. Usually, death receptors combine with death ligands so that the death domain of the intracellular receptor domain is activated, thus stimulating cell apoptosis. Fas/FasL is one of the death receptors that have been studied explicitly. Moragoda found from researches that curcumin could inhibit the proliferation of HCT-116 colon cancer cell and KATO-III gastric cancer cell and thus induce their apoptosis. [23] Curcumin can also inhibit the cell cycle of HCT3226 and block it in G2/M phase in accompanied with down-regulation of cyclinD and cyclinE protein expressions. Furthermore, the results indicated that the underlying mechanisms of cell apoptosis might be via the activation of caspase-3 protein, breakage of PARP and stimulation of Fas apoptotic pathway. [24]

Other studies of TCM pointed out that their antitumor effect in inducing liver cancer cell apoptosis was closely related to signaling molecules such as cyclic adenine monophosphate (CAMP) and protein kinase (PKC). As an antagonist of PKC, quercetin could induce apoptosis by activating caspase-3, inhibiting the expression PKC-α and Bcl-2. [25] Moreover, quercetin could also inhibit cAMP- and cGMP-phosphodiesterase (PDE), which had dramatic impact on the cAMP and cGMP generation. [26] Impaired cAMP and cGMP levels were detected in various tumors and inhibition of the activity of PDE recovered the balance between cAMP and cGMP level, subsequently inducing tumor cell apoptosis. [27] Besides, some studies reported that P38/MAPK plays a vital role in antitumor process. [28] Research findings show that P38/MAPK may exert regulatory apoptotic effects from the following mechanisms. (1) Phosphorylation of p53. A certain serine residue existed in human p53 protein can be phosphorylated by P38/MAPK in vitro and this process can be inhibited by blocking p38/MAPK signaling pathway. [29] (2) Strengthening c-myc expression. Activation of p38/MAPK signaling pathway can enhance the protein translational level of c-myc so as to induce tumor cell apoptosis. [30] (3) Participation in the apoptosis regulated by Fas/FasL. As mentioned above, in the death receptor pathway induced tumor cell apoptosis, a ligand of an important receptor is just Fas/FasL. Researches show that in the experiment process of inducing tumor cell apoptosis, the expression of death receptor/ligand can be detected and p38/MAPK activity is also detected to be strengthened, which indicate that there is a p38/MAPK pathway in drugs when participating in the apoptosis signaling pathway. [31] (4) In the process when Bax flows into mitochondria to induce tumor cell apoptosis, activation of p38/MAPK occupies an all-important position. [32]

TCM antitumor and tumor angiogenesis

Tumor vessels can not only provide sufficient nutrition for tumor itself, but also play a key role in the process of tumor spreading to distal tissues, which result in malignancy, metastasis and relapse of tumor cells. [33] Angiogenesis mainly relies on the equilibrium between variant molecules distributed by host cells and tumor cells, which contains a series of steps, including separation and migration from basement membrane of perithelial cells and vascular endothelial cells, invasion of the whole cell membranes and finally extension to the tumors. [33] Basement membrane of blood vessel and extracellular mesenchyme can be selectively degraded so that breakage, migration and proliferation occur in endothelial cells, and these processes are very important in degradation. The degradation process is regulated by angiogensis inductive agents and inducers. Therein, vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) are important factors in promoting revascularization. [34] Kondo et al., firstly recognized that VEGF could be used for diagnostic markers for potential malignant diseases in serum, [35] in which they found that VEGF level in cancer patients' serums was significantly higher than those without any sign of cancer. Since then, growing evidence supported that VEGF and its receptor are widely expressed in many solid tumors, including breast cancer, [36] colon cancer, [37] ovarian cancer, [38] cervical cancer [39] and lung cancer. [40] Based on the random phase II and phase III clinical tests, bevacizumab is an effective VEGF-directed monoclonal antibody, which is the single agent that is approved in the treatment for certain metastatic cancers, such as non-small cell lung cancer [41] and recurrent glioblastoma. [42] Although the efficiency of bevacizumab against VEGF, it still causes severe side effects, such as hypertension, left ventricular systolic dysfunction and proteinuria. [43],[44] Since then, substitutions are needed urgently. Studies of TCM on VEGF are gradually increasing and thus there have accumulated much experience. Previously, Lin SS et al., reported that curcumin could suppress the expression of VEGF and decrease the invasive cancer cells in non-small lung cancer line, A549, implicating that curcumin has the anti-tumor and anti-angiogenic potential. [45] Scutellaria barbata and Oldenlandia diffusa are commonly used as antitumor TCM for clearing away heat and toxic materials in clinic. Lin et al., [46] found that after treated with Oldenlandia diffusa in human colon cancer cells, the expression of VEGF-A was reduced, which indicated that the effective ingredients of Oldenlandia diffusa have inhibiting effects on tumor vascular endothelial cells and can inhibit formation and migration of these cells. Reports on researches of Scutellaria barbata are in majority. Shiau et al., observed that in low oxygen environment, the activity of Scutellaria barbata was enhanced and thus inhibited the proliferation and migration of tumor endothelial cells by inhibiting the expression of hypoxia-inducible factor (HIF)-1α, which activated the expression and secretion of VEGF. [47] Another TCM, Celastrus orbiculatus Thunb (COT), is originally accepted as a kind of detoxification drug with features of invigorating the circulation of blood and meridian and dispelling wind and eliminating dampness. [48] Further, more reports stated the antitumor activity of COT, especially the anti-angiogenic activity. High-dose and early treatment with COT in the human hepatocellular carcinoma (HCC) orthotopic tumor model significantly suppressed the tumor growth and reduced the metastasis of cancer cells, as well as the VEGF expression, indicating that the antitumor mechanism of COT is achieved through inhibiting the generation of VEGF. [49] Guo et al., found that Shiquan Dabu Tang (SDT) dramatically reduced the average volume of metastases in colon tumor mouse model, when compared with primary tumor resection group. [50] By enzyme linked immunosorbent assay (ELISA) assay, they demonstrated that SDT treatment decreased serum VEGF level accompanied with increased serum endostatin (ES). These results suggested that the potential mechanisms of SDT antitumor activity might be via the restoring the balance between VEGF and ES.

Numerous researches showed that anti-angiogenic activity of TCM is also closely related to the regulation of some apoptotic signals. For example, Radix isatidis not only presents anti-inflammation, but also inhibits tumor growth by suppressing VEGF-mediated JAK/STAT3 signaling. [51] Indigo naturalis is a homologous drug of Radix isatidis, which can inhibit the angiogenesis of prostatic cancer relying on JAK/STAT3 signaling pathway regulated by KDR. [52]

Influence of TCM immunoregulation

It has been widely confirmed that Fas/FasL system plays a key role in the process of tumor immune escape. Hsu et al., found that effective ingredients of Radix bupleuri extractives inhibited tumor cell proliferation and increased the expressions of Fas and FasL in human lung adenocarcinoma cells A549. [53],[54] Kanglaite injection, widely used as adjuvant for chemotherapy in gastric cancer patient, [55] induced liver cancer cells apoptosis and thus inhibited tumor growth, in which the underlying mechanism might be mediated by the Fas/FasL pathway, for kanglaite, the major ingredient Coicis Semen Oil, that is found to increase mRNA expression of Fas/FasL proteins in liver cancer cells. [54] Relevant researches proved the novel antitumor mechanism of Astragalus membranaceus, which is achieved through influencing the immunosuppression effects of immunosuppressive molecules. For example, Astragalus membranaceus can lower the expression level of TGFs secreted by colorectal cancer cells. [56]

Recently, several researches implied that the anti-tumor effect of polysaccharide in TCM is achieved mainly through regulating the immune system. For example, treatment with, Lycium barbarum polysaccharide, Ganoderma lucidum polysaccharides or lentinan strengthened the activity of killer cells induced by lymphocyte factor, [57] as well as Acanthopanax senticosus polysaccharide. [58] In addition, Momordica charantia polysaccharide exhibited its antitumor ability in multiple solid tumors, such as liver cancer, [59] prostate cancer [60] and nasopharyngeal carcinoma. [61] Furthermore, several researches demonstrated that Momordica charantia polysaccharide stimulated mouse lymphocyte proliferation [62] and inhibited TNF-α-mediated secretion of nitric oxide (NO). [63] Based on these, it is implicated that the mechanism of Momordica charantia polysaccharide is achieved through enhancing macrophage activity and activating lymphocytes to regulate immune functions. [64] Cao et al.,[65] explored tumor-bearing mice treated by compound Fuzheng Yiliu Granule. They observed that the numbers of natural killer (NK) cells in peripheral blood, CD3 + and CD4 + cells were increased remarkably, and the secretion of tumor necrosis factor and interleukin-2 (IL-2) also were enhanced significantly, which indicated that Fuzheng Yiliu Granule could strengthen the immune functions. Moreover, when using serums supplemented with this drug to culture liver cancer cells, the results show that compared with the blank control group, the apoptotic rate of tumor cells in the drug serum group were significantly increased, consequently inhibiting tumor growth. [66] Effective ingredients extracted from radix Asteris chekiangensis inhibited tumor growth, and enhanced the activities of cytotoxin T cells and NK cells after intervention, thus remarkably increasing the secretion of cytokines such as interferon and interleukin-2, [67] which indicated that the antitumor mechanism of Radix asteris chekiangensis is through strengthening cell-mediated immunity and humoral immunity. However, the detailed mechanisms need further studies.

Influence of TCM on telomerase activity

Activation of telomerase plays a key role in tumor initiation and progression, given that it is closely correlated with cell cycles and the expression of apoptosis-related genes. [68] Telomeres are ribonucleoprotein structures, located at the every terminal of eukaryocyte chromosome and composed of repeated nucleotides coated with specific protecting proteins. [69] Generally, telomere shortens gradually in accordance with each mitotic cell division, while telomerase, a kind of ribonuclease composed of RNA and protein, promotes extension of telomere terminals in specific cells such as embryonic and adult stem cells. [69] Long-term studies have demonstrated that the stability and length of telomeres determine the life span of cells and are closely related to cell senescence and cancer development. [70] After telomerase being activated, telomere can be extended that is synthesized with self-RNA as template, thus blocking cell apoptosis and promoting tumor oncogenesis. Therefore, targeting telomerase activity can inhibit tumor cell proliferation and urge tumor cell apoptosis, suggesting a promising cancer treatment.

Previously, Zhang LP et al., studied the influence of matrine on the telomerase activity in K562 cells. [71] They found that when treated with matrine, cell growth was dramatically inhibited and telomerase activity detected by PCR-ELISA was markedly suppressed, implying that matrine exhibited great impact on the tumor development mainly mediated by the regulation of telomerase activity. Until recently, another group reported that the combination of matrine and all-trans retinoic acid restored the differentiation ability of retinoid acid-resistant acute promyelocytic leukemia (APL)-derived NB4-LR1 cells, [9] possibly by reducing telomeras activity and increasing the expression of cyclic adenosine monophosphate and protein kinase A activity, suggesting a potential clinical application of matrine for the treatment of retinoic acid-resistant patients. Epigallocatechin gallate (EGCG), major component of polyphenols in green tea, exhibited widely antitumor activity in many tumors. Treatment with EGCG in Hep-2 cells, a cell line of Laryngeal squamous cell carcinoma (LSCC), inhibited cell growth and promoted apoptosis in accompanied with the increasing level of caspase-3 activity and down-regulation of telomerase activity in a dose-dependent manner. [72] Further research demonstrated that EGCG treatment inhibited the transcription of telomerase reverse transcriptase (TERT), the catalytic subunit of telomerase, which was mediated by epigenetic modification of TERT promoter, such as hypomethylation and histone deacetylations. [73] Sun L et al., found that treatment with allicin in gastric cancer SGC-7901 adenocarcinoma cells induced cell apoptosis and inhibited telomerase activity in a time- and concentration-dependent manner. [74]


 > Summary Top


It has confirmed that TCM can induce tumor apoptosis, and inhibiting telomerase activity has already become a new target for treatment of tumors. Meanwhile, there are further studies and advances in the aspects of TCM enhancing body immunity and anti-tumor metastasis. More deep researches on TCM multi-targeted antitumor mechanisms will make TCM in-depth development and application, which is promising to become an important means for treatment of malignant tumors.

 
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