Editor's Note
Esophageal cancer (EC) is the sixth leading cause of cancer-related deaths globally. Western medicine has played a leading role in its treatment, but its prognosis remains unsatisfactory. Therefore, it is important to develop effective treatments. Traditional Chinese Medicine (TCM) has been practiced for thousands of years and involves taking action before the disease occurs, worsens, and recurs. Interestingly, there is growing evidence that traditional Chinese medicine can improve therapeutic efficacy, reverse precancerous lesions, and inhibit recurrence and metastasis of EC. The team of Guang'anmen Hospital of China Academy of Chinese Medical Sciences reviewed the chinese medicine formulas with preventive and therapeutic effects on esophageal cancer, and summarized the application and research status of traditional Chinese medicine in patients with esophageal cancer.
body
introduce
It is estimated that there are 604,000 new cases of esophageal cancer (EC) and 544,000 deaths each year, ranking seventh and sixth in the world in terms of incidence and mortality of esophageal cancer, respectively. EC is mainly divided into esophageal squamous cell carcinoma (ESCC) or esophageal adenocarcinoma (EAC), of which ESCC accounts for about 90%, 5-year survival rate is 10%, 2 and 30% to 40% of cases have local or once distant metastases are found. Smoking, excessive alcohol consumption, red meat, bacon, fried foods, Barrett's esophagus, gastroesophageal reflux disease, obesity, etc. all increase the risk of EC. At present, EC mainly uses surgical resection, radiotherapy, chemotherapy, molecular targeted therapy, immunotherapy and other methods of treatment, but the prognosis is still poor.
Traditional Chinese Medicine (TCM) originated in ancient China. It has gone through different phases of boom, bust, and revival (Figure 1) over 5,000 years of medical practice. The main guiding ideology of "curing diseases and seeking the roots" comes from the classic ancient book "The Yellow Emperor's Inner Classic". Under the concept of wholeness and individualization, Chinese medicine believes that qi, blood, yin and yang are the basic substances that maintain human life activities, and the occurrence of diseases is due to their imbalance. The body is like the "soil environment" and the cancer cells are like the "seeds" . Traditional Chinese medicine can not only directly eliminate the carcinogenic "seed", but also improve the "soil environment" so that the human body is no longer suitable for the growth of "seeds". Keeping the esophagus open (TCM passage) is a beneficial approach to treatment. The key pathological factors of EC are weakness, stasis, fever, and toxicity. Therefore, it is necessary to replenish qi, activate blood, strengthen the spleen and kidneys, rationalize phlegm, clear heat and detoxify and other therapies. Compared with Western medicine, Chinese medicine has played a complementary and substitution role in EC, achieving satisfactory results and attracting widespread attention. In this paper, we review the application status and mechanism research of Traditional Chinese Medicine, and discuss its shortcomings and prospects in the context of integrative medicine, precision medicine and evidence-based medicine.
Figure 1: The rise and fall and revival of Traditional Chinese medicine. Chinese medicine sprouted in the Xia Dynasty and gradually developed and expanded in the Tang, Song, Ming and Qing dynasties. In 1912, due to the influence of Western medicine, Chinese medicine went into decline. It was not until 1950 that Chinese medicine was gradually revived. In 2003, chinese medicine achieved good results in the prevention and treatment of SARS, making it stand out. The 2015 Nobel Artemisinin Research Award promoted the internationalization of traditional Chinese medicine. During the 2019 COVID-19 period, the advantages of Traditional Chinese medicine in improving symptoms and reducing mortality have become more obvious, which has received widespread international attention and recognition.
Ancient recipe for the treatment of EC
Although ec itself is not described in ancient China, TCM is used to improve clinical symptoms such as dysphagia. At the same time, ancient Chinese medicine prescriptions gradually developed from a single herb to a variety of drugs (prescriptions). Some ancient classic formulas have preventive and therapeutic effects on EC. For example, the Six Gentlemen Soup and the Sand Ginseng Pulse Winter Soup can inhibit the growth of EC cells. Xiao Chai Hu Tang and Qizhu Yu Ling Tang Thin Liver Rational Qi . They prevent EC cell proliferation and improve clinical symptoms. Qi Luck Spleen Soup and Liuwei Dihuang Pill are classic remedies for strengthening the spleen and kidneys. They prevent the progress of the EC. Qi Ge San, Tong You Tang and other prescriptions expectorant, dampness, dispel stasis, detoxification, strengthen the body and resist disease. Table 1).
Table 1. Ancient classic formula for the treatment of EC.
Modern application and research of traditional Chinese medicine in the European Community
Prevention of EC occurrence and metastasis of TCM
EC mostly develops from squamous epithelial dysplasia of the esophagus, and chronic inflammation and mucosal hyperplasia are important factors in the gradual development of esophageal epithelium into dysplasia. Clinical studies have shown that Chinese medicine has a promising perspective on the prevention of EC. For example, one randomized controlled trial showed that Fufang Cang Bean Pills (White Art, Mountain Bean Root, and Green Tea) reduced 2-year cancer incidence, cellular DNA content, and proliferation index in critically ill patients. Esophageal epithelial cell proliferation.
Randomized controlled trials have shown that Konaiyi tablets (diospyrifos, indigo, indigo, Selfheal, Yamato sauce, cypress) can reduce the conversion rate of severe esophageal epithelial cell proliferation by 52.2% and 47.3. Percentage at 3 and 5 years, respectively. The herbs (such as Banxia, Skullcap, Skullcap, Ginger, Ginseng, Licorice, Jujube) not only had a reversive effect on esophageal mucosal dysplasia (2 months and 1 month) the annual cure rate was 71.7% and 70.0%, respectively, but also improved clinical symptoms. The total effective rate of mucosal dysplasia after 3 months of intervention of heat-clearing and active blood combination agents (mahogany, angelica, red peony, mountain bean root, bitter ginseng, hawthorn, mutong, tianlong) on gastroscopic pathology in patients with esophageal cancer was 82.76% (24/29). In one non-randomized controlled trial, Jia-Wei-Liu-Wei-Di-Huang-Tang (ripe ground yellow, dogwood, diospyrifos, oriental waterwheel, poria, peony peel, prickly skull grass, white-flowered snake tongue grass, Prunella Asiatica, Oyster Shell) was used to treat patients with esophageal hyperplasia (mild, moderate, and severe) for 3 to 6 months; the total effective rate of gastroscopic pathology was 94.2% (49/52) and no cancerous changes were seen. 54 It can be seen that Chinese medicine has anti-EC potential and has a direct inhibitory and reversing effect on esophageal epithelial hyperplasia. In addition, in the prevention of EC recurrence and metastasis of Chinese herbal medicines, a non-randomized controlled trial reported that the addition of flavored seven-grid powder (salvia, poria, turmeric, sand kernel, poria cocoa, shellfish, xuan ginseng, ripe ground yellow, wheat dong, lotus leaf, floating wheat) can reduce the recurrence metastasis rate of 9.4% and 19.6% (respectively) after radical resection of esophageal cancer, prolonging disease-free survival and improving the quality of life of patients.
Traditional Chinese medicine combined with modern medicine to treat EC
Surgery and chemoradiation, as the main treatment methods of EC, have toxic side effects that affect the quality of daily life of patients. It has been reported that the combination of traditional Chinese and Western medicine can improve the efficacy of such treatments and prolong survival. For example, three randomized controlled trials have shown that supplemental bulk drinking improves symptoms such as postoperative fatigue, slurred speech, shortness of breath, fatigue, and self-sweating, as well as immune and nutritional indicator levels (P< 0.05) after radical resection of EC. Compared with chemotherapy alone, The combination of S-1 and cisplatin improves remission and disease control in patients with advanced EC, and prolongs progression-free survival (PFS) and overall survival (OS). Simultaneous chemoradiation and chemotherapy combined with lung clearing and decontasis decoction in patients with advanced EC can reduce the incidence of radiation pneumonia and radiation lung injury, and improve the survival rate and quality of life of patients (P <.05). A retrospective clinical study confirmed that chemoradiotherapy and β-elecene improve OS, PFS, and 3-year survival in patients with ESCCs, which informs clinical use of β-elecene-chinese herbal medicines such as poria.
Symptoms of patients with improved ec medicine
In EC patients, ginseng and astragalus are often used to improve appetite and fatigue. Half-summer and ochre can improve nausea. Concha Arcae and cuttlefish bone are used to improve heartburn, and rhubarb and betel nut are used to improve constipation. Cancer-related pain is the most common symptom in patients with advanced incurable EC, mainly secondary to dysphagia or localized tumor spread. Two meta-analyses and a systematic review showed that combined matrine injections can relieve cancer-related pain, including lung, EC, liver, stomach and other cancers. Two randomized controlled trials showed that The Ziyin Tongjing Formula (TianmenDong, Mai Dong, Xuan Ginseng, Raw Ground Yellow, Chai Hu, Citrus Aurantium, Yan Hu Suo, Astragalus, White Peony, Angelica, Panax notoginseng, Orange Peel, Peach Kernel, Licorice) can enhance the analgesic effect of opioids. Pain pain flat capsules (Manyo, coix seeds, big wind chimes, frankincense, green pepper, yanhuso, etc.) by increasing the plasma β-endorphin content, reducing the cAMP level, exerting the central analgesic effect, and improving the quality of life to a certain extent.
TCM anti-EC mechanism
Inhibits cell proliferation and induces cellular senescence
Abnormal cell proliferation is a hallmark of cancer. Studies have shown that lupinol acetate and berhoside-I, the active ingredients of the ground, inhibit the proliferation of EC cells by down-regulating the expression of β-catenin and its downstream proteins. β-elecene,an active ingredient in turmeric—inhibits the proliferation of ESCCs by modulating long-chain, non-coding RNA-mediated expression of hTERT. In addition, Chinese herbal medicines and their active ingredients, such as wood turtle (wood beetle), curcumin (the active ingredient of turmeric) and flavored oil soup (peach, safflower, cohosh, betel nut, skullcap, white flower snake tongue) can also inhibit cell proliferation and exert anti-EC effects. The mechanism of action of traditional Chinese medicines on EC is detailed in Figure 2.
Figure 2: Mechanism of Chinese medicine against EC.
Senescence is an irreversible state of cell cycle stagnation. There is growing evidence that inducing cellular senescence is an effective treatment for cancer. Interestingly, studies have shown that gynostemma-associated cyclin L (a saponin isolated from gynostemma) can promote senescent-related cytokines (such as IL-1α, IL-6, TIMP-1, CXCL-1, and CXCL-2) and aging-associated cyclins (p21 and p27) by increasing the activity of SA-β-galactosidase, causing cells to stagnate in phase S. Coincidentally, pathways that regulate cellular senescence have an effect on the development of ESCCs. Among them, p38 MAPK activation may be a key link in the process of ESCC malignancy and transformation; The MAPK/ERK pathway inhibits proliferation and invasion of ESCC cells by targeting MAP3K9. NF-κB signaling is overactivated in ESCC cells, and its inhibition leads to decreased cell growth and cell proliferation. Another study showed that gynostemma Cyanoside L induces EC cell senescence by activating the p38, ERK, MAPK, and NF-κB pathways.
Induction of autophagy and apoptosis
Autophagy is a mechanism by which cellular matter is degraded by lysosomals. It has an opposite and context-sensitive effect in cancer and is proposed as a treatment for tumors. Ursolic acid inhibits the growth and transfer of EC cells through reactive oxygen species (ROS)-mediated autophagy. Echinatin (the active ingredient in licorice), dihydroartemisinin (active ingredient in Artemisinin), and ginsenoside Rk3 (the active ingredient in panax ginseng and panax notoginseng) induce autophagy and exert anti-EC effects by inhibiting the Akt/mTOR signaling pathway.
In addition, apoptosis is a multi-factor-induced biological process of programmed cell death and has also been shown to be a promising and effective way to prevent cancer growth and progression. Studies have shown that traditional Chinese medicine can induce apoptosis to inhibit EC progression. For example, Jaridonin, the active ingredient of wintergreen, has been reported to induce apoptosis by inducing ROS production, releasing cytochrome C, and activating caspase. Picropodophyllotoxin, the main component of Podophyllum Hexandrum Root, has apoptosis effect on ESCC cells by increasing ROS levels and inducing the JNK/p38 signaling pathway. The PI3K/AKT/mTOR signaling pathway is key to the oncogenic process of ESCC and has potential value for prognostic markers and treatments of ESCC. Matrine (the active ingredient of matrine), ricin (the main active ingredient of wattle), toxagon (the active ingredient of the wattle), herb (the active ingredient of the herb) and ginsenoside Rg5 (the main active ingredient of red ginseng) can pass through the BID-mediated mitochondrial pathway, the 95 JNK signaling pathway, the PI3K/AKT/mTOR and Ras/Raf pathways, and the PI3K/PKB signaling pathway, respectively.
Inhibits metastasis and angiogenesis
Metastasis is the true cause of malignancy and causes 90% of cancer-related deaths. Studies have shown that berberine, an active ingredient in berberine, can inhibit EC cell migration by down-regulating the expression of CCR7 and CXCR4. Curcumin, an active ingredient in turmeric, inhibits the formation of a lipid-associated Rac1/PI3K/Akt signaling complex, thereby improving Sdf-1α-induced EC cell invasion. In addition, epithelial interstitial transformation (EMT) is a key factor in regulating tumor cell metastasis. Interestingly, Heptera and Toxosin injections can inhibit EMT by inhibiting the expression of Gas6/axl and the activation of the Snail/Twist pathway, respectively.
Angiogenesis is necessary for tumor growth and metastasis. Inhibiting angiogenesis and tumor vascular supply helps control the growth and metastasis of tumor cells. Scholars speculate that overexpression of PDGFR-α is associated with tumor-associated angiogenesis and progression. The PDGFR-α expression rates of EAC and ESCC are 91% and 100%, respectively. The expression of VEGF is closely related to the angiogenesis, disease progression, and prognosis of ESCC. Studies have shown that Seven Grids and Six Gentlemen Hall can reduce cellular angiogenesis. Among them, Heptera may exert anti-EC effect by down-regulating the expression of EGFR, PDGFR, VEGF and PLC-γ1.
Increased drug resistance
Drug resistance is a common phenomenon in the process of cancer chemotherapy and is one of the causes of poor prognosis. The occurrence of multidrug resistance in tumor cells is closely related to the expression of P-gp and MRP. In addition, traditional Chinese medicines and their active ingredients, such as toadine injection and curcumin, can improve the resistance of EC cells by inhibiting the expression of P-gp and MRP, enhancing the sensitivity of EC cells to chemotherapy drugs. Luteolin can also reverse multidrug resistance by inhibiting the FAK/Src/PI3K/Akt signaling pathway in ESCC cells. Studies have shown that the downregulation of microRNA-138 expression is associated with cellular resistance. Survivin is a target gene for microRNA-138, and EC cancer cells with elevated expression of the survivin protein are resistant. α-Solanine (an active ingredient in Solanum Nigrum Linn) promotes the chemical sensitivity of EC cells to 5-fluorouracil/cisplatin by upregulating microRNA-138 expression and downregulating survivin expression.
Regulation of immune function
Immune escape triggered by T cell depletion or dysfunction is one of the mechanisms by which cancer cells evade the immune system. Studies have shown that compound matrine injection (matrine, he shou wu, knotweed) can increase the level of CD3+, CD4+, CD4+, CD4+ /CD8+ T cells in the elderly EC, and enhance cellular immune function in patients receiving chemoradiotherapy. True Qifuzheng granules can improve CD3+, CD4+, CD8+ level T cells and enhance the immunity of EC patients. In addition, mature dendritic cells (DCs) act as antigen-presenting cells in the immune system, with a superior ability to acquire antigens and present them to T cells. Qi-Ge-San can reduce the inhibition of EC on DCs by suppressing the STAT3 signaling pathway. At the same time, Treg cells also participate in tumor development by inhibiting tumor immunity. One study showed that the company 'symbiosis (forsythia, smallpox pollen, ginseng, and epidermis) slows the progression of precancerous lesions of the esophagus by inhibiting the expression of Treg cells.
conclusion
The prognosis for patients with advanced EC remains unsatisfactory. The 5-year survival rate is about 5%. With the development of more EC-related clinical trials in recent years, targeted and non-targeted immunotherapies have gradually developed. These therapies, combined with surgery, radiation therapy and chemotherapy, are expected to be the future of EC multimodal therapy. However, drug resistance in targeted immunotherapy is a complex issue that cannot be avoided. Traditional Chinese medicine plays an important role in immunization and targeted therapy, such as synergistic attenuation, improving drug sensitivity, and even reversing drug resistance. For example, studies have shown that traditional Chinese medicine has a unique advantage in reversing acquired resistance to lung cancer EGFR tyrosine kinase inhibitors. Therefore, whether TCM plays a positive role in reversing targeting and immunotherapy resistance in EC therapy remains a valuable question to be solved. In addition, it is worth exploring the mechanism of action of Traditional Chinese medicine in the EC microenvironment and its effect on oral and intestinal flora.
TCM Treatment EC shows great potential. Due to its inherent complexity, it is well suited to the complex mechanisms of EC. However, there is also a broader dilemma: due to the many targets and pathways of traditional Chinese medicine, the anti-EC mechanism of most Chinese herbal medicines has not been fully elucidated. It is necessary to explore the regulatory network related to the mechanism of traditional Chinese medicine with the help of multidisciplinary, large sample, and multi-omics techniques. At the same time, due to the lack of high-quality evidence-based research, TCM is at a disadvantage in formulating EC clinical pathways and guidelines, which greatly limits the application and development of TCM. In the future, high-quality randomized clinical trials with larger sample sizes will need to be conducted in multiple centers to improve this.
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