Chinese herbal medicine exhibits anticancer properties via eight cancer hallmarks

INTRODUCTION

Cancer is a phenomenon when abnormal cells begin to grow out of control and end up in spreading to a distant region. Worldwide, the incidence of cancers is among the leading causes of morbidity and mortality, with approximately 14 million new cases and 8.2 million cancer-related deaths in 2012. The number of new cases expected to increase to 22 million within the next two decades (Stewart and Wild, 2014). Anticancer drugs are an important means to mitigate the impact of cancer mortality. Cancer treatment can be categorized into conventional (chemotherapy, radiation therapy, and surgery) and modern therapies (molecularly targeted therapy and immunotherapy). Lately, a holistic way of cancer treatment receives equal attention to treat this deadly disease. As such, the Chinese herbal medicine (CHM) plays a significant role in cancer treatment. Asian countries such as China, Japan, and Korea have been using CHM for thousands of years mainly because they are naturally available and less toxic to normal cells (Mishra and Tiwari, 2011).

A very long history of CHM practice in cancer therapy has started in the last 2,000 years. An important proof was documented first in the classical works, such as The Yellow Emperor’s Inner Canon and The Classic of Medical Problems (Liu et al., 2015; Wang, 2003). CHM practitioners follow merely the same approach to treat or manage cancer patients. The treatment is focused on strengthening body resistance, eliminating pathogens, and treating both the manifestation and root cause. Apart from that, they also practice treating the same disease with different methods and treating different diseases with the same method based on symptoms and signs. For example, treating patients with the common cold is not identical in CHM principle. Common cold is usually further divided into two types of syndrome: either caused by wind heat or wind cold. Herbs, pungent in flavor and cool in property, can relieve the wind heat, whereas herbs, pungent in flavor and warm in property, relieves wind cold. Next, chronic dysentery and prolapse of the rectum and uterus are two different diseases, but both exhibit the same syndrome of sinking Middle-Qi. Therefore, according to the CHM concept, both can be treated with identical therapeutic to elevate Middle-Qi (Chan and Lee, 2002). These concepts of diagnosis and treatments have been proved by clinical practice (Liu et al., 2015).

Many CHM-derived anticancer drugs have been used in Western medicine. Between 1940 and 2014, around 49% of approved cancer chemotherapeutic drugs are derived from natural products (Newman and Cragg, 2016). Vinblastine, vincristine, paclitaxel, camptothecin, and epipodophyllotoxin are few examples of plant-derived CHMs that have been used in Western medicine (Pereira et al., 2012). Millions of people around the world have been accepting and using CHM. It is not only used as standalone therapy but often used as an adjuvant or in combination with other therapies to improve health. Undoubtedly, CHM is a valuable resource to discover novel anticancer agents.

ROLE OF CHM IN TREATING VARIOUS DISEASES

CHM utilizes a unique approach by combining the advantages of physiological and holistic theories. Its prime method to heal patients is by modulating and exploiting interactions between the patients and their environment. Therefore, it is important to understand the patient’s environment and herbal formulae in CHM perspectives. In this holistic approach, the human’s health system is explained based on ancient theory “Qi,” which said that the life force energy is carried in the body via meridians. Qi is said to be responsible for physiological functions. Any disruption in Qi ultimately results in disharmony in the body such as disruptions to homeostasis and diseases. In the event of disruption in Qi, CHM aims to address these imbalances to enable the body to heal itself (Li and Zhao, 2012).

The principle of CHM explains that herbal formulae consist of four elements. First, the monarch (Jun) that aims at the cardinal pathological of a disease. Second, the minister (Chen) that helps monarch to treat secondary symptoms. Next, assistant (Zuo) and servant (Shi) both are mainly coordinate the formulae, facilitate the first two elements, and decrease their side effects. All the elements eventually help each other to maintain harmonious of body to achieve an ideal therapeutic outcome (Zhou et al., 2016).

CHM was used in various diseases such as hypertension (Lu et al., 2007), coronary heart (Jian et al., 2010), and rheumatoid arthritis (Lu et al., 2010) or biomedical conditions such as neuroendocrine–immune network (Li et al., 2007) including cancer for more than hundred years. Today, there are many options available to treat cancer including surgery, radiation, chemotherapy, immunotherapy, hormonal therapy, targeted therapy, and many more. Among them, herbal medicine is emerging as an important alternative therapy in cancer treatment. This ancient therapy not only plays a key role in prevention but also has been reported to enhance pain management and to improve the lifespan (Ritenbaugh et al., 2012).

A special characteristic of CHM is utilizing the precision medicine concept. The ideology of this treatment is based on the right patient, right diagnosis, and right treatment with the right amount of drug to treat the disease efficiently. Even though this concept is well established in CHM practice, its role as precision medicine was only emerged recently worldwide. A great evolution started when President Obama announced the launch of new Precision Medicine Initiative (Fox, 2015) in the State of the Union address, in which he has mentioned that every patient is unique, and it is essential that they are tailored with individual treatment. Currently, efforts are taken to evaluate CHM’s efficacy in cancer treatment by utilizing pharmaceutical-based approaches to reveal the mode of actions at molecular levels.

MODE OF ACTION: HOW CHM REGRESSES CANCER

A large number of studies show that the multitargeted nature of CHM may comprise multiple herbs and components acting simultaneously on multiple cellular mechanisms and molecular targets that derived from its biological compounds (Yoo et al., 2018). CHM contains many active compounds that can target the eight hallmarks of cancer. The eight hallmarks of cancer shown in Figure 1 are inhibiting proliferative signaling, inducing growth suppressors, inducing cell death, inhibiting replicative immortality, antiangiogenesis, inhibition of invasion and metastasis, energy metabolism, and immune destructive (Hanahan and Weinberg, 2011).

Antiangiogenesis

Angiogenesis is a process to form a new blood vascular system around the cells and tissues. When normal cells require nutrient and oxygen to remove metabolic waste products, angiogenesis will occur. In the normal human body, during embryogenesis, formation of new endothelial cells and surrounded vascular allows sprouting of new vessels from the existing ones. Angiogenesis is constitutively activated in normal cells during wound healing and female menstrual cycle. However, in highly proliferative cancer cells, angiogenesis is always activated to support neoplastic growth and tumor progression (Hanahan and Folkman, 1996).

Angiogenesis in tumor environment ensures continuous supply of nutrient and oxygen and elimination of carbon dioxide and waste materials from neoplastic cells. Pro- and antiangiogenesis factors from tumor microenvironment control the formation of vascularization. As shown in Figure 2, binding of pro-angiogenesis factors to cell receptors induces growth, proliferation, and formation of tubules, whereas binding of antiangiogenesis factors activates caspases, which leads to apoptotic cell death. The well-known angiogenesis inducer is vascular endothelial growth factor (VEGF). Basic fibroblast growth factor (bFGF and FGF2), angiogenin, transforming growth factor (TGF)-α, TGF-β, tumor necrosis factor (TNF)-α, platelet-derived endothelial growth factor, granulocyte colony-stimulating factor, placental growth factor, interleukin-8, hepatocyte growth factor, and epidermal growth factors are among other commonly listed inducers (Mousa and Davis, 2016). Negative regulators such as thrombospondin, angiostatin, endostatin, interferon, platelet factor 4, prolactin 16-kd fragment, and tissue inhibitor of metalloproteinase-1, -2, and -3 also play a critical role in controlling angiogenesis (Nishida et al., 2006). When tumor cells demand nutrient and oxygen, angiogenesis is activated; angiogenic activators are upregulated, whereas negative regulators will be downregulated. A balance between these two types of markers is vital to control vascular homeostasis or angiogenesis.

CHM inhibits cancer development and progression by altering tumor microenvironment and by directly inhibiting angiogenesis and lymphangiogenesis. Extract from Ginkgo biloba was reported to show inhibitory effects in in vitro and in vivo against multiple cancers such as ovarian (Ye et al., 2007), breast (Papadopoulos et al., 2000), hepatocellular (Chao and Chu, 2004), and oral (Kim et al., 2005). Scutellaria barbata D. Don is another CHM that proved to suppress angiogenesis in colon cancer by downregulating VEGF-α (Wei et al., 2011). It has been used in clinical trials, revealed to be safe and well-tolerated, and showed promising clinical evidence against metastatic breast cancer patients (Perez et al., 2010). The Yangzheng Xiaoji (YZXJ) capsule, derived from a CHM formula, exhibited anticancer actions on primary hepatic carcinoma (Zhang et al., 2009). This capsule contains the following 16 ingredients: Panax ginseng C.A. Mey., Astragalus membranaceus (Fisch.) Bge.var. mongholicus (Bge.) Hsiao, Ligustrum lucidum Ait., Curcuma phaeocaulis Val., Ganodema lucidum, Gynostemma pentaphylla (Thunb) Mak, Atractylodes macrocephala Koidz., S. barbata D. Don, Oldenlandia diffusa (Willd.) Roxb., Poria cocos, Duchesnea indica Focke, Solanum lyratum Thunb., Artemisia scoparia (Bge.) Ki., Cynanchum paniculatum Kitag, Eupolyphaga sinensis Walker, and Gallus domesticus Brisson. YZXJ was demonstrated to inhibit angiogenesis by directly targeting endothelial cells and significantly affect endothelial tubule formation, migration, and cell matrix attachment (Jiang et al., 2012). Ginsenoside Rg3, a pure compound extracted from ginseng (Lu et al., 2009; Zheng et al., 2014), showed an antiangiogenic effect in colorectal cancer. It was executed by downregulating the expression of 22 pro-angiogenic-related genes (Tang et al., 2017). The antiangiogenesis effect of Rg3 was also reported in glioblastoma (Sun et al., 2016).

Figure 1. The hallmarks of cancer. This illustration encompasses the eight hallmarks of cancer proposed by Hanahan and Weinberg in 2011 (Hanahan and Weinberg, 2011). [Click here to view]

Inhibit invasion and metastasis

Tumor microenvironment is made up of complex non-malignant cells such as endothelial, pericytes, fibroblasts, and immune cells that surround cancer cells (Jia et al., 2012). The tumor environment largely depends on signals including tumor promoter and tumor suppressor produced from these various cells. CHM has been shown to control tumor environment by inhibiting tumor-promoting signals while inducing the production of cytokines to suppress tumor development. Matrix metalloproteinases (MMPs) are enzymes that activate tumor microenvironment to undergo metastasis, spreading of tumor cells from the primary sites. Highly expressed MMPs often result in poor clinical outcome due to cell invasiveness and metastasis (Sherman-Baust et al., 2003). Several studies showed CHM’s ability to inhibit MMP expression in cancer environment upon treatment. A standard formulation of Si-Jun-Zi-Tang (composed of four Chinese herbs: ginseng root, A. macrocephala, licorice root, and poria root) with the addition of Myristica fragrans and five-leaf akebia fruit (known as Yi-Qi-Fu-Sheng) has shown to initiate ERK1/2-dependent inhibition of MMP-2/9 expression. By selectively targeting ERK phosphorylation, this decoction modulates the REK/Mitogen-activated protein kinases (MAPK) pathway and its downstream factors (Deng et al., 2013). Other Chinese herbs that can promote anti-invasiveness by controlling the inhibition and regression of MMPs are Mu BieZi (Momordica cochinchinensis) (Zheng et al., 2014). Artemisinin, which is an active compound from Chinese wormwood (Artemisia absinthium), acts by lowering both VEGF and its receptors (Efferth et al., 2002), turmeric (Curcuma longa) (Arbiser et al., 1998), and Scutellaria Baicalensis (Yance et al., 2006).

Figure 2. Role of pro- and antiangiogenesis factors on vascularization. VEGF binds to its receptors on endothelial cells to initiate a break through existing blood vessels, grow and migrate to form new blood vessels. Binding of inhibitors to the receptors triggers the activation of caspases to activate apoptosis. [Click here to view]

Antigrowth suppressor

Many programs in cancer cells help in proliferation to ensure the formation of tumor without interruption. When these programs are negatively regulating cell proliferation, it will control cancer progression and ultimately prevent tumor formation. These programs are mainly activated by tumor suppressor proteins. They play important roles in suppressing uncontrolled proliferation, immortality, and tumorgenicity. The two main tumor suppressors are retinoblastoma susceptibility gene (RB) and p53 proteins. RB is a negative regulator of the cell cycle that inhibits both G₁ and S-phase progression (Bartek et al., 1997). RB (unphosphorylated or hypo-phosphorylated) suppresses cell cycle progression by binding to transcription factors such as E2f1 (transcription factor 1) to inhibit their activation. The phosphorylation of RB-E2f1 complex leads to dissociation and consequently enters S-phase (Cobrinik et al., 2005; Martin and Gerd, 2017). Apart from controlling cell cycle regulation, RB also controls other cellular processes such as differentiation (Lipinski et al., 1999), senescence (Dasgupta et al., 2006), and apoptosis (Chau and Wang, 2003).

Figure 3. Antiproliferative actions of CHM against human cancers and its targets. [Click here to view]

p53, a tumor suppressor, controls various genetic expression, cell proliferation, and modulation of signal transduction pathway. During DNA damage in a cell, p53 will be accumulated to initiate cell arrest and trigger apoptosis to control abnormal cell proliferation. Besides, p53 is also involved in DNA repair to prevent the accumulation of mutation and suppresses tumor development (O’Neil and Rose, 2006). Other examples of tumor suppressors include phosphatase and tensin homolog (PTEN) (phosphatase and tensin homolog on chromosome 10), p21WAF1, p27KIP1, and adenomatosis polyposis coli (APC) (adenomatosis polyposis coli). As shown in Figure 4, the accumulation of p53 induces p21WAF1/p27KIP1 to initiate cell cycle arrest, whereas APC a multidomain protein, through which it binds to various binding proteins such as beta-catenin, Asef, and Rac, leads to the prevention of cancer cell overgrowth (Kitagishi et al., 2012).

Figure 4. Schematic representation of tumor suppressor signaling including p53, Rb, APC, p21WAF1/p27KIP1, and PTEN. Examples of molecules known to act on cell proliferation and cell survival via the regulatory pathways are shown (Adapted from Kitagishi et al., 2012). [Click here to view]

Several studies revealed the role of CHM in tumor suppression. Chinese herbal formula, Yangyinjiedu, inhibits the proliferation of lung cancer cell lines (95-D, A549, H460, and H1975) by inducing cell cycle arrest and senescence via an elevated level of p53 (Zheng et al., 2017). Kanglaite (KLT), an extract from Coix seed, induces apoptosis of tumor cell by increasing the mRNA level of p53 (Lu et al., 2008). Honokial, a component of oriental herb Magnolia officinalis, significantly reduces the level of Rb protein in prostate cancer cells (Hahm et al., 2007). It also reduces the PTEN protein level in adipocyte cancer by controlling angiogenic activity (Liu et al., 2008). Similarly, Acanthopanax gracilistylus inhibits the proliferation of MT-2, Raji, HL-60, TMK-1, and HSC-2 through cell cycle arrest accompanied by a decreased phosphorylated level of pRb (Shan et al., 2000). Liposome-encapsulated curcumin and resveratrol in combination reported to effectively inhibit cell growth and to induce apoptosis. The finding also confirms that the cell death of prostate cancer was due to the loss of PTEN suppressor (Narayanan et al., 2009). Carnosol, a constituent from rosemary herb, has shown to prevent APC-associated intestinal tumorigenesis by increasing E-cadherin-mediated adhesion and suppression of beta-catenin tyrosine phosphorylation (Moran et al., 2005). APC-mediated suppression was also reported in human cervical cancer cells such as Caski and HeLa on exposure with trichosanthin. Trichosanthin is a main bioactive component from CHM, the root tuber of Trichosanthes kirilowii Maxim. In a study done by Huang (Huang et al., 2012), trichosanthin showed to inhibit DNA methyltransferase and restore the expression of methylation-silenced tumor suppressor genes. Therefore, it was categorized as potentially useful demethylation agent for the clinical treatment of human cervical cancer. An extract of Magnolia inhibits the proliferation of urinary cancer cells via G1 cell cycle arrest. Post-treatment and expression of p21WAF1 and p27KIP1 were reported to be upregulated. They were also believed to interact with cell cycle proteins, CDKs, and nuclear antigens to form complex, which trigger the prevention of cell proliferation. Similarly, baicalin, a flavonoid compound extracted from the root of S. baicalensis Georgi, reported to inhibit the proliferation of prostate cancer cells such as PC-3 and LN-CaP by activating the expression of cyclin-dependent kinase inhibitor, p27KIP1. Table 1 shows the role of CHM and active compound as a tumor suppressor.

Cell death

In early 2018, Galluzzi (Galluzzi et al., 2018) highlighted 14 different types of cell death such as intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition – driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic, NETotic, lysosome-dependent, autophagy-dependent, immunogenic, cellular senescence, and mitotic catastrophe. Among them, three major cell deaths are apoptosis, autophagy, and necrosis. The role of CHM against these cell deaths will be discussed in this session.

Apoptosis has taken the central stage as the principal mechanism of programmed cell death (PCD). PCD basically refers to its strong genetic controls (Daniel and Korsmeyer, 2004) where it ends up in the disintegration of cellular components and engulfment by surrounding cells. Apoptosis is a biochemical event involving cell membrane blebbing, shrinkage, chromatin condensation, and nucleosomal fragmentation (Kroemer et al., 2008). Apoptosis is classified as a major mechanism of chemotherapy-induced cell death. Therefore, cytotoxic agents/drugs that target this pathway are the main focus of many preclinical discovery investigations. Apoptosis can be further divided into intrinsic and extrinsic apoptosis. These two pathways are controlled by its own initiator caspases (intrinsic apoptosis govern by caspase-9 and extrinsic apoptosis initiated by caspase-8) and follow similar execution pathways via caspase 3.

Ursolic acid is an active ingredient found in several CHMs, such as O. diffusa (Willd.) Roxb. and L. lucidum W.T. Aiton. It was showed to induce cancer cell death via caspase-dependent pathway in prostate cancer cells (Kwon et al., 2010). This active compound has elevated caspase-9 and caspase-3 levels in prostate cancer cells. In general, the activation of intrinsic apoptosis involves the release of cytochrome-c from mitochondria, apaf-1, and apoptosome formation before it enters into the cascade of caspase activation. Other CHMs such as Aloe emodin (Dong et al., 2010), artemisinins (Chen et al., 2017), arsenic trioxide (Lam et al., 2005), baicalin (Peng et al., 2015), hesperetin (Palit et al., 2015), and matrine (Zhang et al., 2012) were also reported to induce mitochondrial-mediated apoptosis.

While intrinsic apoptosis mediated by internal organelle (mitochondria), external apoptosis involves the binding of death ligands (Fas and FasL) at cellular membrane to facilitate apoptosis. Oridonin (Kang et al., 2010), polyphenols from green tea (Oz et al., 2010; Tsukamoto et al., 2012), and glycyrrhizin (Haghshenas et al., 2014) are the examples of CHM, which target cancer cell death via this pathway.

Autophagy is also a genetically controlled cell death and classified under PCD. It is activated during essential nutrient starvation such as carbon and amino acid, resulting in intracellular component degradation. During autophagy, autophagosomes in cytoplasm combine with the key organelle, lysosome. On fusion, the release of lysosomal hydrolases allows the degradation of misfolded proteins and organelles (Shintani et al., 2004). The presence of beclin one protein indicates the activation of autophagy. Anticancer drug combination of Sun-Bai Pi extract with commercial drug cisplatin was reported to synergistically kill non-small cell lung cancer and allows rapid low-dose cancer cell elimination via autophagy cell death (Tseng et al., 2016).

Next, necrosis is most likely controlled by signal transduction pathways and catabolic mechanisms. Its features include translucent cytoplasm, swollen organelles, dilatation of nuclear membrane, chromatin condensation, and increased cell volume (Vandenabeele et al., 2010). In cancer cell, imbalance of intracellular calcium flux, reactive oxygen species (ROS) generation, and activation of non-apoptotic proteases influence each other to activate necrosis. Cell dying via necrotic death initiates pro-inflammatory signals to release inflammatory cytokines and spill their content during lyses. Due to this, necrosis is considered to be a more harmful way for a cell to die compared with apoptosis. However, very less CHMs were reported to induce necrotic cell death. Shikonin from Lithospermum erythrorhizon Siebold was showed to induce necrosis in MCF-7 and HEK293 cells (Han et al., 2007; Han et al., 2009). Interestingly, Han (Han et al., 2009) further stated the presence of necrostatin-1 (Nec-1), a specific necroptosis inhibitor, that can revert back necrosis to apoptosis. This switch mode is associated with Bax translocation partially due to the conversion of mitochondrial inner membrane permeability to outer membranes. Their data also suggested that apoptosis and necroptosis may function as reciprocal backup mechanisms of cellular demise. Similarly, a synergistic combination of 5-FU with gambogenic acid against human lung cancer cells A549 was reported to induce a typical cellular necrotic death which was primarily necroptosis and posteriorly apoptosis (Su et al., 2014).

Table 1. The role of CHM and active compound as tumour suppressor. [Click here to view]

Energy metabolism

Energy metabolism in normal cells occurs in aerobic and anaerobic conditions. In aerobic condition, the presence of oxygen allows glucose breakdown to pyruvate in the cytoplasm. Later, pyruvate with the help of oxygen breaks down in mitochondria to release carbon dioxide and 36 molecules of adenosine triphosphate (ATP). This phenomenon is known as oxidative phosphorylation. In anaerobic condition, normal cells undergo anaerobic glycolysis in the cytoplasm, where glucose converted to pyruvate then lactate. Anaerobic glycolysis produces less energy, which is only 2-ATP. In conclusion, normal cells select oxidative phosphorylation in the presence of oxygen to release high energy, whereas uses anaerobic glycolysis in the absence of oxygen to release less energy. Interestingly, this is not the norm in cancer cells (Fig. 5). Energy metabolism in cancer cells does not depend on aerobic or anaerobic conditions. Proliferative tissues or tumor consumes glucose to produce pyruvate and then converts it to mostly lactate even in the presence of ample of oxygen (DeBerardinis et al., 2008; Warburg, 1956). Cancer cell adaptation to this pathway is known as the Warburg effect or aerobic glycolysis which is critical for tumor cell growth, proliferation, angiogenesis, and stress resistance. As one of the hallmarks of cancer, active aerobic glycolysis by cancer cells has been utilized in the clinical sector as a means of diagnosis and monitoring cancer treatment response in positron emission tomography, positron emission tomography scan (Sotgia et al., 2011).

Figure 5. Schematics of aerobic glycolysis – ‘’Warburg effect.’’ To enable rapid proliferation, cancer cells favor high levels of glucose uptake and lactate production. [Click here to view]

Table 2. List of CHM that inhibits cancer metabolic expression-Warburg effect. [Click here to view]

Metabolic adaptation of tumor cells is regulated by a number of oncogenes and tumor suppressors including Myc (Lewis et al., 1997), hypoxia-inducible factor, HIF-1α (Kim et al., 2006), p 53 (Bensinger and Christofk, 2012), and PI3K/Akt/mTOR signaling pathway (Elstrom et al., 2014). Interrupting any of the above could lead to metabolism blockade followed by cell death.

The distinct phenomena of energy production in cancer cell via aerobic glycolysis open the door to target this metabolism and its related critical enzymes such as glucose transporter GLUT1, HK, PFKFB3, mTORC1, and OXPHOS to be exploited as targets for cancer therapy. By controlling/preventing aerobic glycolysis, cancer cells can undergo starvation, and the inhibition of proliferation can be reached. Subsequently, cancer progression can be prevented. As such, the role of CHM in the development of glycolysis-based therapeutic interventions for cancer is focused in this session.

Apigenin, a plant flavonoid compound isolated from Apium graveolensvar. Dulce, acts as a HIF-1α inhibitor (Semenza, 2009). This active compound showed to inhibit proliferation and to induce apoptosis in various cancers including breast (Choi and Kim, 2009), ovarian (Li et al., 2009), prostate (Shukla and Gupta, 2006), and lung (Lu et al., 2010). Apigenin was reported to inactivate PI3K/Akt pathway in prostate cancer cells (Shukla and Gupta, 2007) and reduce HIF-α stability via PI3K/Akt/GSK-3 β pathway (Mirzoeva et al., 2008). Apart from this, Chrysin (Fu et al., 2004), EGCG (Tachibana, 2009), and curcumin (Bae et al., 2006) are among other reported CHM-derived pure compounds that could control aerobic glycolysis by inhibiting HIF-1α expression.

Expression of c-Myc oncogene is upregulated in the majority of human cancers including breast, colon, bladder, and prostate cancers (Dang et al., 2009). Overexpression of c-Myc is also linked to increase in many glucose metabolism enzyme genes, such as GLUT1, HK2 (Kim et al., 2007), phosphofructokinase, enolase 1, lactate dehydrogenase A, mitochondrial ROS, and pyruvate dehydrogenase kinase, thus stimulating the Warburg effect (Lewis et al., 1997; Shim et al., 1997). Table 2 shows the various CHMs in targeting the Warburg effect.

CHINESE HERBAL MEDICINES UNDER CLINICAL TRIAL

CHM has become an important and growing part of public healthcare around the world. Initially, its importance was overlooked due to the lack of scientific evidence to evaluate safety and efficacy. In this review, we have highlighted the mechanism behind the potential use of CHM in inhibiting cancer development. However, to further widen their acceptance globally and to promote herbal medicines into conventional medical practices, clinical trials of these medicinal plants are encouraged. As such, Table 3 shows the completed clinical trials of CHM in breast, lung, anal, leukemia, liver, and colorectal cancers (http://clinicaltrials.gov/). Among the listed 13 completed clinical studies, only two studies were shown to have available results. A phase II study was carried out from 2008 to 2018 to investigate the mechanism and efficacy of CHM as an adjunct to chemotherapy in the treatment of patients with metastatic colorectal cancer. In the CHM, KD018 is an oral form of a spray-dried aqueous extract composed of Huang Qin Tang herbal mixture (Glycyrrhiza uralensis Fisch, Paeonia lactiflora Pall, S. baicalensis Georgi, and Ziziphus jujube Mill), which have been used against gastrointestinal (GI) infectious symptoms including diarrhea and nausea/vomiting. A therapeutic use of KD018 was tested for its potential activity in reducing chemotherapy-induced toxicity, especially diarrhea. The CHM was shown to decrease GI toxicity induced by the chemotherapeutic drug CPT-11 (irinotecan) and increase the antitumor activity of irinotecan while decreasing weight loss caused by irinotecan (Lam et al., 2010). Next, phase II study on anal high-grade squamous intraepithelial lesions (HSIL) through the use of a Chinese herbal topical cream by the University of California was carried out from 2008 to 2012. This CHM that consists of Arnebia Indigo Jade Pearl (AIJP) was applied as a noninvasive topical cream for the treatment of precancerous anal lesions caused by human papillomavirus to prevent their progression to anal cancer.

Table 3. Completed clinical trials of CHM in cancer. [Click here to view]

With the growing scientific evidence on the safety and efficacy of CHM in clinical trial, CHM-based drugs can be confidently used to treat cancer. With more clinical trials on CHM conducted, this may allow the integration of CHM into the current conventional healthcare systems.

CONFLICT OF INTEREST

No potential conflicts of interest are disclosed.

FUNDING

None.

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