|Year : 2020 | Volume
| Issue : 2 | Page : 152-162
Xihuang pills, a traditional chinese preparation used as a complementary medicine to treat cancer: An updated review
OncoWitan, Lille (Wasquehal) 59290, France
|Date of Submission||08-Oct-2019|
|Date of Acceptance||14-Jan-2020|
|Date of Web Publication||31-Mar-2020|
Dr. Christian Bailly
OncoWitan, Lille (Wasquehal) 59290
Source of Support: None, Conflict of Interest: None
The traditional Chinese medicine, Xihuang pills (XHP), has long been used for the management of cancers, both to limit tumor cells proliferation and dissemination, and to protect nontumor cells from damages induced by conventional therapeutic agents. XHP is made from two plant extracts (from Boswellia carteri and Commiphora myrrha) and two animal-derived products (from Moschus moschiferus and Calculus bovis). Recent advances into the mechanism of action of XHP and its clinical efficacy are reviewed here to highlight its potential to treat breast and colon cancers in particular. The immunoregulatory effects of XHP are underlined. Similar traditional medicinal preparations containing Boswellia and Commiphora are discussed, as well as the activities of the major natural products found in XHP including abietic acid, acetyl-keto-boswellic acid, and muscone. Pharmacological and clinical studies of XHP and similar medicinal preparations, such as the Korean medicine HangAmDan-B, are encouraged.
Keywords: Anticancer drugs, cancer therapy, natural products, traditional Chinese medicine
|How to cite this article:|
Bailly C. Xihuang pills, a traditional chinese preparation used as a complementary medicine to treat cancer: An updated review. World J Tradit Chin Med 2020;6:152-62
|How to cite this URL:|
Bailly C. Xihuang pills, a traditional chinese preparation used as a complementary medicine to treat cancer: An updated review. World J Tradit Chin Med [serial online] 2020 [cited 2020 Jul 2];6:152-62. Available from: http://www.wjtcm.net/text.asp?2020/6/2/152/281626
| Xihuang Pills|| |
Xihuang pill (XHP) (西黄丸), also called Xihuang Wan, is a traditional Chinese medicine (TCM) used for a long time for the treatment of cancers in China. Its origin can be traced back to the Qing dynasty. The preparation was recorded in the classical book of TCM “Wai Ke Zheng Zhi Quan Sheng Ji” (1740 A.D.) and then cited in several books in years 1770 (Xu Mingyi Lei'an), 1831 (Wai Ke Zheng Zhi Quan Shu), and 1878 (Yan Fang Xin Bian). XHPs are used orally to treat several tumor types, such as breast, lung, and colon carcinomas and lymphomas, either alone or in combination with conventional chemotherapies.
This preparation contains four ingredients, including two plant extracts from Boswellia carteri (the exuded gum resin of the plant, named Olibanum) and Commiphora myrrha (myrrh) and two animal-derived products from Moschus moschiferus (musk exudate) and Calculus bovis (bovine bezoar) [Figure 1] and [Table 1]. According to TCM philosophy, each ingredient provides a specific advantage: frankincense and myrrh promote blood and vital energy circulation and decrease swelling and pain; musk is believed to activate blood stagnation and vital energy circulation; and bezoar to clear heat and detoxify [Figure 2]. In the ancient time, the TCM product was prepared by mixing the four ingredients with steamed yellow rice. Nowadays, tablet and capsule formulations are available. XHP is used essentially in East and Southeastern Asia for the treatment of neoplastic diseases, mainly to reduce the side effects of chemotherapy such as pain, nausea, and stomatitis. In addition, the use of XHP to treat pulmonary abscess, furunculosis, and scrofula has been cited, but there are little published data to support these other indications.
|Figure 2: Illustration of the mechanism of action of XHP according to the traditional Chinese medicine principles. Xihuang pill (the triangles represent its four components) regulates the body energy, flux and correct health imbalances|
Click here to view
| Anticancer Activities of Xihuang Pills and Signaling Pathways|| |
A significant activity of XHP was observed in breast cancer models, bothin vitro and in vivo. The antiproliferative action was first evidenced using the two human breast cancer cell lines MCF-7 and MDA-MB231, and in both cases, the product showed relatively similar growth-inhibitory effects, without interference with cell cycle progression and with a moderate degree of apoptosis. In a later study, an aqueous extract of XHP was found to inhibit the proliferation of triple-negative breast cancer Hs578Y cells in vitro. In this case, the extract induced S-phase cell cycle arrest with concomitant decreased expression of cyclin A and CDK2 and increased expression of cyclin E. A more prominent apoptosis was noted, via a Bcl-2/Bax-independent pathway. Anotherin vitro study with breast cancer cells suggested the implication of TP53 in XHP-induced apoptosis. A modest reduction of tumor growth was foundin vivo using XHP alone or combined with 5-fluorouracil (5-FU) in the breast cancer xenograft models 4T1 and SKBR-3. In both models, XHP and 5-FU reduced tumor growth to a similar extent; the combination of XHP + 5FU showed roughly the same modest growth inhibitory effect. A much more pronounced effect was reported using the estrogen receptor (ER)-positive breast cancer cells MCF-7 and T47D. Interestingly, in this study, a similar antitumor activity was observed with the 4-component product XHP and the combination of two extracts from Olibanum and C. myrrh, suggesting clearly that these two products support most of, if not all, the activity of XHP. The two extracts individually were much less active than their combination. The anticancer effect was associated with a downregulation of the signaling molecules EGFR, Raf, Akt, and Erk, possibly resulting from a direct inhibition of the chaperone protein HPS90. Based on modeling and preliminary binding studies, the authors proposed a mechanism whereby the active components of XHP dually target simultaneously the membrane ER and HSP90, to block the transport of ER to the cell nuclei. Interestingly, Su et al. reported the capacity of XHP to dose dependently reduce the number of regulatory Treg (T) cells in the microenvironment in a murine 4T1 model of breast cancer. It promoted apoptosis of T cells via activation of the AP-1 pathway. Both the mRNA and protein expression levels of MEKK1, SEK1, JNK1, and AP-1 were increased in T cells upon treatment with XHP, leading to cell death and immunoregulation. An immunoregulatory effect has also been noted using a rat mammary cancer model. An increased expression of interleukin-2 and interferon-γ was observed in a rat bearing Walker 256 tumor cells and treated with XHP.
In China, XHP has been used to treat cancer patients for a long time. A meta-analysis covering 13 eligible clinical studies including 1272 patients treated with XHP alone or in combination with chemotherapy (636 each) has been published recently. The analysis indicated that the use of XHP reduced significantly the extent of chemotherapy-induced adverse effects in patients, notably nausea and vomiting. The hematological toxicities were also reduced. A trend toward an immunoregulatory effect was noticed (increase of CD3+ and CD4+ and decrease of CD8+ cells) in patients treated with XHP+ chemotherapy versus chemotherapy alone, but these are preliminary results, due to the limited sample population. Nevertheless, this retrospective study supports the use of XHP as an adjunctive therapy in breast cancer to limit the side effects of conventional chemotherapy.
Patients with colorectal cancer may also benefit from the use of XHP. An analysis of a clinical study with 62 patients with colon cancer treated with standard chemotherapy (FOLFOX or FOLFIRI regimen), with or without XHP (2 × 32 patients), has shown that the XHP-containing experimental group has less side effects than the XHP-free control group. The tumor response to treatment was better in the XHP group (47% vs. 23%) and quality of life score was better than in the control group (performance status Eastern Cooperative Oncology Group 0.75 vs. 1.16). However, there was no difference in terms of chemotherapy-induced side effects (similar extent of bone marrow suppression, gastrointestinal reactions, and liver/renal functions). It was concluded that XHP can be a useful therapeutic adjuvant to enhance the effectiveness of chemotherapy in colorectal cancer. A later meta-analysis, but not very well defined in terms of tumor type considered, has also concluded that XHP can enhance tumor treatment when combined with chemotherapy. The mechanism of action of XHP in colon cancer has been investigated using the Lovo human colorectal cancer cell line to show that the compound affected the proliferation, invasion, and migration of these cells. XHP was found to downregulate the signaling molecules ERK1/2 and the transcriptional repressor ZEB1, which is implicated in the control of cell junction molecules such as JAM1 and occludin.
Beyond the above-cited studies in breast and colon cancers, there is limited information about the activity of XHP in other tumor pathologies. An old publication referred to the activity of XHP in a L7212 murine leukemia model, but no additional information about the use of XHP in oncohematology has been published. The last case to mention refers to brain cancer. Tumor cell growth inhibition by XHP has also been observed using U-87 glioblastoma cells in vitro. In this case, the product blocked cell cycle in the S-phase and triggered apoptosis via a mitochondrial-dependent pathway implicating the production of reactive oxygen species. The Akt/mTOR/FOXO1 signaling pathway was found to be implicated as well. XHP inhibited phosphorylation of Akt, mTOR, and FOXO1, thereby enabling FOXO1 nuclear transport to promote FOXO1-mediated transcription of proapoptotic proteins [Figure 3].
|Figure 3: A snapshot of the mechanism of action of Xihuang pill with three major pathways activated. Xihuang pill inhibits phosphorylation of diverse signaling molecules in cancer cells, notably the Pi3K/Akt/mTOR pathway and the mitogen activated protein kinases pathway. In parallel, the medicine (at least its plant constituent's myrrh and frankincense) can recruit and restore the immunosuppressing activity of CD8+ Treg cells in hepatocellular carcinoma|
Click here to view
Finally, it is worth mentioning another TCM preparation called Niuhuang Xingxiao Wan (NXW) very similar to XHP. It contains the same four ingredients, plus realgar which mainly consists of arsenic sulfide (As2S2). A specific microformulation of NXW has been developed and has revealed an antitumor efficacy in a hepatoma rat cancer model.
| Other Herbal Preparations Containing Commiphora And Boswellia|| |
Plant-based complementary alternative medicines are popular in many countries, not only in China. We found several indications of the use of the plants Commiphora and Boswellia (or Olibanum) in traditional herbal preparations to treat cancers or associated pathologies. We can refer to several medicinal preparations:
- Korean medicine therapy has been largely influenced by TCM. HangAmDan (HAD) is a multiherbal Korean preparation derived from Xihuang Wan which has been modified after multiple screening of herbs. There are several formulas. HAD-B includes C. myrrha, B. carterii, and C. bovis, in addition to five other plants. Recently, the extracts HAD-B and HAD-B1 have shown activities in lung cancer.,, HAD-B is used for stimulating immune function (activation of vital energy) in cancer patients. It activates the antitumor function of tumor-associated macrophages. However, the activation of macrophages toward an M1 phenotype would be due to the plant Panax notoginseng, also present in this extract. HAD-B also displays antiproliferative, antiangiogenic, and antimetastatic effects.,, An effective treatment of a patient with lung-metastasized bladder cancer with the herbal preparation HAD-S also containing C. myrrha has been reported. The antitumor effect cannot be attributed to this plant specifically because the patient received several multiplant extracts, but this case provides another example of anticancer activity with C. myrrha in humans
- Ayurvedic medicine: Guggul is a medication largely used in Ayurveda to treat various diseases, such as cardiovascular diseases, arthritis, diabetes, and many other pathologies. Guggul refers to the gum resin obtained from the two plants Commiphora (usually Commiphora wightii) and Boswellia (generally B. serrata). In India, the C. wightii oleoresin has been overexploited. The polyherbal formulation Sandhika, used in India for many years as an anti-inflammatory agent, contains fractions of Commiphora (Commiphora mukul) and Boswellia (B. serrata) and two other plant extracts. It has shown anti-inflammatory activities and is used to treat bone-related disorders. A similar standardized preparation, named BHUx, has revealed antioxidant and anti-inflammatory properties associated with an inhibition of the enzymes cyclooxygenase-2 and 15-lipoxygenase ,
- Traditional Iranian medicine frequently refers to myrrh preparations (sabgh or sabigh). The semisolid oleo-gum resin derived from C. myrrha provides a convenient multipurpose pharmaceutical excipient. Commiphora and Boswellia are among the main plants recommended to treat gastrointestinal diseases according to some traditional Persian topical medications. Commiphora and Boswellia are also used in polyherbal paste to help wound healing 
- The Jerusalem balsam is a general remedy formulated in 1719 in the pharmacy of the Franciscans Saint Savior monastery in the old city of Jerusalem. It contains four plants, including the resin of Boswellia spp. and Commiphora spp. This preparation would be at the origin of balm of Commander of Pernes, well known in France., The Jerusalem balsam displays anti-inflammatory and anti-septic properties. It was found to modulate kynurenic acid synthesis in vitro.
There are other traditional preparations containing these two plants. For example, several Yemeni medicinal plants from the Soqotra island, including Boswellia and Commiphora species, have revealed antiproliferative properties.
| Combination of Commiphora and Boswellia|| |
Several studies have underlined the benefit of combining myrrh and frankincense. For example, a combined extract was found to exhibit superior antimicrobial effects than the individual extracts. Furthermore, the combination of myrrh + frankincense was more potent than the individual extracts to suppress inflammation in a rat model of arthritic progression. Inhibition of prostaglandin E2 was more pronounced with the combined extract than with myrrh or frankincense extract alone. Similarly, a combined extract was more potent for mitigating inflammatory pain. Recently, it was demonstrated that a combined extract displayed an antitumor activity in a model of hepatocellular carcinoma cells (HCC) via inhibition of the activation of nuclear factor-κB (NF-κB) and STAT3 signaling. A solid lipid nanoparticle formulation of myrrh or frankincense has shown a significant antitumor activity in a murine model. The combined essential oil seems to be able to promote membrane permeability. The immuno-anticancer activity is apparently mediated by tumor-infiltrating CD8+ T cells which can reduce the immunosuppressive microenvironment in HCC. The combined extract seems to restore the suppressed activity of these CD8+ T cells at the tumor site. This is a potentially important discovery. An affordable natural extract susceptible to reverse tumor-induced T-cell exhaustion/dysfunction could be extremely useful to treat patients with different types of immune-sensitive cancers, such as HCC, melanoma, lung, and colon cancers, for example. It is interesting to mention that the number of CD8+ cells was found to be increased upon treatment with Moschus, Olibanum, and myrrh in a mice local lymph node assay.
| Active Ingredients of Xihuang Pill|| |
We can refer successively to each of the four ingredients of XHP: the two plant extracts and then the two animal-derived products.
C. myrrha, or myrrh, is probably the most active ingredient of the preparation. Myrrh is a resinous ingredient that refers to a mixture of gum (40%–60%), resin (20%–40%), bitter principles (10%–20%), and volatile oil (2%–8%). Myrrh extracts have been found to inhibit proliferation of cancer cells in vitro. Standardized myrrh extracts can now be found, such as the analgesic extract MyrLiq ®, a C. myrrha extract with a high furanodiene content. Plants of the Commiphora species are known to contain a variety of phytochemicals including mono-, di-, and triternoids and steroids. A review of C. myrrha chemistry cited a large variety of sesquiterpenes and saccharides. One of the most active ingredients is the phytosterol guggulsterone [Z isomer, [Figure 4], which is an antagonist of farnesoid X receptor and exerts bone protective and antioxidant stress properties through activation of Nrf2/HO-1 signaling in a model of osteoporosis, bothin vivo and in vitro. The compound has been studied in different pharmacological models: (i) it shows anti-inflammatory properties through preventing activation of TLR4-mediated pathway, (ii) it can protect against colitis via suppression of TREM-1 and modulation of macrophages, (iii) it produces antidepressant-like effects in mice through activation of the BDNF signaling pathway, and (iv) it exhibits an antiadipogenic activity suggesting its use to limit obesity. In the oncology field, guggulsterone has been found to induce apoptosis in different cancer types via activation of JNK, suppression of Akt, and NF-κB activities , and to enhance the cytotoxic effect of doxorubicin through a Cox-2/P-gp-dependent pathway.C. molmol resin provides protection against methotrexate-induced acute kidney injury, via activation of Nrf2 signaling and mitigation of oxidative stress. Guggulsterone derivatives have been designed as kidney cell protective agents against cisplatin-induced nephrotoxicity.C. myrrha extracts contain other compounds, generally in very small quantities. Another interesting anticancer compound from C. myrrha is abietic acid [Figure 4], which was found recently to abrogate tumor necrosis factor-α-induced phosphorylation of inhibitor of NF-κB kinase and to inhibit nuclear translocation of NF-κB. This abietane-type terpenoid exerts inhibitory effects on the proliferation and growth of non-small-cell lung cancer cell lines  and melanoma cells. It displays diverse pharmacological effects, including (i) anti-inflammatory activities by activating PPARγ, (ii) an osteoprotective action via inhibition of NF-κB and mitogen-activated protein kinase (MAPK) signaling, (iii) acceleration of cutaneous wound healing via the enhancement of angiogenesis, (iv) attenuation of allergic airway inflammation, and (v) inhibition of protein tyrosine phosphatase 1B, a negative regulator of insulin signaling. Abietic acid can be used as a starting material to design more potent anticancer derivatives., In particular, derivatives of abietic acid and leelamine (structurally close to abietic acid) were found to inhibit intracellular cholesterol transport and to hinder xenografted melanoma tumor development.
|Figure 4: Structures of selected active compounds found in each ingredient of Xihuang pill|
Click here to view
B. carteri extracts clearly display anti-inflammatory and anticancer activities. The aromatic gum resin of Boswellia is commonly steam distilled to produce an oil (frankincense oil) used in aromatherapy practices. A frankincense oil derived from B. carteri was found to induce bladder tumor cell-specific cytotoxicity  and a later study reported antiproliferative effectsin vitro using different tumor cell lines. Frankincense oil may also be useful to treat cancer-related fatigue. One of the main active compounds in B. carteri is boswellic acid (BwA), but the extracts contain many other compounds, notably different pentacyclic triterpenic acids as well as polysaccharides that also contribute to the immunostimulatory activity. The cytotoxic activity of Boswellia oleo-gum resins correlates significantly with the pentacyclic triterpenic acid contents in the extracts. In particular, the BwA derivative 3-O-acetyl-11-keto-β-boswellic acid [AKBA, [Figure 4] displays potent growth suppression activity in HCCs. It triggers premature senescence via induction of DNA damage accompanied by impairment of DNA repair genes. AKBA, administered orally, was found to suppress the tumorigenicity of U87-MG human glioblastoma cells in a xenograft mouse model. Alone or combined with radiations, AKBA could be useful to treat brain tumors. AKBA derivatives are designed to enhance its solubility, bioavailability, and anticancer potency. Another triterpenoid isolated from the oleo-gum resin of B. carteri, acetyl-lupeolic acid [Figure 4], was shown to inhibit Akt signaling and to induce apoptosis in chemoresistant prostate cancer cellsin vitro and in vivo. B. carteri extracts contain other secondary metabolites such as a number of cembrane-type macrocyclic diterpenoids recently named Boscartins. Some of these compounds have revealed a hepatoprotective activity against D-galactosamine-induced HL-7702 cell damage. Different standardized extracts can be found. For example, a recent product designated Serratrin (LI13019F1), prepared from B. serrata gum resin extracts, has been characterized as a safe product in animal toxicological studies. Standardized extracts of B. carteri are currently evaluated in humans, for the management of osteoarthritis of the knee (e.g., Boswellin ®) and as an antitumor agent in patients with breast primary tumors in the US.
Only the main natural products found in B. carteri and C. myrrha are cited above. Of course, there are many more secondary metabolites present in myrrh and frankincense. In 2008, a repertoire of 55 bioactive metabolites was established. Today, there are probably many more compounds identified from these two species.
Moschus as a Chinese herbal material was first recorded in the book The Herbal Classic of the Divine Plowman (Shen Nong Ben Cao Jing) in about 2700 BC. It is officially listed in the Chinese Pharmacopoeia and known as a blood activator. In fact, musk should be considered as an animal spice medicine; it refers to a ventral glandular secretion of the male musk deer, with a strong smell, secreted to mark the deer territory and to seduce females from far away during the mating season. The genus Moschus includes at least six species (M. moschiferus used in XHP and Moschus leucogaster, Moschus fuscus, Moschus berezovskii, Moschus Chrysogaster, and Moschus anhuiensis). The microbiota in the musk gland plays an important role in the maturation process of musk and hence its chemical components.Moschus can be found in a other TCM preparations such as the Radix Curcumae formula used to treat certain cardiovascular and cerebrovascular diseases, Dangqui long hwei wan used for the treatment of hepatitis, Xijian Tongshuan pills to treat cerebral thrombosis, or the Tongqiaohuoxue protective decoction.Moschus is also a component of Shexiang-Baoxin and Shexiang-Wulong pills used to treat cardiovascular diseases and rheumatoid arthritis, respectively., A decoction of Moschus and Toona sinensis (herb used in TCM) has shown anticancer activities in vitro.Moschus contains various active compounds, notably cholic acid and muscone [Figure 4], which is a potent anti-inflammatory agent. This natural product (also used in perfumery) was found to downregulate the levels of LPS-induced inflammatory cytokines and to inhibit NF-κB and NLRP3 inflammasome activation in bone marrow-derived macrophages. It displays protective effect against alcohol-induced osteonecrosis of the femoral headin vitro and in vivo and it can protect PC12 cells against glutamate-induced apoptosis by attenuating ROS generation and calcium influx. Muscone is considered as a cardio- and neuroprotecting agent. It could be useful to prevent or treat diabetic peripheral neuropathy.
C. bovis (bovine gallstones, also called Goou in Japanese medicine) is a rare medicinal material that can be found in different traditional Chinese remedies, not only XHP, but also the Shexiang Baoxin pills used to treat cardiovascular diseases and to potentiate the activity of some anticancer drugs. Because it is a rare material, artificial forms have been developed, designated “in-vitro cultured C. bovis” or Chlamydia suis or C. bovis Sativus or C. bovis Artifactus. They are classically used to relieve fever and hepatobiliary diseases, to diminish inflammation and normalize gallbladder function. However, the content of minerals and bile acids differs between the natural and synthetic forms.,C. bovis is believed to eliminate heat and toxic components and to prevent the accumulation of phlegm and blood stasis in the liver. It contains bile acids, such as chenodeoxycholic acid [Figure 4] and hyodeoxycholic acid which is a neuroprotector. It is also rich in bilirubin [the principal bioactive component, [Figure 4], cholesterol, and oxysterols (e.g., 7β-hydroxycholesterol and cholestane-3β,5α,6β-triol) which function as neuroprotectants. There is no information about the anticancer activity of C. bovis, but it can certainly contribute to the cytoprotective effects. On the one hand, bile acids play a role in cancer prevention and therapy. One the other hand, other types of bezoars exhibit anticancer properties, such as porcupine bezoar which was recently found to display selective cytotoxic effect, to induce apoptosis, and to inhibit cancer cell migration and invasion.,
The four components of XHP are important, each contributing to the pharmacological effects of XHP pills. Nevertheless, it seems that a good part of the anticancer activity is supported by the plant-derived molecules rather than the molecules of animal origin which could contribute essentially to the cytoprotective effects. However, the two animal components Moschus (Shexiang in Chinese) and C. bovis (Niuhuang in Chinese) also bring active components. They are both present in another anticancer and antifibrotic TCM preparation called Pien-Tze-Huang., It is interesting to consider the XHP constituents together to cumulate the direct effects on tumor cells and the indirect effects on the tumor environment (e.g., the surrounding immune cells) and the protection of nontumor cells.
| Discussion|| |
TCM has been practiced for 1000 of years and today it is widely accepted as a complementary or alternative treatment for cancer. Myrrh and frankincense are among the oldest medicines in the world. They have been mentioned in ancient Chinese and Egyptian medical texts since about 3000 years BCE. The Magi, coming from the East (Arabia) carried myrrh, frankincense, and gold to reach Jerusalem and Egypt. These products were intended to provide a “universal fortification for all complexions and ages.” The antiseptic and hemostatic actions of myrrh and frankincense, respectively, have been recognized for a very long time and both have anti-inflammatory properties. The Hippocratic writings (4th century BC) also contain many references to myrrh. Therefore, it is not surprising to see traditional Chinese medicinal products, containing these plants. The peculiarity of XHPs is the four ingredients: two plant extracts and two animal-derived products. XHP ingredients have not been associated randomly; the formula certainly results from ancient Chinese theory (such as the prescription rule “Jun-Chen-Zuo-Shi”). It is a precious heritage of a TCM practiced for 1000 years in Asia. However, it is also a kind of black box, containing a few known and many unknown natural products. Therefore, it can be difficult to evaluate the exact clinical efficacy of these preparations and/or to evaluate (and sometime to reproduce) their effects in laboratories.
Animal medicinal materials are regularly found in TCM. Different animal ingredients can be identified, such as the glandular secretion of musk deer, Moschus, as found here in XHP pills but also Bullwhip, the external genital organ of male cattle, or the horns of rhinoceros (Rhinoceri Asiatici Cornu), Saiga antelope (Saigae Tataricae Cornu) and water buffalo (Bubali Cornu). The use of endangered animal products is a concern, which drives the search for appropriate substitutes. In some cases, the threatened animal organs or ingredients can be producedin vitro or replaced with an artificial equivalent, as it is the case with C. bovis, but this is not always possible. However, it may be possible to substitute the material issued from endangered animals with sustainable alternatives from domestic animals. A good example is the analysis of the Uyghur medicine named Yimusake formula commonly used to treat erectile dysfunction and premature ejaculation. The original formula contains 11 medicinal species, with three animal ingredients. A detailed mechanistic study has shown that it is quite possible to remove those three animal components, without altering the pharmacological effects. A modified animal-free formula, as potent as the original one, has been proposed. A similar approach can be adopted to investigate the optimization of the XHP formula, with the objective to remove or replace one or both animal ingredients. An artificial substitute already exists for C. bovis. It would be useful to determine if the Moschus component can be removed or substituted, without compromising the efficacy of the formula. Personally, I believe that the time has come to abandon the use of endanger animal components of medical preparations. Apparently, there exists an “artificial musk” prepared by adding nitric acid to oil of amber and a “Moschus factitius” corresponding to trinitro-t-butyl-toluene, but these artificial ingredients have not been extensively developed thus far. As illustrated in [Figure 5], modulation of the initial XHP formula can lead to new therapeutic extracts endowed with novel or alternative properties, as it is the case with the Korean medicine therapy HAD-B, derived from XHP. Alternatively, a component-based approach could lead to the identification of efficient new drug combinations.
|Figure 5: Research principle to illustrate how the 4-component traditional Chinese medicine Xihuang pill can be redesigned to generate novel extracts and natural products. The removal of the animal ingredients would give a plant product combining C. myrrha and B. carteri extracts. Alternatively, new plant extracts (Xx) can be added to generate novel medicinal products, as it was the case for the Korean medicine HangAmDan-B. These traditional medicinal products can then be deconvoluted to identify new chemical substances and/or drug combinations use for the management of cancer, to inhibit tumor growth, or to protect nontumor cells|
Click here to view
According to the TCM principles, the main patterns appearing in cancer are blood stasis, phlegm, and toxic heat, which could be associated with the accumulated hard tumor mass, the swollen inflamed tumor environment, and the spreading of the tumor, respectively, as represented in [Figure 2]. In other words, the objective is to balance Qi, Xue, Yin, and Yang, to eliminate phlegm and to remove dampness. The two plant ingredients of XHP, Boswellia and Commiphora, are intended to promote blood and vital energy circulation. They should contribute also to reduce swelling and pain. In parallel, the two animal-derived products complement the effect, preventing blood stagnation (musk) and clearing toxic heat (bezoar). Pathogenic heat and toxins are akin to the inflammatory factors. The combination of the four ingredients is expected to provide a global protection. However, a TCM like XHP is usually not intended to treat cancer directly, but essentially as a support to a treatment with conventional therapies such as chemo- or radiotherapy. As such, XHP can be useful to reduce side effects induced by cytotoxic drugs or radiations. The TCM product is intended to tonify the body to restore vital energy, to clear heat, and to stimulate the flow. In this context, XHP with its capacity to protect cells from damages and to activate the immune system could be a profitable supportive remedy, to improve the quality of life related to drug side effects. The objective is to strengthen and rebalance the body's yin and yang. However, it is important to underline that it is a supportive therapeutic agent, not a medicine for primary treatment of cancer. An add-on therapy, safe and useful to address the symptoms of patients with cancer. The efficacy of XHP is not sufficiently proven according to the standards of evidence-based Western medicine, but it is popular as a complementary and alternative medicine among the general public in Several countries.
Unsurprisingly, the mechanism of action of XHP is multifactorial, due to the presence of several active compounds. The TCM product exerts both direct action on tumor cells and effects on the tumor microenvironment. The antitumor activity of XHP has been exemplified in several types of cancers, mainly breast and colorectal cancers, as discussed here. It is difficult to summarize the mechanism of action because multiple components are implicated. Nevertheless, we can delineate at least three branches [Figure 3]. XHP affects the Pi3K/Akt/mTor pathway, inhibiting phosphorylation of these mediators as well as the tumor suppressor FOXO1 which expression is upregulated on XHP treatment. As a consequence, activation of nuclear FOXO1 leads to a transcriptional activation of key genes implicated in cell cycle arrest and cell death. Pi3K/Akt/mTor inhibition also impacts the nuclear accumulation of NFκB. In parallel, XHP suppresses inflammation via regulation of the MAPK signaling pathway implicating ERK1/2, p38, and JNK and subsequent downregulation of the transcription factor AP-1 via its components c-Fos/c-Jun. Moreover, XHP reduces activation of NFκB and STAT3 signaling to promote an improve antitumor immunity response, via the recruitment and the restoration of the immuno-suppressing activity of CD8+ T cells. This is a simplified view of the mechanism of action of XHP [Figure 3]. The global mechanism must be considerably more complex with multiple crossing molecular pathways because XHP also interferes with angiogenesis (vascular endothelial growth factor pathway), invasion and metastasis (epithelial–mesenchymal transition), drug transport, etc. XHP represents a combination of natural bioactive molecules useful to combat cancer via different mechanisms, both to inhibit the proliferation of tumor cells and to protect nontumor cells from damages induced by chemo- or radiotherapy. This literature survey provides further pharmacological groundwork for developing XHP as an adjunct for the treatment of solid tumors.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Guo Q, Lin J, Liu R, Gao Y, He S, Xu X, et al
. Review on the applications and molecular mechanisms of Xihuang pill in tumor treatment. Evid Based Complement Alternat Med 2015;2015:854307.
Yu D, An GY. Clinical Effects of Xihuang Pill Combined with Chemotherapy in Patients with Advanced Colorectal Cancer. Evid Based Complement Alternat Med 2017;2017:5936086.
Pan G, Wang W, Wang L, Zhang F, Yin X, Wang J, et al
. Anti-breast cancer effects and mechanisms of Xihuang pill on human breast cancer cell lines. J Tradit Chin Med 2013;33:770-8.
Zheng W, Han S, Jiang S, Pang L, Li X, Liu X, et al
. Multiple effects of Xihuang pill aqueous extract on the Hs578T triple-negative breast cancer cell line. Biomed Rep 2016;5:559-66.
He LJ, Li JS, Chen X, Zhang HT, Zhu XG, Zhang XD, et al
. Effect of serum containing Xihuang pill on proliferation of human breast cancer cell line MDA-MB-435 and MCF-7 cells. Zhongguo Zhong Yao Za Zhi 2018;43:2784-8.
Zhang J, Zhang FH, Yang SJ. Anticancer effects of Xi Huang capsule on breast cancer in vivo
. Trad Med Res 2017;2:33-40.
Hao J, Jin Z, Zhu H, Liu X, Mao Y, Yang X, et al
. Antiestrogenic Activity of the Xi-Huang Formula for Breast Cancer by Targeting the Estrogen Receptor α. Cell Physiol Biochem 2018;47:2199-215.
Su L, Jiang Y, Xu Y, Li X, Gao W, Xu C, et al
. Xihuang pill promotes apoptosis of Treg cells in the tumor microenvironment in 4T1 mouse breast cancer by upregulating MEKK1/SEK1/JNK1/AP-1 pathway. Biomed Pharmacother 2018;102:1111-9.
Ma J, Wang YY, Yang W, Guan S, Zeng CQ, Gao WB, et al
. Experimental study on anti-tumor effect of Xihuang pill and its immune clearance function. Zhongguo Zhong Yao Za Zhi 2014;39:1499-501.
Mao D, Feng L, Huang S, Zhang S, Peng W, Zhang S. Meta-analysis of Xihuang pill efficacy when combined with chemotherapy for treatment of breast cancer. Evid Based Complement Alternat Med 2019;2019:3502460.
Guo Q, Xu X, He S, Yuan Y, Chen S, Hua B. Xihuang pills enhance the tumor treatment efficacy when combined with chemotherapy: A meta-analysis and systematic review. J Cancer Res Ther 2018;14:S1012-S1018.
Wang M, Meng JY, He SF. Xihuang Pill () induces mesenchymal-epithelial transition and inhibits loss of apical-basal polarity in colorectal cancer cell through regulating ZEB1-SCRIB loop. Chin J Integr Med 2014;20:751-7.
Tang YJ, Chen G. Experimental study on anti-acute leukemia with Chinese traditional drugs. Zhong Xi Yi Jie He Za Zhi 1990;10:734-6, 710.
Shao M, He Z, Yin Z, Ma P, Xiao Q, Song Y, et al
. Xihuang pill induces apoptosis of human glioblastoma U-87 MG cells via targeting ROS-mediated Akt/mTOR/FOXO1 pathway. Evid Based Complement Alternat Med 2018;2018:6049498.
Shi F, Zhang Y, Yang G, Guo T, Feng N. Preparation of a micro/nanotechnology based multi-unit drug delivery system for a Chinese medicine Niuhuang Xingxiao Wan and assessment of its antitumor efficacy. Int J Pharm 2015;492:244-7.
Yoon SW, Jeong JS, Kim JH, Aggarwal BB. Cancer prevention and therapy: integrating traditional Korean medicine into modern cancer care. Integr Cancer Ther 2014;13:310-31.
Yoo HS, Lee HJ, Kim JS, Yoon J, Lee GH, Lee YW, et al
. A toxicological study of HangAmDan-B in mice. J Acupunct Meridian Stud 2011;4:54-60.
Bae K, Kim E, Kong JS, Kim J, Park SJ, Jun HJ, et al
. Integrative cancer treatment may have a survival benefit in patients with lung cancer: A retrospective cohort study from an integrative cancer center in Korea. Medicine (Baltimore) 2019;98:e16048.
Kang HJ, Park JH, Yoo HS, Park YM, Cho CK, Kang IC. Effects of HAD-B1 on the proliferation of A549 cisplatin-resistant lung cancer cells. Mol Med Rep 2018;17:6745-51.
Kang HJ, Kim J, Cho SH, Park SJ, Yoo HS, Kang IC. Inhibitory Effects of HangAmDan-B1 (HAD-B1) combined with afatinib on H1975 lung cancer cell-bearing mice. Integr Cancer Ther 2019;18:1534735419830765.
Park HR, Lee EJ, Moon SC, Chung TW, Kim KJ, Yoo HS, et al
. Inhibition of lung cancer growth by HangAmDan-B is mediated by macrophage activation to M1 subtype. Oncol Lett 2017;13:2330-6.
Kim B, Kim EY, Lee EJ, Han JH, Kwak CH, Jung YS, et al
. Panax notoginseng
inhibits tumor growth through activating macrophage to M1 polarization. Am J Chin Med 2018;46:1369-85.
Bang JY, Kim KS, Kim EY, Yoo HS, Lee YW, Cho CK, et al
. Anti-angiogenic effects of the water extract of HangAmDan (WEHAD), a Korean traditional medicine. Sci China Life Sci 2011;54:248-54.
Choi YJ, Shin DY, Lee YW, Cho CK, Kim GY, Kim WJ, et al
. Inhibition of cell motility and invasion by HangAmDan-B in NCI-H460 human non-small cell lung cancer cells. Oncol Rep 2011;26:1601-8.
Kim KH, Kwon YK, Cho CK, Lee YW, Lee SH, Jang SG, et al
. Galectin-3-independent Down-regulation of GABABR1 due to Treatment with Korean Herbal Extract HAD-B Reduces Proliferation of Human Colon Cancer Cells. J Pharmacopuncture 2012;15:19-30.
Lee DH, Kim SS, Seong S, Woo CR, Han JB. A case of metastatic bladder cancer in both lungs treated with Korean medicine therapy alone. Case Rep Oncol 2014;7:534-40.
Kunnumakkara AB, Banik K, Bordoloi D, Harsha C, Sailo BL, Padmavathi G, et al
. Googling the Guggul (Commiphora
) for Prevention of Chronic Diseases. Front Pharmacol 2018;9:686.
Cunningham AB, Brinckmann JA, Kulloli RN, Schippmann U. Rising trade, declining stocks: The global gugul (Commiphora wightii
) trade. J Ethnopharmacol 2018;223:22-32.
Tripathi YB, Reddy MM, Pandey RS, Subhashini J, Tiwari OP, Singh BK, et al
. Anti-inflammatory properties of BHUx, a polyherbal formulation to prevent atherosclerosis. Inflammopharmacology 2004;12:131-52.
Tripathi YB. BHUx: A patented polyherbal formulation to prevent hyperlipidemia and atherosclerosis. Recent Pat Inflamm Allergy Drug Discov 2009;3:49-57.
Erfanfar F, Montaseri H, Mohagheghzadeh A, Hosseinkhani A. Myrrh a traditional medicine or a multipurpose pharmaceutical excipient. Trends Phar Sci 2015;1:207-12.
Tafti LD, Shariatpanahi SM, Damghani MM, Javadi B. Traditional Persian topical medications for gastrointestinal diseases. Iran J Basic Med Sci 2017;20:222-41.
Jahandideh M, Hajimehdipoor H, Mortazavi SA, Dehpour A, Hassanzadeh G. Evaluation of the Wound Healing Activity of a Traditional Compound Herbal Product Using Rat Excision Wound Model. Iran J Pharm Res 2017;16:153-63.
Moussaieff A, Fride E, Amar Z, Lev E, Steinberg D, Gallily R, et al
. The Jerusalem Balsam: From the Franciscan monastery in the old city of Jerusalem to Martindale 33. J Ethnopharmacol 2005;101:16-26.
Labrude P. New thoughts on the hypothesis of the origin of the balm of commander of pernes: It originated from the balm of Jerusalem. Vesalius 2006;12:37-40.
Storck J. The Baume du chevalier de St-victor otherwise the Baume du commandeur de pernes. Rev Hist Pharm (Paris) 1998;46:439-46.
Barana H, Pietryja MJ, Kronsteinera C, Kepplinger B. Jerusalem balsam lowers kynurenic acid formation: Anin vitro
study. J Trad Med Clin Naturopathy 2017;6:224.
Ben-Yehoshua S, Borowitz C, Hanus LO. Frankincense, myrrh and balm of Gilead: Ancient spices of southern Arabia and Judea. Hortic Rev 2011;39:1-76.
Mothana RA, Lindequist U, Gruenert R, Bednarski PJ. Studies of thein vitro
anticancer, antimicrobial and antioxidant potentials of selected Yemeni medicinal plants from the island Soqotra. BMC Complement Altern Med 2009;9:7.
de Rapper S, Van Vuuren SF, Kamatou GP, Viljoen AM, Dagne E. The additive and synergistic antimicrobial effects of select frankincense and myrrh oils – A combination from the pharaonic pharmacopoeia. Lett Appl Microbiol 2012;54:352-8.
Su S, Duan J, Chen T, Huang X, Shang E, Yu L, et al
. Frankincense and myrrh suppress inflammation via regulation of the metabolic profiling and the MAPK signaling pathway. Sci Rep 2015;5:13668.
Su S, Hua Y, Wang Y, Gu W, Zhou W, Duan JA, et al
. Evaluation of the anti-inflammatory and analgesic properties of individual and combined extracts from Commiphora myrrha
, and Boswellia carterii
. J Ethnopharmacol 2012;139:649-56.
Xu C, Lu X, Liu W, Chen A, Meng G, Zhang H, et al
. CD8+T cells mediate the antitumor activity of frankincense and myrrh in hepatocellular carcinoma. J Transl Med 2018;16:132.
Zhu XF, Luo J, Guan YM, Yu YT, Jin C, Zhu WF, et al
. Effects of frankincense and myrrh essential oil on transdermal absorptionin vitro
of chuanxiong and penetration mechanism of skin blood flow. Zhongguo Zhong Yao Za Zhi 2017;42:680-5.
Guan YM, Tao L, Zhu XF, Zang ZZ, Jin C, Chen LH. Effects of frankincense and myrrh essential oil on transdermal absorption of ferulic acid in chuanxiong. Zhongguo Zhong Yao Za Zhi 2017;42:3350-5.
Lv L, Yan GY, Zhao YL, He XJ, Jiang X, Zhuo YQ, et al
. Investigation of the dermal sensitizing potential of traditional medical extracts in local lymph node assays. Exp Biol Med (Maywood) 2009;234:306-13.
Chen Y, Zhou C, Ge Z, Liu Y, Liu Y, Feng W, et al
. Composition and potential anticancer activities of essential oils obtained from myrrh and frankincense. Oncol Lett 2013;6:1140-6.
Germano A, Occhipinti A, Barbero F, Maffei ME. A pilot study on bioactive constituents and analgesic effects of MyrLiq®, a Commiphora myrrha
extract with a high furanodiene content. Biomed Res Int 2017;2017:3804356.
Shen T, Li GH, Wang XN, Lou HX. The genus Commiphora
: A review of its traditional uses, phytochemistry and pharmacology. J Ethnopharmacol 2012;142:319-30.
Hanus LO, Rezanka T, Dembitsky VM, Moussaieff A. Myrrh-Commiphora
chemistry. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2005;149:3-27.
Xu Y, Guan J, Xu J, Chen S, Sun G. Z-Guggulsterone attenuates glucocorticoid-induced osteoporosis through activation of Nrf2/HO-1 signaling. Life Sci 2019;224:58-66.
Liu T, Liu M, Zhang T, Liu W, Xu H, Mu F, et al
. Z-Guggulsterone attenuates astrocytes-mediated neuroinflammation after ischemia by inhibiting toll-like receptor 4 pathway. J Neurochem 2018;147:803-15.
Che X, Park KC, Park SJ, Kang YH, Jin HA, Kim JW, et al
. Protective effects of guggulsterone against colitis are associated with the suppression of TREM-1 and modulation of macrophages. Am J Physiol Gastrointest Liver Physiol 2018;315:G128-39.
Liu FG, Hu WF, Wang JL, Wang P, Gong Y, Tong LJ, et al
. Z-Guggulsterone produces antidepressant-like effects in mice through activation of the BDNF signaling pathway. Int J Neuropsychopharmacol 2017;20:485-97.
Miller CN, Samuels JS, Azhar Y, Parmar A, Shashidharamurthy R, Rayalam S. Guggulsterone activates adipocyte beiging through direct effects on 3T3-L1 adipocytes and indirect effects mediated through RAW264.7 Macrophages. Medicines (Basel) 2019;6. pii: E22.
Bhat AA, Prabhu KS, Kuttikrishnan S, Krishnankutty R, Babu J, Mohammad RM, et al
. Potential therapeutic targets of guggulsterone in cancer. Nutr Metab (Lond) 2017;14:23.
Yamada T, Sugimoto K. Guggulsterone and its role in chronic diseases. Adv Exp Med Biol 2016;929:329-61.
Xu HB, Fu J, Huang F, Yu J. Guggulsterone sensitized drug-resistant human hepatocarcinoma cells to doxorubicin through a Cox-2/P-gp dependent pathway. Eur J Pharmacol 2017;803:57-64.
Mahmoud AM, Germoush MO, Al-Anazi KM, Mahmoud AH, Farah MA, Allam AA. Commiphora
molmol protects against methotrexate-induced nephrotoxicity by up-regulating Nrf2/ARE/HO-1 signaling. Biomed Pharmacother 2018;106:499-509.
Lee D, Kim T, Kim KH, Ham J, Jang TS, Kang KS, et al
. Evaluation of guggulsterone derivatives as novel kidney cell protective agents against cisplatin-induced nephrotoxicity. Bioorg Med Chem Lett 2017;27:3156-61.
Liu X, Chen W, Liu Q, Dai J. Abietic acid suppresses non-small-cell lung cancer cell growth via blocking IKKβ/NF-κB signaling. Onco Targets Ther 2019;12:4825-37.
Hsieh YS, Yang SF, Hsieh YH, Hung CH, Chu SC, Yang SH, et al
. The inhibitory effect of abietic acid on melanoma cancer metastasis and invasivenessIn vitro
and In vivo
. Am J Chin Med 2015;43:1697-714.
Kang S, Zhang J, Yuan Y. Abietic acid attenuates IL-1β-induced inflammation in human osteoarthritis chondrocytes. Int Immunopharmacol 2018;64:110-5.
Thummuri D, Guntuku L, Challa VS, Ramavat RN, Naidu VG. Abietic acid attenuates RANKL induced osteoclastogenesis and inflammation associated osteolysis by inhibiting the NF-KB and MAPK signaling. J Cell Physiol 2018;234:443-53.
Park JY, Lee YK, Lee DS, Yoo JE, Shin MS, Yamabe N, et al
. Abietic acid isolated from pine resin (Resina Pini) enhances angiogenesis in HUVECs and accelerates cutaneous wound healing in mice. J Ethnopharmacol 2017;203:279-87.
Gao Y, Zhaoyu L, Xiangming F, Chunyi L, Jiayu P, Lu S, et al
. Abietic acid attenuates allergic airway inflammation in a mouse allergic asthma model. Int Immunopharmacol 2016;38:261-6.
Hjortness MK, Riccardi L, Hongdusit A, Ruppe A, Zhao M, Kim EY, et al
. Abietane-type diterpenoids inhibit protein tyrosine phosphatases by stabilizing an inactive enzyme conformation. Biochemistry 2018;57:5886-96.
Ukiya M, Kawaguchi T, Ishii K, Ogihara E, Tachi Y, Kurita M, et al
. Cytotoxic activities of amino acid-conjugate derivatives of abietane-type diterpenoids against human cancer cell lines. Chem Biodivers 2013;10:1260-8.
Xu H, Liu L, Fan X, Zhang G, Li Y, Jiang B. Identification of a diverse synthetic abietane diterpenoid library for anticancer activity. Bioorg Med Chem Lett 2017;27:505-10.
Gowda R, Inamdar GS, Kuzu O, Dinavahi SS, Krzeminski J, Battu MB, et al
. Identifying the structure-activity relationship of leelamine necessary for inhibiting intracellular cholesterol transport. Oncotarget 2017;8:28260-77.
Kumar R, Singh S, Saksena AK, Pal R, Jaiswal R, Kumar R. Effect of Boswellia serrata
extract on acute inflammatory parameters and tumor necrosis factor-α in complete freund's adjuvant-induced animal model of rheumatoid arthritis. Int J Appl Basic Med Res 2019;9:100-6.
Frank MB, Yang Q, Osban J, Azzarello JT, Saban MR, Saban R, et al
. Frankincense oil derived from Boswellia carterii
induces tumor cell specific cytotoxicity. BMC Complement Altern Med 2009;9:6.
Reis D, Jones TT. Frankincense essential oil as a supportive therapy for cancer-related fatigue: A case study. Holist Nurs Pract 2018;32:140-2.
Hosain NA, Ghosh R, Bryant DL, Arivett BA, Farone AL, Kline PC. Isolation, structure elucidation, and immunostimulatory activity of polysaccharide fractions from Boswellia carterii
frankincense resin. Int J Biol Macromol 2019;133:76-85.
Schmiech M, Lang SJ, Werner K, Rashan LJ, Syrovets T, Simmet T. Comparative analysis of pentacyclic triterpenic acid compositions in oleogum resins of different Boswellia
species and theirIn vitro
cytotoxicity against treatment-resistant human breast cancer cells. Molecules 2019;24. pii: E2153.
Wang S, Wang H, Sun B, Li D, Wu J, Li J, et al
. Acetyl-11-keto-β-boswellic acid triggers premature senescence via induction of DNA damage accompanied by impairment of DNA repair genes in hepatocellular carcinoma cellsin vitro
and in vivo
. Fundam Clin Pharmacol 2020;34:65-76.
Li W, Liu J, Fu W, Zheng X, Ren L, Liu S, et al
. 3-O-acetyl-11-keto-β-boswellic acid exerts anti-tumor effects in glioblastoma by arresting cell cycle at G2/M phase. J Exp Clin Cancer Res 2018;37:132.
Conti S, Vexler A, Edry-Botzer L, Kalich-Philosoph L, Corn BW, Shtraus N, et al
. Combined acetyl-11-keto-β-boswellic acid and radiation treatment inhibited glioblastoma tumor cells. PLoS One 2018;13:e0198627.
Bini Araba A, Ur Rehman N, Al-Araimi A, Al-Hashmi S, Al-Shidhani S, Csuk R, et al
. New derivatives of 11-keto-β-boswellic acid (KBA) induce apoptosis in breast and prostate cancers cells. Nat Prod Res 2019:1-10.
Schmidt C, Loos C, Jin L, Schmiech M, Schmidt CQ, Gaafary ME, et al
. Acetyl-lupeolic acid inhibits Akt signaling and induces apoptosis in chemoresistant prostate cancer cellsin vitro
and in vivo
. Oncotarget 2017;8:55147-61.
Byler KG, Setzer WN. Protein Targets of Frankincense: A Reverse Docking Analysis of Terpenoids from Boswellia
oleo-gum resins. Medicines (Basel) 2018;5. pii: E96.
Wang YG, Ren J, Ma J, Yang JB, Ji T, Wang AG. Bioactive cembrane-type diterpenoids from the gum-resin of Boswellia carterii
. Fitoterapia 2019;137:104263.
Alluri VK, Dodda S, Kilari EK, Golakoti T, Sengupta K. Toxicological assessment of a standardized Boswellia serrata
Gum Resin Extract. Int J Toxicol 2019;38:423-35.
Majeed M, Majeed S, Narayanan NK, Nagabhushanam K. A pilot, randomized, double-blind, placebo-controlled trial to assess the safety and efficacy of a novel Boswellia serrata
extract in the management of osteoarthritis of the knee. Phytother Res 2019;33:1457-68.
Shen T, Lou HX. Bioactive constituents of myrrh and frankincense, two simultaneously prescribed gum resins in Chinese traditional medicine. Chem Biodivers 2008;5:540-53.
Pan T, Wang H, Hu C, Sun Z, Zhu X, Meng T, et al
. Species delimitation in the genus Moschus
(Ruminantia: Moschidae) and its high-plateau origin. PLoS One 2015;10:e0134183.
Li Y, Zhang T, Qi L, Yang S, Xu S, Cha M, et al
. Microbiota changes in the musk gland of male forest musk deer during musk maturation. Front Microbiol 2018;9:3048.
Tao W, Xu X, Wang X, Li B, Wang Y, Li Y, et al
. Network pharmacology-based prediction of the active ingredients and potential targets of Chinese herbal Radix Curcumae formula for application to cardiovascular disease. J Ethnopharmacol 2013;145:1-10.
Chen JH, Ho HO, Yen KY, Yan LL. Hepatoprotection by “dangqui-long-hwei-wan” in male mice. Am J Chin Med 2000;28:115-21.
Zhao L, Zhang Y, Xu ZX. Clinical effect and experimental study of xijian tongshuan pill. Zhongguo Zhong Xi Yi Jie He Za Zhi 1994;14:71-3, 67.
Wang N, Deng Y, Wei W, Song L, Wang Y. Serum containing Tongqiaohuoxue decoction suppresses glutamate-induced PC12 cell injury. Neural Regen Res 2012;7:1125-31. [Full text]
Xu ML, Zheng ZY, Xia YJ, Liu EY, Chan SK, Hu WH, et al
. Shexiang baoxin pill, a formulated Chinese herbal mixture, induces neuronal differentiation of PC12 cells: A signaling triggered by activation of protein kinase a. Front Pharmacol 2019;10:1130.
Zhang Z, Cao Y, Yuan Q, Zhang A, Zhang K, Wang Z. Shexiang-wulong pills attenuate rheumatoid arthritis by alleviating inflammation in a mouse model of collagen-induced arthritis. Evid Based Complement Alternat Med 2019;2019:5308405.
Zhen H, Zhang Y, Fang Z, Huang Z, You C, Shi P. Toona sinensis and Moschus
decoction induced cell cycle arrest in human cervical carcinoma HeLa cells. Evid Based Complement Alternat Med 2014;2014:121276.
Du Y, Gu X, Meng H, Aa N, Liu S, Peng C, et al
. Muscone improves cardiac function in mice after myocardial infarction by alleviating cardiac macrophage-mediated chronic inflammation through inhibition of NF-κB and NLRP3 inflammasome. Am J Transl Res 2018;10:4235-46.
Guo YJ, Luo SH, Tang MJ, Zhou ZB, Yin JH, Gao YS, et al
. Muscone exerts protective roles on alcohol-induced osteonecrosis of the femoral head. Biomed Pharmacother 2018;97:825-32.
Yu L, Wang N, Zhang Y, Wang Y, Li J, Wu Q, et al
. Neuroprotective effect of muscone on glutamate-induced apoptosis in PC12 cells via antioxidant and Ca (2+) antagonism. Neurochem Int 2014;70:10-21.
Dong J, Li H, Bai Y, Wu C. Muscone ameliorates diabetic peripheral neuropathy through activating AKT/mTOR signalling pathway. J Pharm Pharmacol 2019;71:1706-13.
Yang LQ, Li RY, Yang XY, Cui QF, Wang FY, Lin GQ, et al
. Co-administration of shexiang baoxin pill and chemotherapy drugs potentiated cancer therapy by vascular-promoting strategy. Front Pharmacol 2019;10:565.
Xiang D, Yang J, Liu Y, He W, Zhang S, Li X, et al
. Calculus bovis
sativus improves bile acid homeostasis via farnesoidxreceptor-mediated signaling in rats with estrogen-induced cholestasis. Front Pharmacol 2019;10:48.
Shi Y, Xiong J, Sun D, Liu W, Wei F, Ma S, et al
. Simultaneous quantification of the major bile acids in artificial Calculus bovis
by high-performance liquid chromatography with precolumn derivatization and its application in quality control. J Sep Sci 2015;38:2753-62.
Liu WX, Cheng XL, Guo XH, Hu XR, Wei F, Ma SC. Identification of Calculus bovis
and its mixed varieties by ultra-high-performance liquid chromatography/quadrupole time-of-flight mass spectrometry (UHPLC-Q/TOF-MS) combined with the principal component analysis (PCA) method. J Pharm Biomed Anal 2020;179:112979.
Li CX, Wang XQ, Cheng FF, Yan X, Luo J, Wang QG. Hyodeoxycholic acid protects the neurovascular unit against oxygen-glucose deprivation and reoxygenation-induced injury in vitro
. Neural Regen Res 2019;14:1941-9.
] [Full text]
Wang Y, Jiang H, Huang H, Xie Y, Zhao Y, You X, et al
. Determination of neuroprotective oxysterols in Calculus bovis
, human gallstones, and traditional Chinese medicine preparations by liquid chromatography with mass spectrometry. J Sep Sci 2015;38:796-803.
Goossens JF, Bailly C. Ursodeoxycholic acid and cancer: From chemoprevention to chemotherapy. Pharmacol Ther 2019;203:107396.
Khan AY, Ahmed QU, Narayanamurthy V, Razali S, Asuhaimi FA, Saleh MS, et al
. Anticancer activity of grassy Hystrix brachyura bezoar and its mechanisms of action: Anin vitro
based study. Biomed Pharmacother 2019;114:108841.
Firus Khan AY, Abdullah Asuhaimi F, Jalal TK, Roheem FO, Natto HA, Johan MF, et al
. Hystrix brachyura Bezoar Characterization, Antioxidant Activity Screening, and Anticancer Activity on Melanoma Cells (A375): A Preliminary Study. Antioxidants (Basel) 2019;8. pii: E39.
Huang L, Zhang Y, Zhang X, Chen X, Wang Y, Lu J, et al
. Therapeutic Potential of Pien-Tze-Huang: A Review on Its Chemical Composition, Pharmacology, and Clinical Application. Molecules 2019;24. pii: E3274.
Zheng H, Wang X, Zhang Y, Chen L, Hua L, Xu W. Pien-Tze-Huang ameliorates hepatic fibrosis via suppressing NF-κB pathway and promoting HSC apoptosis. J Ethnopharmacol 2019;244:111856.
Xiang Y, Guo Z, Zhu P, Chen J, Huang Y. Traditional Chinese medicine as a cancer treatment: Modern perspectives of ancient but advanced science. Cancer Med 2019;8:1958-75.
Hillson RM. Gold, frankincense and myrrh. J R Soc Med 1988;81:542-3.
Zhao M, Chen Y, Wang C, Xiao W, Chen S, Zhang S, et al
. Systems pharmacology dissection of multi-scale mechanisms of action of Huo-Xiang-Zheng-Q formula for the treatment of gastrointestinal diseases. Front Pharmacol 2018;9:1448.
Liu R, Wang F, Huang Q, Duan JA, Liu P, Shang E, et al
. Available sustainable alternatives replace endangered animal horn based on their proteomic analysis and bio-effect evaluation. Sci Rep 2016;6:36027.
Wang J, Li Y, Yang Y, Chen X, Du J, Zheng Q, et al
. A new strategy for deleting animal drugs from traditional Chinese medicines based on modified Yimusake formula. Sci Rep 2017;7:1504.
Zhang JH, Zhu Y, Fan XH, Zhang BL. Efficacy-oriented compatibility for component-based Chinese medicine. Acta Pharmacol Sin 2015;36:654-8.
Wang S, Long S, Wu W. Application of Traditional Chinese Medicines as Personalized Therapy in Human Cancers. Am J Chin Med 2018;46:953-70.
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]