Yiwen PENG, Shuyi SHEN, Yueyan HUANG

College of Medicine, Jiaxing University, Jiaxing 314001, China

Abstract Combating poison with poison is an important method of traditional Chinese medicine to treat malignant tumors. This study reviews the experimental research on anti-tumor effects of toxic traditional Chinese medicines in recent years. It summarizes the action mechanism of toxic traditional Chinese medicines for the treatment of malignant tumors, including: inhibiting tumor cell proliferation and angiogenesis, inducing tumor cell apoptosis and differentiation, reversing tumor cell multidrug resistance (MDR), inhibiting tumor cell invasion and metastasis, and enhancing the body’s immune functions. Finally, it discusses the research and development prospects of toxic traditional Chinese medicines as new anti-tumor drugs.

Key words Toxic traditional Chinese medicines, Malignant tumors, Mechanism

1 Introduction

Malignant tumor is a major disease that seriously threatens human health and life, and its prevention and treatment strategies have always been the focus of medical workers’ research. In the past, physicians often used toxic traditional Chinese medicines with strong medicinal properties to achieve the purpose of tackling tough sores, dispelling blood stasis, and combating poison with poison. Modern medical research has proved that toxic traditional Chinese medicines have a significant effect in the treatment of malignant tumors, but their toxicity also restricts their clinical application. In addition, whether the anti-tumor effects of many toxic traditional Chinese medicines are directly related to their toxic effects is still controversial. In this study, we reviewed the experimental research on anti-tumor effects of toxic traditional Chinese medicines in recent years, to provide basis and reference for the research and development of toxic traditional Chinese medicines as new anti-tumor drugs.

2 Toxic components of toxic traditional Chinese medicines

Toxic traditional Chinese medicines refer to those traditional Chinese medicines that contain highly toxic components, have a desperate medicinal property, and have a narrow therapeutic window, and improper use may cause poisoning or death. Their different components have different effects on the human body. The main toxic components of toxic traditional Chinese medicines include metal elements, alkaloids, toxic proteins, glycosides, terpenes, and lactones.

2.1 Metal elementsMineral traditional Chinese medicines containing arsenic, lead, mercury, and other metal elements, such as arsenic, realgar, mercury, cinnabar, lead powder,etc., are highly toxic to human health. Mercury has a strong stimulating and corrosive effect, inhibits the activity of a variety of enzymes, and causes central nervous and autonomic disorders. Arsenic has a protoplasmic toxic effect, can inhibit the activity of sulfhydryl-containing enzyme proteins, expand capillaries, lower blood pressure, and can damage nerve cells. Lead is a multi-affinity toxic substance that damages the nervous, hematopoietic, digestive and cardiovascular systems.

2.2 AlkaloidsAlkaloids are mainly toxic to the central nervous system. Herbal medicines such as Chuanwu (Aconiti Radix), Caowu (Aconiti Kusnezoffii Radix), and Fuzi (Aconiti Lateralis Radix Praeparaia) contain diterpenoid alkaloids, which act on the central and peripheral nerves, causing them to excite first and then inhibit or even paralyze them. They also act on the heart and cause arrhythmia. Maqianzi (Strychni Semen) contains saponine, which selectively excites the spinal cord, causes special tonic spasm, and causes suffocation due to tonic contraction of respiratory muscles. Leigongteng (Tripterygiumwilfordii) contains triptolide, which causes pathological changes in the optic thalamus, medulla oblongata, midbrain, spinal cord, and causes hemorrhage and necrosis of the heart, liver, and kidney.

2.3 Toxic proteinsToxic proteins are mainly toxic to the digestive system, which can strongly stimulate and corrode the gastrointestinal tract and cause internal organ bleeding. Cang’erzi (Xanthii Fructus), Badou (Crotonis Fructus), and Bimazi (Ricini Semen) contain toxic proteins, which can cause severe vomiting and diarrhea, blood in the urine, and even convulsions and death.

2.4 GlycosidesCardiac glycosides in small doses have a cardiotonic effect, while application of high doses or longer periods of time can lead to cardiac poisoning or even cardiac arrest. Jiazhutao (Neriumoleander), Bajiaofeng (Alangiumchinense), Wannianqing (Rohdeajaponica) contain toxic cardiac glycosides. Kuxingren (Armeniacae Semen Amarum) and Baiguo (Ginkgo Semen) contain cyanogenic glycosides, and hydrocyanic acid produced by enzymatic hydrolysis in the body is a strong cytotoxic substance. Mutong (Akebiae Caulis), Shanglu (Phytolaccae Radix), and Huangyaozi (Airpotato Yam Rhizome) contain saponins which are toxic to the circulatory system, inhibit breathing, damage the heart, and cause hemolysis. Yuanhua (Genkwa Flos) and Guangdougen (Subprostrate Sophora Root) contain flavonoid glycosides which stimulate the gastrointestinal tract, cause liver damage, and can cause malignant vomiting and jaundice.

2.5 Terpenes and lactonesTerpenoids and lactones have strong local irritation and can inhibit the central nervous system. Aiye (Artemisiae Argyi Folium) contains volatile oil which can stimulate the gastrointestinal tract and cause liver damage. Coriaria contains coriaria lactone, which can excite the brain and oblongata, lower body temperature, and cause convulsions or suffocation. Masang (Coriarianepalensis) contains coriarialactone which can excite the brain and oblongata, lower body temperature, cause convulsions or suffocation.

3 Anti-tumor mechanism of toxic traditional Chinese medicines

Modern pharmacological studies have confirmed that a variety of toxic traditional Chinese medicines have obvious anti-tumor effects, but the mechanism is complicated. The relevant anti-tumor mechanisms of toxic traditional Chinese medicines that have been studied deeply include the following aspects (Table 1).

3.1 Inhibiting tumor cell proliferationA main cause of tumor is the immortal proliferation of cells caused by cell cycle disorders. More toxic traditional Chinese medicines have different degrees of direct killing effect on different tumor cells, or they can inhibit the proliferation of tumor cells by blocking the cell cycle and give play to the anti-tumor effects. For example, Chonglou (Paridis Rhizoma)[1], Yadanzi (Bruceae Fructus)[2], Banxia (Pinelliae Rhizoma)[3], Wugong (Scolopendra)[4-5], Chuanwu (Aconiti Radix)[6], Xiangjiapi (Periplocae Cortex)[7], Maqianzi (Strychni Semen)[8], Tiannanxing (Arisaematis Rhizoma)[9], Xionghuang (Realgar)[10]，F(xiàn)uzi (Aconiti Lateralis Radix Praeparaia)[11], and Bimazi (Ricini Semen)[12],etc.According to the study of Zheng Yingetal.[2], the survival rate of osteosarcoma 143B HOS cells decreased, the number of cell clones decreased, the ratio of cells in G0/G1 phase increased, and the ratio of apoptosis increased after application of Bruceine D. Zhang Mingchuanetal.[3]found thatPinelliapedatisectaprotein has a significant cell proliferation inhibitory effect on human lung cancer cell A549, and it is dose-dependent;P.pedatisectaprotein group has a significant increase in lung cancer cells in G0-G1 phase, while lung cancer cells in S phase are significantly reduced; the differences are statistically significant, which may be through regulating the balance of anti-apoptotic/pro-apoptotic factors (Bcl-2/Bax) to inhibit cell proliferation. Liu Bingetal.[4]found that within a certain range, the active protein ofScolopendrasubspinipesmutilanshas a certaininvitroanti-tumor activity on tongue cancer Tea-8113 cells, and shows a dose-effect and time-dependent relationship, and it is speculated that its anti-tumor activity is related to the destruction of the complete structure of tumor cells by silk protease.

3.2 Inducing tumor cell apoptosisApoptosis is a physiological or pathological autophagy mode regulated by multiple genes, and it is closely related to the occurrence and development of tumors. Leigongteng (Common Threewingnut Root)[13-14], Chonglou (Paridis Rhizoma)[15], Xiangjiapi (Periplocae Cortex)[16], Chuanlianzi (Toosendan Fructus)[17], Wuzhuyu (Euodiae Fructus)[18], Maqianzi (Strychni Semen)[19], Banmao (Mylabris)[20], Wugong (Scolopendra)[5], and Kuxingren (Armeniacae Semen Amarum)[21]can induce cell apoptosis and inhibit tumor growth and proliferation by regulating the expression of tumor cell apoptosis-related genes and activating related signal transduction pathways. This is an important anti-tumor mechanism of toxic traditional Chinese medicines. Tozawaetal.[13]found that celastrol can arrest multiple myeloma cell lines in G phase and induce apoptosis. The mechanism may be related to the activation of nuclear transcription factor-κb and Caspase-3 pathways. Zheng Binetal.[15]found that Polyphyllin I and Polyphyllin II have significant anti-tumor effects on glioma cells U251, and their action mechanism is related to up-regulating the expression of Fas, Caspase-8 and Caspase-3 and promoting cell apoptosis. According to findings of Feng Chengcheng[17], after acting on human intestinal cancer SW480 cells, toosendanin can obviously cause early apoptosis, show apoptotic body and other apoptotic morphological changes, which are concentration-dependent; before the G0/G1 phase, there is obvious hypodiploid and the cells are blocked in the S phase, which may induce tumor cell apoptosis through the AKT/GSK-3β/β-catenin signaling pathway.

3.3 Inhibiting tumor angiogenesisTumor angiogenesis is the proliferation of a network of blood vessels which supplies a tumor with a supportive microenvironment rich with oxygen and nutrients to sustain optimal growth. Tumor growth and metastasis are largely dependent on the formation of new blood vessels. Therefore, inhibiting angiogenesis has become an effective way of anti-tumor therapy. In the process of tumor angiogenesis, the proliferation and migration of vascular endothelial cells is the most important part of angiogenesis. Shuizhi (Hirudo)[22], Quanxie (Scorpio)[23], Banmao (Mylabris)[24-25],etc.can play their anti-tumor effects by inhibiting tumor angiogenesis. Li Xiaojuetal.[22]found that Hirudo can exert anti-tumor effects by improving the tumor hypoxic microenvironment and inhibiting angiogenesis, and its mechanism may be through reducing the level of HIF-1a protein and mRNA expression, and reducing the expression of target gene VEGFmRNA mediated by HIF-1a. Sui Wenwen[23]found that the scorpion venom polypeptide extract can inhibit the growth of H22 liver cancer xenograft tumors in mice by affecting the expression of PTEN, PI3K, P-Akt, COX-2, HIF-1a and VEGF-A in the tumor microenvironment, so as to achieve the effect of anti-tumor angiogenesis. Zhang Longetal.[24]studied the effects of demehylcantharidin on vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptor (VEGFR2) and downstream signaling molecules MEK and ERK, and found that demehylcantharidin can inhibit the activation of VEGFR2/MEK/ERK signaling pathway, weaken the effect of VEGF, and reduce tumor angiogenesis.

3.4 Inducing tumor cell differentiation and agingAbnormal cell differentiation is the most essential feature of tumor cells. Induced differentiation refers to the phenomenon that malignant tumor cells reverse to normal cells under the action ofinvivoandinvitrodifferentiation inducers. Tumor cell aging defects, unable to enter the complete aging process, or immature aging, activated by oncogenes, can lead to tumor recurrence. Therefore, inducing tumor cell differentiation and promoting the complete aging of cells are also important methods and research hotspots for the treatment of tumors, such as toxic traditional Chinese medicines Shuizhi (Hirudo)[26], Shechuangzi (Cnidii Fructus)[27], Leigongteng (Common Threewingnut Root)[28],etc.Xiao Yishengetal.[26]found that the expression of CD11b in human leukemia HL-60 cells treated with Hirudo extracts increased, indicating that leech extracts can induce HL-60 to differentiate into mature granulocytes, thereby inhibiting tumor cell proliferation. According to findings of Su Liping[27], the anti-tumor effect of osthole on the two liver cancer rat models is reflected in the increase in tumor differentiation in the administration group, thereby reducing its invasion ability, and at the same time significantly reducing the expression of VEGF in vascular endothelial cells. As found by Pan Yanyan[28], triptonide significantly inhibits the growth of leukemia cells HL60 and U937 cells, induces morphological changes in cell aging such as increased size and difficulty in cell nucleus division, activates the expression of key aging genesTERTin leukemia cells, and up-regulates the expression ofp16andp21, and at the same time activates the MKK3-p38-DDIT3 signaling pathway to promote the apoptosis of aging cells and exert anti-cancer effects.

3.5 Reversing multidrug resistanc (MDR) of tumor cellsResistance to single or multiple drug treatments is a characteristic of malignant tumors and it is very likely to lead to chemotherapy failure and recurrence. Reversing drug resistance is an important means of anti-tumor therapy. The mechanism of action includes inhibiting the function and expression of mdr1, inhibiting the expression of P-glycoprotein, improving the activity of DNA topoisomerase II, and inhibitin the expression of glutathione-S-adenosyltransferase-π,etc.Leigongteng (Common Threewingnut Root)[29-30], Maqianzi (Strychni Semen)[31], Shechuangzi (Cnidii Fructus)[32],etc.exert anti-tumor effects through such mechanisms. Guo Qiongetal.[29]found that DU145/ADM cells pretreated with triptolide had a significant decrease in mdr1 expression, and tumor cells were more sensitive to adriamycin, suggesting that triptolide may become a drug resistance reversal agent. Liang Hongetal.[31]found that Maqianzi (Strychni Semen) reduced the expression of drug efflux pump P-glycoprotein (P-gp) on the cell membrane by down-regulating the expression of K562/A02 cell multidrug resistance gene mRNA, and reduced the overflow of chemotherapeutic drugs from the cells, thereby partially reversing the drug resistance of the human chronic leukemia cell line K652/A02 cells.

3.6 Inhibiting tumor cell invasion and metastasisInvasion and metastasis are the biological characteristics of malignant tumors, and they are also important reasons for tumor treatment failure and patient death. Matrix metalloproteinases (MMPs), heparinase, vasodilation-stimulating phosphoproteins, angiogenesis factors,etc., play a major role in the metastasis and invasion of tumor cells. Quanxie (Scorpio)[33], Leigongteng (Common Threewingnut Root)[34-37], Qingfengteng (Sinomenii Caulis)[38],etc.can exert such action mechanisms. Hao Zhengetal.[33]found that scorpion venom peptides can inhibit uPA and uPAR, MMP2, MMP9 genes and proteins, interfere with the mechanism of extracellular matrix degradation, and inhibit the progression of acute leukemia extramedullary infiltration (EMI). Yadavetal.[34]found that celastrol can inhibit the invasion and metastasis of colon cancer and pancreatic cancer cells by down-regulating the expression of CXCR4 chemokine receptor. According to the study of Kimetal[35], celastrol inhibits PMA-induced invasion and migration of breast cancer cells by inhibiting the expression of MMP-9 mediated by NF-κB. Zhu Hongetal[36]found that celastrol inhibits the adhesion of extracellular matrix (ECM) of human lung cancer 95-D and mouse melanoma B16F10 cells, and inhibits lung metastasis in C57BL/6 mouse model injected with B16F10 green fluorescent protein geneinvivo, indicating celastrol has good anti-metastatic activity bothinvivoandinvitro.

3.7 Enhancing the body’s immune functionThe pathogenesis of tumors is closely related to the reduction of immune response and immune regulation. Immunotherapy plays an utmost role in improving the quality of life of patients and fighting malignant tumors. Toxic traditional Chinese medicines such as Chuanlianzi (Toosendan Fructus)[39], Baifuzi (Typhonii Rhizoma)[40-41], and Chanchu (Toad)[42]can exert anti-tumor effects by enhancing the immune function. Hou Xidong[39]found that Chuanlianzi (Toosendan Fructus) decoction is dose-dependent, can inhibit the proliferation of Lewis and A549 lung cancer cells, significantly down-regulate the expression of autophagy-related proteins LC3 and Beclinl, and can reduce the expression of hs-CRP and IL-6 in the serum of lung cancer mice and increase the expression of IgG, indicate that the anti-tumor and anti-metastasis mechanism of Chuanlianzi (Toosendan Fructus) may be related to the enhancement of the body’s immune function, preventing tumor cell autophagy, and improving the environment in the body. Yu Xiaohongetal.[40-41]found that Baifuzi (Typhonii Rhizoma) can significantly inhibit the growth of H22 cells and promote the development of thymus in tumor-bearing mice; by improving the imbalance of CD4/CD8in tumor-bearing organisms, it can promote the expression of IL-2 and other TH1 cytokines, and improve the immune function of tumor-bearing organisms.

Table 1 Overview of research on common toxic traditional Chinese Medicines used in resisting tumor

Toxic traditionalChinese MedicinesActive componentsTumor typeAnti-tumor mechanismLiteratureCommon Threew-ingnut RootCelastrolProstate cancer Inhibiting the expression of miR-27a, and migration and invasion of prostate cancer[37]Sinomenii CaulisSinomenineOsteosarcoma Regulating the expression of MMP-2, MMP-9, RANKL, VEGF, inhibiting osteolysis caused by abnor-mal activation of osteoclasts, and inhibiting the invasion and metastasis of osteosarcoma[38]Toosendan FructusDecoctionLewis lung carcinoma and cell line A549 Enhancing immune function, preventing autophagy of tumor cells, and delaying tumor growth[39]ToadToad skin active compon-entsHuman gastric cancer cell line BGC823, colorectal carcinoma cell line HCT116, and pancreatic adenocarcinoma cell line SW1990 Inhibiting tumor growth and lymph node metastasis, stimulating the proliferation of immune organs, and pro-moting immune cells to secrete cytokines and antibodies[42]

4 Conclusions and prospects

Tumor is a new organism formed by the proliferation of local tissue cells under the action of various tumor-causing factors. There has been a long history of treating malignant tumors with highly toxic traditional Chinese medicines. The essence of traditional Chinese medicine dialectical treatment is to combat evil poison with the medicine poison. The method of combating evil poison with the medicine poison makes a batch of toxic traditional Chinese medicines have the potential to be screened objects for new anti-tumor drugs, and have a good prospect for research and development. By reviewing the research on the anti-tumor mechanism of toxic traditional Chinese medicines, we can make toxic traditional Chinese medicine play a greater role in anti-tumor effects.

With the development of science and technology, using modern extraction, separation and purification methods, modern analytical techniques such as UV, HPLC, GC-MS, modern molecular biology techniques and methods, and the establishment of a multi-level new drug screening platform,etc., it is possible to study the toxicity of toxic traditional Chinese medicine in more depth-the medicinal material basis, internal process, mechanism of action, and its processing, preparation, compatibility, and application rules, reveal the scientific connotation of toxic traditional Chinese medicines, and provide scientific support and theoretical basis for the research and development of new anti-tumor drugs and the sustainable development of the traditional Chinese medicine industry.