Chinese Medicines for Cancer Treatment from the Metabolomics Perspective

Cancer is one of the most prevalent diseases all over the world with poor prognosis and the development of novel therapeutic strategies is still urgently needed. The large amount of successful experiences in fighting against cancer-like diseases with Chinese medicine has suggested it as a great source of alternative treatments to human cancers. Cancer cells have been shown to own a predominantly unique metabolic phenotype to facilitate their rapid proliferation. Metabolic reprogramming is a remarkable hallmark of cancer and therapies targeting cancer metabolism can be highly specific and effective. Based on the sophisticated study of small molecule metabolites, metabolomics can provide us valuable information on dynamically metabolic responses of living systems to certain environmental condition. In this chapter, we systematically reviewed recent studies on metabolism-targeting anticancer therapies based on metabolomics in terms of glucose, lipid, amino acid, and nucleotide metabolisms and other altered metabolisms, with special emphasis on the potential of metabolic treatment with pure compounds, herb extracts, and formulations from Chinese medicines. The trends of future development of metabolism-targeting anticancer therapies were also discussed. Overall, the elucidation of the underlying molecular mechanism of metabolism-targeting pharmacologic therapies will provide us a new insight to develop novel therapeutics for cancer treatment

Polarization of Tumor-Associated Macrophages by Chinese Medicine Intervention: Mechanisms and Applications

Macrophage polarization is a spectrum of phenotypes and generally can be classified into two states: (1) classically activated or M1 macrophages, which can be driven by lipopolysaccharide (LPS) alone or in association with Th1 cytokines and produce pro-inflammatory cytokines such as TNF-α, IL-6 and, IL-12, and (2) alternatively activated M2 macrophages, which can be promoted by Th2 mediators IL-4 and IL-13 and produce anti-inflammatory cytokines such as TGF-β and IL-10. Current studies have found that the phenotypic switch between M1 and M2 macrophages governs the fate of an organ in inflammation or injury. The imbalance of M1/M2 polarization is closely involved in various pathological processes and is becoming a potential target for therapeutic strategies. Traditional Chinese medicine is an integrated healthcare system composed of many practices and is characterized by multi-target, multi-level, and coordinated intervention effects. Chinese medicines nowadays are applied to regulate phenotype polarization of macrophages to improve the microenvironment, thus ameliorating or even eliminating the symptoms. In this chapter, we will discuss the molecular mechanisms of macrophage polarization, their roles in health and disease, and the intervention with Chinese medicines to modulate the polarization of macrophages in tumor microenvironment (TME) for therapeutic purpose

Cancer Management by Tyrosine Kinase Inhibitors: Efficacy, Limitation, and Future Strategies

Tyrosine kinase inhibitors are taking up an increasingly significant role in treating cancers. There are different types of TKIs currently used in clinical settings. However, TKI-associated limitations such as resistance and adverse effects are frequently reported. In this chapter, we would comprehensively review the clinical efficacy of current TKIs using the currently available clinical trial data. Significant limitations of TKIs on cancer treatment will be further summarized and discussed. The strategies on overcoming the limitations of TKIs to maximize their clinical effectiveness and efficiency, such as complementary use of Chinese medicine or development of novel TKIs, will be proposed. In conclusion, an overall picture of the clinical use and limitation of the current TKIs will be drawn and the prospective development in overcoming the limitations will be discussed. Evaluation of clinical efficacy of TKIs, evaluation of limitations of TKIs, strategies in overcoming the limitations of TKIs, and conclusion (including prospective development of TKIs) are discussed below

The Underlying Mechanisms of Chinese Herbal Medicine-Induced Apoptotic Cell Death in Human Cancer

The high incidence of cancer is a global burden. Cancer cells acquire immortality, which results in loss of control in cell proliferation and population expansion. Cancer cells undergo a series of genomic instability, leading to mutated amplification or deletion of certain genes that strictly control the cell fate. Programmed cell death is a mechanism of cell fate control that is aberrantly regulated in cancer cells. Apoptosis is the major form of programmed cell death regulated by both intrinsic and extrinsic pathways. Discovering effective and specific alternative solutions that can reprogram apoptosis in cancer cells is always a challenge. Chinese herbal medicine has captured increasing attention from both researchers and manufacturers, as evidenced by observable curative effects from previous clinical experience. Hence, to clarify and reinforce the understanding of the effect of Chinese medicine on cancer, in this chapter, we will retrospectively review the latest 5 years of literature and summarize the mode of action of Chinese herbal medicine on apoptotic cell death in cancer. Both Chinese medicine-induced intrinsic and extrinsic mechanisms of apoptosis will be discussed, and common compounds from Chinese medicine with druggable potential as novel apoptosis-inducing agents will be highlighted

Dual Effects of Chinese Herbal Medicines on Angiogenesis in Cancer and Ischemic Stroke Treatments: Role of HIF-1 Network

This work is licensed under a Creative Commons Attribution 4.0 International License.Hypoxia-inducible factor-1 (HIF-1)–induced angiogenesis has been involved in numerous pathological conditions, and it may be harmful or beneficial depending on the types of diseases. Exploration on angiogenesis has sparked hopes in providing novel therapeutic approaches on multiple diseases with high mortality rates, such as cancer and ischemic stroke. The HIF-1 pathway is considered to be a major regulator of angiogenesis. HIF-1 seems to be involved in the vascular formation process by synergistic correlations with other proangiogenic factors in cancer and cerebrovascular disease. The regulation of HIF-1–dependent angiogenesis is related to the modulation of HIF-1 bioactivity by regulating HIF-1α transcription or protein translation, HIF-1α DNA binding, HIF-1α and HIF-1α dimerization, and HIF-1 degradation. Traditional Chinese herbal medicines have a long history of clinical use in both cancer and stroke treatments in Asia. Growing evidence has demonstrated potential proangiogenic benefits of Chinese herbal medicines in ischemic stroke, whereas tumor angiogenesis could be inhibited by the active components in Chinese herbal medicines. The objective of this review is to provide comprehensive insight on the effects of Chinese herbal medicines on angiogenesis by regulating HIF-1 pathways in both cancer and ischemic stroke.National Natural Science Foundation of China (No. 81673627)Guangzhou Science Technology and Innovation Commission Research Projects (201805010005)Research Grant Council, HKSAR (Project code: RGC GRF 17152116)Commissioner for Innovation Technology, HKSAR (Project code: ITS/091/16FX

The Potential and Action Mechanism of Polyphenols in the Treatment of Liver Diseases

Liver disease, involving a wide range of liver pathologies from fatty liver, hepatitis, and fibrosis to cirrhosis and hepatocellular carcinoma, is a serious health problem worldwide. In recent years, many natural foods and herbs with abundant phytochemicals have been proposed as health supplementation for patients with hepatic disorders. As an important category of phytochemicals, natural polyphenols have attracted increasing attention as potential agents for the prevention and treatment of liver diseases. The striking capacities in remitting oxidative stress, lipid metabolism, insulin resistance, and inflammation put polyphenols in the spotlight for the therapies of liver diseases. It has been reported that many polyphenols from a wide range of foods and herbs exert therapeutic effects on liver injuries via complicated mechanisms. Therefore, it is necessary to have a systematical review to sort out current researches to help better understand the potentials of polyphenols in liver diseases. In this review, we aim to summarize and update the existing evidence of natural polyphenols in the treatment of various liver diseases by in vitro, in vivo, and clinical studies, while special attention is paid to the action mechanisms

Preclinical Models for Investigation of Herbal Medicines in Liver Diseases: Update and Perspective

Liver disease results from a dynamic pathological process associated with cellular and genetic alterations, which may progress stepwise to liver dysfunction. Commonly, liver disease begins with hepatocyte injury, followed by persistent episodes of cellular regeneration, inflammation, and hepatocyte death that may ultimately lead to nonreversible liver failure. For centuries, herbal remedies have been used for a variety of liver diseases and recent studies have identified the active compounds that may interact with liver disease-associated targets. Further study on the herbal remedies may lead to the formulation of next generation medicines with hepatoprotective, antifibrotic, and anticancer properties. Still, the pharmacological actions of vast majority of herbal remedies remain unknown; thus, extensive preclinical studies are important. In this review, we summarize progress made over the last five years of the most commonly used preclinical models of liver diseases that are used to screen for curative herbal medicines for nonalcoholic fatty liver disease, liver fibrosis/cirrhosis, and liver. We also summarize the proposed mechanisms associated with the observed liver-protective, antifibrotic, and anticancer actions of several promising herbal medicines and discuss the challenges faced in this research field

Expansion of Granulocytic, Myeloid-Derived Suppressor Cells in Response to Ethanol-Induced Acute Liver Damage

The dual role of ethanol in regulating both pro-inflammatory and anti-inflammatory response has recently been reported. Myeloid-derived suppressor cells (MDSCs) are one of the major components in the immune suppressive network in both innate and adaptive immune responses. In this study, we aim to define the role of a population expressing CD11b+Ly6GhighLy6Cint with immunosuppressive function in response to ethanol-induced acute liver damage. We find this increased granulocytic-MDSCs (G-MDSCs) population in the blood, spleen, and liver of mice treated with ethanol. Depletion of these cells increases serum alanine aminotransferase and aspartate aminotransferase levels, while G-MDSCs population adoptive transfer can ameliorate liver damage induced by ethanol, indicating the protective role in the early stage of alcoholic liver disease. The significant changes of T-cell profiles after G-MDSCs populations adoptive transfer and anti-Gr1 injection signify that both cytotoxic T and T helper cells might be the targeted cells of G-MDSCs. In the in vitro study, we find that myeloid precursors preferentially generate G-MDSCs and improve their suppressive capacity via chemokine interaction and YAP signaling when exposed to ethanol. Furthermore, IL-6 serves as an important indirect factor in mediating the expansion of G-MDSCs populations after acute ethanol exposure. Collectively, we show that expansion of G-MDSCs in response to ethanol consumption plays a protective role in acute alcoholic liver damage. Our study provides novel evidence of the immune response to acute ethanol consumption

The suppressive effect of baicalin on hepatocellular carcinoma through mediating tumour associated macrophages repolarization

High aggressiveness and resistance of hepatocellular carcinoma (HCC) renders the inefficient of current therapies in completely eradicating the tumor cells. The aggressive phenotype of HCC is partially attributed by the communication between tumor cells with stromal cells in microenvironment. The tumor microenvironment has been revealed as the prognostic implication for HCC progression, and tumor associated macrophages (TAM) in particular is one of the effectors in HCC microenvironment. Aiming at TAM may thus be a promising strategy for HCC management. Scutellaria baicalensis is one of the most commonly employed herbs for tumor control in traditional Chinese medicinal practice and baicalin is its feature component. However, the in vitro and in vivo HCC inhibitory effect of baicalin remains scanty. Meanwhile, the immuno-modulatory effect of baicalin has been recently underscored. Thus, whether baicalin induces HCC regression via its immuno-modulatory effect and the underlying mechanism worth to be further explored. In this study, we aimed to systematically investigate the in vivo anti-tumour effect of baicalin and the role of TAM in baicalin-mediated tumour inhibition. Firstly, we examined the in vivo effect of baicalin using (i) orthotopic HCC implantation and (ii) choline-deficient L-amino acid defined diet and carbon tetrachloride induced liver carcinogenic murine model. We observed reduced HCC orthotopic growth with no observable toxicity to immuno-compromised mice. The effect was accompanied with increased M1 macrophage population and minimal inflammatory monocytes infiltration. Also, deceleration of liver tumor growth was observed in baicalin-intervened 6- and 9-month diet-fed immuno-competent mice. It was followed with increased ratio of intrahepatic M1 to M2 macrophages and cytotoxic 〖CD〗^(8+) cytotoxic T populations. Surprisingly, we did not observe any inhibition of baicalin on HCC cellular functions. The involvement of macrophages in baicalin-mediated HCC suppression was confirmed by macrophage deletion using liposome clodronate. Subsequently, the effect of baicalin on TAMs functions was systematically investigated using the optimized in vitro culture systems. Our findings postulate that high dose of baicalin induced no specific cytotoxicity to macrophages. Whereas it reduced in vitro monocyte-to-macrophage differentiation and C-C chemokine receptor type-2 (CCR2) expression, a crucial element for monocyte recruitment. Besides, baicalin intervention phenotypically and functionally shifted macrophages towards M1-like, away from M2 in dose-dependent manner. Further co-culturing of baicalin-pre-treated macrophages with Hepa1-6 cells declined survival and motility of Hepa1-6. Lastly, we sought to delineate the mechanism of baicalin-mediated TAMs polarization. Baicalin intervention induced autophagy in macrophages. Autophagy deactivation using pharmacological inhibitor balfilomycin A1 and RNA interference against Atg5 abolished baicalin-mediated macrophage repolarization. Baicalin also promoted IKKα-dependent RelB/p52 activation. While autophagy blockade triggered loss of induction of IKKα and RelB. Baicalin-mediated activation of IKKα-RelB-p52 cascade is negatively regulated by TRAF2. Autophagic degradation of TRAF2 by baicalin was confirmed following observation of recruitment of ubiquitinated TRAF2 to autophagosome. In summary, the study underscores the crucial role of TAM reprogramming mediated HCC inhibition by baicalin, which relying on autophagy-regulated RelB/p52 activation. Further clinical investigation on human safety and efficacy of baicalin may offer novel immune-targeted drug candidate for HCC treatment.published_or_final_versionChinese MedicineDoctoralDoctor of Philosoph

Glutamic-Pyruvic Transaminase 1 Facilitates Alternative Fuels for Hepatocellular Carcinoma Growth—A Small Molecule Inhibitor, Berberine

Metabolic reprogramming is an essential hallmark of cancer. Besides the “Warburg effect”, cancer cells also actively reprogram amino acid metabolism to satisfy high nutritional demands in a nutrient-poor environment. In the glucose–alanine cycle, exogenous alanine taken up by hepatocytes is converted to pyruvate via glutamic-pyruvic transaminases (GPTs). However, the precise role of the glucose–alanine cycle in hepatocellular carcinoma (HCC) remains elusive. The current study revealed that alanine, as an alternative energy source, induced the metabolic reprogramming of HCC cells via activation of the downstream glucose–alanine cycle and thus promoted HCC growth in nutrient-depleted conditions. Further overexpression and loss-of-function studies indicated that GPT1 was an essential regulator for alanine-supplemented HCC growth. Combining molecular docking and metabolomics analyses, our study further identified a naturally occurring alkaloid, berberine (BBR), as the GPT1 inhibitor in HCC. Mechanically, BBR-mediated metabolic reprogramming of alanine-supplemented HCC via GPT1 suppression attenuated adenosine triphosphate (ATP) production and thus suppressed HCC growth. In conclusion, our study suggests that GPT1-mediated alanine–glucose conversion may be a potential molecular target for HCC therapy. Further demonstration of BBR-mediated metabolic reprogramming of HCC would contribute to the development of this Chinese medicine-derived compound as an adjuvant therapy for HCC