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The Role of Traditional Chinese Herbal Medicines in Cancer Therapy – from TCM Theory to Mechanistic Insights

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The Role of Traditional Chinese Herbal Medicines in Cancer Therapy – from TCM Theory to Mechanistic Insights 1118 Reviews The Role of Traditional Chinese Herbal Medicines in Cancer Therapy – from TCM Theory to Mechanistic Insights Authors W. L. Wendy Hsiao, Liang Liu Affiliation Center for Cancer & Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China Key words Abstract Casp10: caspase 10 l" Chinese herbal medicines ! cytoC: cytochrome C l" traditional Chinese medicine Traditional Chinese medicine-based herbal medi- ERK1/2: extracellular signal-regulated kinase l" ‑ anti cancer drugs cines have gained increasing acceptance world- 1/2 l" mechanism of action of wide in recent years and are being pursued by FADD: FAS-associated death domain Chinese herbal medicines pharmaceutical companies as rich resources for FASL: FAS ligand drug discovery. For many years, traditional Chi- FOXO1: forkhead box 1 nese medicines (TCM) have been applied for the Gp130: glycoprotein 130 treatment of cancers in China and beyond. Herbal GRB2: growth factor receptor-bound protein medicines are generally low in cost, plentiful, and 2 show very little toxicity or side effects in clinical HER2: human epidermal growth factor practice. However, despite the vast interest and receptor 2 ever-increasing demand, the absence of strong IκB: IkappaB evidence-based research and the lack of standard- IKK: IkappaB kinase ization of the herbal products are the main ob- IL-6: interleukin-6 stacles toward the globalization of TCM. In recent IL-6R: interleukin-6 receptor years, TCM research has greatly accelerated with JAK: Janus kinase the advancement of analytical technologies and MCL-1: myeloid cell leukemia sequence 1 methodologies. This review of TCM specifically MDM2: murine double minute 2 used in the treatment of cancer is divided into MEK1/2: MAP kinase kinase 1/2 two parts. Part one provides an overview of the MMP: matrix metalloproteinase philosophy, approaches and progress in TCM- Mule: Mcl-1 ubiquitin ligase E3 based cancer therapy. Part two summarizes the NF‑kB: nuclear factor-kappaB received May 3, 2010 revised July 1, 2010 current understanding of how TCM-derived com- NIK: MEK kinase 14 accepted July 5, 2010 pounds function as anticancer drugs. p90RSK: p90 ribosomal S6 kinase PARP: poly (ADP-ribose) polymerase Bibliography PI3K: phosphoinositide 3-kinase This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. DOI http://dx.doi.org/ 10.1055/s-0030-1250186 Abbreviations PIP3: phosphatidylinositol 3,4,5-trisphos- Published online July 15, 2010 ! phate Planta Med 2010; 76: AFAP-1: actin filament-associated protein 1 PUMA: p53 upregulated modulator of apo- – 1118 1131 © Georg Thieme AIF: apoptosis-inducing factor ptosis Verlag KG Stuttgart · New York · ISSN 0032‑0943 BAD: Bcl-2-associated death promoter SH2: Src-homology 2 BAK: BCL2-antagonist/killer SOS: son of sevenless Correspondence BAX: BCL2-associated X protein STAT3: signal transducer and activator of Prof. W. L. Wendy Hsiao School of Chinese Medicine BCL2: B cell leukemia/lymphoma 2 transcription 3 Hong Kong Baptist University BCL‑XL: B cell leukemia/lymphoma xL t-BID: truncated BH3 interacting domain Kowloon Tong BID: BH3 interacting domain protein protein Kowloon Hong Kong BIM: Bcl-2 interacting mediator TIMP: tissue inhibitor of matrix metallo- Peopleʼs Republic of China Casp3: caspase 3 proteinase Phone: + 85234112959 Casp6: caspase 6 TNFαR1: TNF-alpha R1 Fax: + 85234112461 α [email protected] Casp7: caspase 7 TNF R2: TNF-alpha R2 [email protected] Casp8: caspase 8 Topo I: topoisomerase I Hsiao WLW, Liu L. The Role of… Planta Med 2010; 76: 1118–1131 Reviews 1119 Topo II: topoisomerase II TRAILR: TRAIL receptor TRADD: TNFRSF1A-associated death domain VEGF: vascular endothelial growth factor TRAF2: TNF receptor-associated factor 2 VEGFR: vascular endothelial growth factor receptor TRAIL: TNF-related apoptosis-inducing ligand XIAP: X-linked inhibitor of apoptosis protein Introduction nents delivering a comprehensive, integrated treatment of cancer ! through multiple targets and their associated pathways. This ap- TCM views of cancer and the approach proach is in line with the view of TCM that cancer is a systemic toward cancer treatment disease that requires a holistic approach and medicines that can Cancer is one of the major causes of mortality in humans produce therapeutic actions through multiple targets. While this throughout the world. According to a report dealing with the in- approach differs from that of conventional medicine, the effects cidence and mortality of cancers in the USA, a total of 1479 350 of treatment still come down to biochemistry. If treatments are new cancer cases and 562340 deaths from cancer were projected effective, then there must be underlying mechanisms that can to occur in 2009 [1]. For cancer treatment by conventional medi- be investigated and verified scientifically. Understanding these cine, surgery, chemotherapy and radiotherapy have been the pri- mechanisms can help us expand the efficacy of both Western mary approaches, but they are not always effective. As of today, and Chinese medicines in a logical, rational way. cancer is still the most threatening and difficult to treat disease. Cancerous conditions are well-known in the traditional Chinese medical system. In the classics of TCM, “Huang Di Nei Jing Di” Evaluation of the Therapeutic Effects of (黃帝內經) published more than 2000 years ago, there are de- TCM Herbal Medicines in Cancer Treatment – scriptions of the pathogenesis, appearances and treatment prin- The Benefits and the Obstacles ciples of tumors (瘤), such as muscle, tendon and bone carcino- ! mas; however, this term does not differentiate between malig- To provide the scientific basis for the effectiveness of TCM against nant and nonmalignant tumors. It was not until the Sung Dy- cancer, a number of clinical and laboratory studies have been nasty (ca. 1300 AD) that the first reference to cancer – the Chi- done in the past decades. However, due to various factors – in- nese word Ai (癌) meaning malignant carcinoma – first appeared cluding inconsistency in treatment schemes, the limited sam- in the ancient medical book “Wei Ji Bao Shu” (衛濟寶書). Accord- pling sizes, and lack of quality assurance of the herbal products ing to the theories of TCM, cancer is caused by imbalances be- – well-designed randomized controlled trials (RCT) to prove the tween endogenous physical conditions of the body and exoge- effectiveness of TCM as adjuvant therapy for cancer are scarce. In nous pathogenic factors. The internal condition of the body plays general, most of the published clinical studies are at evidence lev- a dominant role in the onset of cancer. In other words, factors can el III; in other words, they were trials without rigorous randomi- induce cancer only when the bodyʼs own defense system fails. zation or they involved single group pre-post, cohort, time series, Those pathogenic factors, in Chinese medicine terms, include ac- or matched case-control studies [3]. As a result, there are a num- cumulated toxins, heat and blood stasis, and they attack when a ber of contradictory reports regarding the therapeutic effective- person is in a weak physical condition, without the strength to ness of TCM on the treatment of cancer. resist. Furthermore, malfunction of the body-mind communica- In TCM prescriptions, herbs are generally used in combination as tion network may also trigger the development of cancer [2]. So, ‘formulas’, in the belief that the combinations enhance their ben- TCM doctors view cancer as a systemic disease associated with efits and simultaneously reduce side effects. With proper diagno- the state of the whole body (or disturbance of the signaling net- sis and understanding of the component herbs, practitioners can work, to use a modern term). “Systemic” in the TCM doctorsʼ adjust or customize the formulas to suit individual cancer pa- views, means “state of the whole body”. “Cancer is the manifesta- tients. Through synergistic interactions between different effec- tion of a breakdown in the bodyʼs ability to handle pathogenic tive ingredients, the herbal preparation, according to the clinical factors, not a local disease of cells or organs.” Accordingly, the experiences, can exert its effects in several ways: (i) they can pro- treatment philosophy and strategy of TCM emphasizes holistic tect the noncancerous cells and tissues in the body from the pos- modulation and improvement of the whole body rather than re- sible damage caused by chemo/radiotherapy; (ii) they can en- moving the tumor mass or killing the cancerous cells. This treat- hance the potency of chemo/radiotherapy; (iii) they can reduce This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. ment strategy is particularly enforced for cancer patients at the inflammatory and infectious complications in the tissues sur- late stages. In these stages, the focus of treatment is extending rounding the carcinoma; (iv) they can enhance immunity and the life expectancy and improving the quality of life of the pa- body resistance; (v) they can improve general condition and tient; in other words, the focus is on the patient not the tumor quality of life; and (vi) they can prolong the life span of the pa- mass (帶瘤生存). tients in the late stages of cancer (l" Fig. 1). So, for an evaluation The other major principle of TCM is the emphasis on an individ- of the effect and benefit of TCM therapy for cancer patients, all ual therapy. For the same type of cancer in different persons, the of these above-mentioned aspects need to be considered. A typi- diagnosis and treatment schemes could be very different. This is cal example of the synergistic, complex function of the herbs has called the principle of “treatment based on symptom pattern dif- been given in the study of PHY906, a Chinese herbal preparation ferentiation (辨證論治)”. In other words, TCM doctors make the made from the herbs of Scutellaria baicalensis, Paeonia lactiflora, diagnosis and prepare a treatment scheme based on the assess- Ziziphus jujuba and Glycyrrhiza glabra.
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