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Review Oncologic, Endocrine & Metabolic 1. Introduction 2. Major targets in cancer therapy 3. Ayurvedic concept of cancer 4. Source of anticancer drugs from…
Review Oncologic, Endocrine & Metabolic 1. Introduction 2. Major targets in cancer therapy 3. Ayurvedic concept of cancer 4. Source of anticancer drugs from Ayurvedic medicine 5. Ayurvedic agents as chemosensitisers and radiosensitisers 6. Herb–drug interactions 7. Expert opinion 8. Conclusions From traditional Ayurvedic medicine to modern medicine: identification of therapeutic targets for suppression of inflammation and cancer Bharat B Aggarwal†, Haruyo Ichikawa, Prachi Garodia, Priya Weerasinghe, Gautam Sethi, Indra D Bhatt, Manoj K Pandey, Shishir Shishodia & Muraleedharan G Nair †The University of Texas, MD Anderson Cancer Center, Cytokine Research Laboratory, Department of Experimental Therapeutics, Box 143, 1515 Holcombe Boulevard, Houston, Texas 77030, USA, Cancer is a hyperproliferative disorder that involves transformation, dysregulation of apoptosis, proliferation, invasion, angiogenesis and metastasis. Extensive research during the last 30 years has revealed much about the biology of cancer. Drugs used to treat most cancers are those that can block cell signalling, including growth factor signalling (e.g., epidermal growth factor); prostaglandin production (e.g., COX-2); inflammation (e.g., inflammatory cytokines: NF-κB, TNF, IL-1, IL-6, chemokines); drug resistance gene products (e.g., multi-drug resistance); cell cycle proteins (e.g., cyclin D1 and cyclin E); angiogenesis (e.g., vascular endothelial growth factor); invasion (e.g., matrix metalloproteinases); antiapoptosis (e.g., bcl-2, bcl-XL, XIAP, survivin, FLIP); and cellular proliferation (e.g., c-myc, AP-1, growth factors). Numerous reports have suggested that Ayurvedic plants and their components mediate their effects by modulating several of these recently identified therapeutic targets. However, Ayurvedic medicine requires rediscovery in light of our current knowledge of allopathic (modern) medicine. The focus of this review is to elucidate the Ayurvedic concept of cancer, including its classification, causes, pathogenesis and prevention; surgical removal of tumours; herbal remedies; dietary modifications; and spiritual treatments. Keywords: apoptosis, Ayurvedic medicine, cancer, inflammation, metastasis Expert Opin. Ther. Targets (2006) 10(1):87-118 1. Introduction Ashley Publications According to the International Agency for Research on Cancer (IARC), in 2002, cancer killed > 6.7 million people around the world; another 10.9 million new cases were diagnosed; and at the current rate, an estimated 15 million people will be diagnosed annually by 2020. Cancer is one of the leading causes of death in the US and around the world. Several chemotherapeutic, cytotoxic and immunomodulating agents are available in Western medicine to treat cancer. Besides being enormously expensive, these drugs are associated with serious side effects and morbidity. Still, the search continues for an ideal treatment that has minimal side effects and is cost-effective. Today, in Western medicine, only a limited number of plant products are being used to treat cancer. However, some of the widely used anticancer drugs, such as taxol and vinca alkaloids, are obtained from medicinal plants. This review focuses on the ancient perspective of cancer and how it can be integrated 10.1517/14728222.10.1.87 © 2006 Ashley Publications ISSN 1472-8222 87 Traditional Ayurvedic medicine to modern medicine: identification of targets for suppression of inflammation and cancer Golden triangle Modern technology Traditional knowledge (Ayurvedic medicine, Egyptian medicine Kampo, Traditional Chinese medicine) Modern knowledge (allopathic medicine) Figure 1. Relationship between Ayurveda and modern medicine. colon, gastrointestinal, prostate, breast and other cancers when compared with their Western counterparts. It is likely that dietary constituents, such as garlic, ginger, soya, curcumin, onion, tomatoes, cruciferous vegetables, chilies and green tea, play an important role in protection from these cancers. These dietary agents are believed to suppress the transformative, hyperproliferative and inflammatory processes that initiate carcinogenesis. Their inhibitory influences may ultimately suppress the final steps of carcinogenesis as well, namely angiogenesis and metastasis. These dietary constituents have been classified as chemopreventive agents, and their ability to delay the onset of carcinogenesis has been studied extensively. Because these chemopreventive agents are derived from natural sources, they are considered pharmacologically safe. The current review, although brief, evaluates the untapped therapeutic potential of these agents in the setting of several molecular targets that are currently under investigation. 2. Major with modern science for the best treatment of cancer (Figure 1). Ayurveda, one of the major traditional forms of medical practice in India, has produced many useful leads in developing medications for chronic diseases. Almost 25 centuries ago, Hippocrates proclaimed, ‘Let food be thy medicine and medicine be thy food.’ According to a recent report by Newman et al., as many as 65% of formally synthetic hypertension drugs are plant based [1]. Of the 121 prescription drugs in use today for cancer treatment, 90 are derived from plants. Almost 74% of these, including taxol, were discovered by investigating a folklore claim [2,3]. Between 1981 and 2002, 48 out of 65 drugs approved for cancer treatment were natural products, based on natural products, or mimicked natural products in one form or another [1]. These phytochemicals are commonly called chemotherapeutic or chemopreventive agents. Phytochemicals may fight disease through suppression of the inflammatory response. Dysregulated inflammation contributes to many diseases, including cancer [4,5]. It stands to reason then, that suppression of inflammation, whether by phytochemicals or other means, should delay the onset of disease [2,3]. Tumourigenesis is a multistep process that begins with cellular transformation, progresses to hyperproliferation and culminates in the acquisition of invasive potential and angiogenic properties and the establishment of metastatic lesions [6]. This process can be activated by any of various environmental carcinogens (such as cigarette smoke, industrial emissions, gasoline vapors), inflammatory agents (such as TNF and H2O2), tumour promoters (such as phorbol esters and okadaic acid). This multistep process of carcinogenesis involves three phases: tumour initiation, promotion and progression. Several population-based studies indicate that people in Southeast Asian countries have a much lower risk of developing 88 targets in cancer therapy Within the last 50 years, major advances have been made in our understanding of the basic biology of cancer. One important advance is the understanding that suppression of certain cell signalling pathways can suppress tumourigenesis. These signalling pathways are discussed below. 2.1 Role of the NF-κB activation pathway in tumourigenesis NF-κB is a family of closely related protein dimers that bind to a common sequence motif in DNA called the κB site [7]. The molecular identification of its p50 subunit (v-REL) as a member of the reticuloendotheliosis (REL) family of viruses provided the first evidence that NF-κB is linked to cancer. Research over the past decade has revealed that NF-κB is an inducible transcription factor for genes involved in cell survival, cell adhesion, inflammation, differentiation and growth. In most resting cells, NF-κB is sequestered in the cytoplasm by binding to the inhibitory IκB proteins that block the nuclear localisation sequences of NF-κB. NF-κB is activated by a variety of stimuli, such as carcinogens, inflammatory agents, and tumour promoters, including cigarette smoke, phorbol esters, okadaic acid, H2O2 and TNF. These stimuli promote dissociation of IκBα through phosphorylation, ubiquitinylation and its ultimate degradation in the proteasomes. This process unmasks the nuclear localisation sequence of NF-κB, facilitating its nuclear entry, binding to κB regulatory elements and activation of transcription of target genes. Many of the target genes that are activated are critical to the establishment of the early and late stages of aggressive cancers, including expression of cyclin D1, apoptosis suppressor proteins such as bcl-2 and bcl-XL and those required for metastasis and angiogenesis, such as matrix metalloproteases (MMPs) and vascular endothelial growth factor (VEGF). Expert Opin. Ther. Targets (2006) 10(1) Aggarwal, Ichikawa, Garodia, Weerasinghe, Sethi, Bhatt, Pandey, Shishodia & Nair 2.2 Role of the AP-1 activation pathway in cancer prevention Activated protein-1 (AP-1) is another transcription factor that regulates the expression of several genes involved in cell differentiation and proliferation. Functional activation of the AP-1 transcription complex is implicated in tumour promotion as well as in malignant transformation. This complex consists of either homo- or heterodimers of the members of the JUN and FOS family of proteins [8]. This AP-1-mediated transcription of several target genes also can be activated by a complex network of signalling pathways that involve external signals such as growth factors, mitogen-activated protein kinases (MAPKs), extracellular signal-regulated protein kinases and c-jun N-terminal kinase (JNK). Some of the target genes activated by the AP-1 transcription complex mirror those activated by NF-κB and include cyclin D1, bcl-2, bcl-XL, VEGF, MMP and urokinase plasminogen activator (uPA). Expression of genes such as MMP, and especially uPA, promotes angiogenesis and invasive growth of cancer cells. Most importantly, AP-1 can also promote the transition of tumour cells from an epithelial to a mesenchymal morphology, one of the early steps in tumour metastasis. These oncogenic properties of AP-1 are primarily dictated by the dimer composition of the AP-1 family proteins and their post-transcriptional and translational modifications. 2.3 Role of proliferation and apoptosis in tumourigenesis Several reports have been published in the past eight years showing that activation of NF-κB promotes cell survival and proliferation, and downregulation of NF-κB sensitises the cells to apoptosis. The mechanism through which NF-κB promotes these proliferation and cell survival mechanisms has become increasingly clear. Expression of several genes, including bcl-2, bcl-XL, inhibitor-of-apoptosis protein (IAP), survivin, cyclin D1, TNF receptor-associated factor 1(TRAF1), and TRAF2, has been reported to be upregulated by NF-κB [9]. The proteins coded by these genes function primarily by blocking the apoptosis pathway. Several studies have demonstrated that NF-κB activation promotes cell survival and proliferation mechanisms and that suppression of NF-κB leads to abrogation of these mechanisms. Similarly, c-JUN is primarily a positive regulator of cell proliferation because c-jun-deficient fibroblasts have a marked proliferation defect in vitro and in vivo. c-jun protein, once fully activated by JNK kinases, induces transcription of the positive regulators of cell cycle progression, such as cyclin D1, and represses the negative regulators, such as the tumour suppressor p53 and the cyclin-dependent kinase inhibitor p16 (INK4A). Moreover, activated and oncogenic AP-1 can antagonise apoptosis in several tumours. 2.4 Growth factor activation pathway in tumourigenesis The potent cell proliferation signals generated by various growth factor receptors, such as the epidermal growth factor receptor, insulin-like growth factor-1 receptor and VEGF receptor networks, constitute the basis for receptor-driven tumorigenicity in the progression of several cancers [6]. The consequence of these abnormal growth factor receptor signalling pathways include increased cell proliferation, suppression of apoptotic signals (especially under anchorage-independent conditions), and an increase in the tumour’s invasive behaviour, which contributes to metastatic spread and the growth of new blood vessels. Several chemopreventive phytochemicals, including curcumin, genistein, resveratrol and catechins, recently have been shown to be powerful inhibitors of several growth factor receptors, including epidermal growth factor receptor (EGFR). Some of these phytochemicals, such as curcumin, also have the capacity to inhibit the ligand-stimulated activation of the EGFR, indicating that they have the potential to break the autocrine loops that are established in several advanced cancers [10]. The inhibitory actions of these phytochemicals have several other potential advantages in treating patients with late-stage cancers. A blockade of EGFR, for example, may predispose the cancer cells to apoptosis. Moreover, inhibition of EGFR disables the protein’s capacity to provide the cancer cell the matrix-independent survival support it needs to expand and acquire invasive potential. Third, these chemopreventive chemicals function by inhibiting other tyrosine kinases, such as c-src, that are involved in the activation of the G-protein-coupled receptor to the transactivation of EGFR, as occurs extensively in established cancers. Finally, most of these phytochemicals also inhibit, by a similar mechanism, the HER2/neu receptor, which is overexpressed in breast, prostate, ovarian and lung cancers. Curcumin has been shown not only to inhibit the tyrosine kinase activity of this receptor, but also to deplete the protein itself. It does so by interfering with the function of the ATP-dependent GRP94 chaperone protein, which is involved in maintaining the properly folded state of the receptor [11]. Moreover, by inhibiting HER2/neu, most of these phytochemicals also can interfere with the cross-talk between the receptor and the estrogen receptor pathways in these cancers. Thus, they may be beneficial in treating hormone-resistant breast cancer patients by restoring their hormone responsiveness. 2.5 Role of the JAK–STAT pathway in tumourigenesis Although cancer arises through several genetic or epigenetic mechanisms that contribute to a number of abnormal oncogenic signalling pathways, all seem to converge on a very limited number of nuclear transcription factors that function as final effectors, triggering specific gene expression patterns for a particular cancer. These belong to the canonical signal transducers and activators of transcription (STAT) family of proteins [12]. They can be activated by phosphorylation through janus kinase (JAK) or cytokine receptors, G-protein-coupled receptors or growth factor receptors (such as EGFR); by platelet-derived growth factor receptors that have intrinsic tyrosine kinase activity; or by intracellular nonreceptor tyrosine kinase recruitment. Of the seven STAT proteins identified so far, Expert Opin. Ther. Targets (2006) 10(1) 89 Traditional Ayurvedic medicine to modern medicine: identification of targets for suppression of inflammation and cancer constitutive activations of STAT3 and STAT5 have been implicated in multiple myeloma, lymphomas, leukaemias and several solid tumours, making these proteins logical targets for cancer therapy. These STAT proteins contribute to cell survival and growth by preventing apoptosis through increased expression of antiapoptotic proteins, such as bcl-2 and bcl-XL. Recently, STAT 3 was shown to be a direct activator of the VEGF gene, which is responsible for increased angiogenesis. More importantly, the increased expression of STAT3 and STAT5 transcription factors is crucially involved in the processes through which tumours evade immunological surveillance by increasing the expression of immune-suppressing factors and decreasing the expression of pro-inflammatory cytokines that are responsible for the maturation of the dendritic cells [13]. 2.6 Role of multi-drug resistance in tumourigenesis MDR in human cancer is often associated with overexpression of the mdr-1 gene, which encodes a 170 kDa transmembrane protein, termed P-glycoprotein (P-gp). P-glycoprotein is considered to be of prognostic relevance in different tumour types. It is involved in resistance to natural product-based chemotherapeutics, including taxanes, anthracyclines, vinca alkaloids, podophyllotoxins and camptothecins. Although several reports suggest that P-170 is clinically relevant in haematological malignancies, its role in solid tumours is not well understood. Its overexpression has been found to be correlated with the poor outcome observed in patients treated with chemotherapy and presenting drug resistance. Activation of the MDR-1 gene or selection of intrinsically MDR neoplastic cells may occur at early stages of tumourigenesis of oral cancers, before the real evidence of cellular transformation [14]. Thus, the contact with possible chemical carcinogens, such as those of tobacco smoke, may induce activation of MDR-1 gene. MDR-1 product expression in oral squamous cell carcinoma might suggest that an overexpression of this protein could constitute a hallmark of potential more aggressive phenotype for this type of neoplasia. Quantitative flow-cytometric analysis of P-gp expression showed a significant increase in P-gp levels in untreated primary oral tumours and in dysplastic lesions as compared with normal oral tissues. A marked significant increase in P-gp expression was observed in recurrent oral carcinomas as compared with normal oral tissues and dysplastic lesions. Among recurrent tumours, a significant increase in the level of P-gp was observed in T4-stage tumours as compared with T3-stage tumours. Thus, P-gp is differentially expressed during oral tumourigenesis, and may be an indicator of the biological behaviour of oral malignancies [15]. Activation of MDR-related gene expression also occurs during the tumourigenesis of urothelial cancers and that it may confer de novo and acquired drug resistance on urothelial cancers [16]. Like cytochrome P450s (CYP3A4), P-gp is vulnerable to inhibition, activation or induction by herbal constituents. 90 2.7 Role of COX-2 in tumourigenesis Numerous preclinical studies point to the importance of regulating cyclooxygenase-2 (COX-2) expression in the prevention and, most importantly, treatment of several malignancies. This enzyme is overexpressed in practically every premalignant and malignant condition involving the colon, liver, pancreas, breast, lung, bladder, skin, stomach, head and neck and oesophagus [17]. COX-2 overexpression is a consequence of the deregulation of transcriptional and post-transcriptional control. Several growth factors, cytokines, oncogenes and tumour promoters stimulate COX-2 transcription. Expression of COX-2 is increased in HER2/neu-expressing breast carcinomas owing to enhanced ras signalling. Depending upon the stimulus and the cell type, different transcription factors, including AP-1, NF-IL-6, and NF-κB, can stimulate COX-2 transcription [17]. Wild-type p53 protein expression can suppress COX-2 transcription, whereas the mutant p53 protein cannot. Consistent with this observation, increased COX-2 levels are seen in several epithelial cancers that express mutant p53. Taken together, these findings suggest that the balance between the activation of oncogenes and the inactivation of tumour suppressor genes and the expression of several pro-inflammatory cytokines can modulate the expression of COX-2 in tumours. Complicating matters further is the fact that conventional cancer therapies such as radiation and chemotherapy can induce COX-2 and prostaglandin biosynthesis. Thus, inhibition of this enhanced COX-2 activity in tumours clearly has therapeutic potential. 2.8 Role of angiogenesis in tumourigenesis Angiogenesis, the regulated formation of new blood vessels from existing ones, is the basis of several physiological processes, such as embryonic development, placenta formation and wound healing. It is
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