Reports of therapeutic success with traditional Chinese medicine (TCM) have until very recently been met with much scepticism and pessimism by the West, due in-part to the sheer lack of available credible and rigorous clinical data and at claims that a given TCM can remedy common ailments and be just as efficacious in eliminating life threatening diseases, such as cancer. The tide is now beginning to turn on this negative outlook, aided by the ever-increasing migration of people and along with them knowledge (based upon ancestral cultural influences) from two of the world's fasting growing populations, China and India, to the West [1
]. This translation to the West of ancient complementary and alternative medicine formularies and their ever-increasing integrative role in the armoury against cancer means that their presence and place in modern medicine can no longer be overlooked, by regulatory authorities and clinicians alike, as being merely anecdotal.
The age-old holistic approach employed by Chinese practitioners proposes that a multitude of events are key to returning a patient to a healthy state; where cancer therapy is concerned these primarily include an interplay between the induction of apoptosis/cell-cycle arrest, inhibition of angiogenesis, overcoming multidrug resistance (MDR), and boosting the immune system (Figure ). Following an extensive review of the literature we describe the detailed molecular basis of a proven group of TCM, and highlight reported synergies when administered alongside so-called 'conventional therapies' in tumour cell regulation and in bringing about homeostasis.
The many physiological growth control mechanisms that regulate cell proliferation and tissue homeostasis are linked to apoptosis and it follows that resistance developed to this 'programmed cell death
' can be directly linked to prolonged tumour cell survival and resistance to therapy [2
]. The processes resulting in apoptosis are mediated by extrinsic (via
death receptors) or intrinsic (via
mitochondrial) pathways and although their paths are not mutually exclusive, evidence suggests the latter certainly predominates where TCM is concerned [4
]. Here we look in some detail at two of the primary mechanisms – 'apoptosis
' and 'angiogenesis
' in the context of TCM, proposed to be key avenues responsible for imparting therapeutic efficacy against a wide range of cancers.
Molecular basis of TCM – Angiogenesis
Angiogenesis – the creation of a healthy vascularised network by a tumour is a key underlying process in the induction and establishment of cancer [50
]. It, like apoptosis, involves multi-step biochemical interactions that require activation of cell-signalling pathways, supply of nutrients and a host immune response. A range of TCM such as the Chinese wormwood (Artemisia absinthium
– Figure ), turmeric (Curcuma longa
– Figure ) and Scutellaria Baicalensis
are commonly employed by traditional practitioners and studies demonstrate that their actions are at least in-part achieved by blocking the critical process of tumour vascularisation [51
]. In order for cancer cells to grow and develop a healthy network of blood vessels high sources of nutrients and oxygen are vital. The rapidly dividing cells are subject to a hypoxic environment, so failure to set-up this fundamental framework results in stunted growth of the tumour (≤ 1–2 mm) and development of necrosis at its core [52
]. Starving an established tumour of its blood supply involves an intervention in the complex angiogenic cascade, of which vascular endothelial growth factor (VEGF) is the most reported biomarker [54
]. VEGF production is considered essential for angiogenesis and cancer metastasis, with high titres being indicative of a poor prognosis [55
]. A wide array of oncogenes (e.g. ras
) and growth factors (EGF, TGF, IGF and PDGF) have been identified as up-regulating VEGF-mRNA and so TCM that inhibits their expression and production, respectively, are also considered invaluable tools in cancer therapy.
Plant of Artemisia absinthium ('Chinese wormwood').
Plant (A) and root (B) of Curcuma longa ('curcumin') where root scale is shown as 1 cm.
Artemisinin, an active constituent of Chinese wormwood (Artemisia absinthium
– Figure ) is a potent antimalarial, however more recently it has been shown to possess anti-angiogenic properties, acting by lowering both VEGF and its receptor (VEGF-R2(in embryo), KDR(in humans) and flk-1(in mice)) in tumour and endothelial cells in a dose-dependent manner [56
Phytochemicals have long been used as 'lead compounds' to generate drugs with better pharmacokinetic profiles and reduced toxicity in vivo
. Artesunate (ART) and dihydro-ART are semi-synthetic derivatives of artemisinin with demonstrable activity against a wide range of cancer cell lines including KML-562 (chronic myeloid leukaemia), HeLa (cervical cancer) and HO-8910 (ovarian cancer) [60
]. Human umbilical vein endothelial cells (HUVECs) are commonly employed alongside cancer cell assays to assess the extent to which angiogenesis is induced by way of new micro-vessel tube formation. Studies using this model show that dihydro-ART has significant anti-angiogenic activity compared to ART and prevents new-microvessel formation by 70–90% in vitro
]. Along with the low toxicity profile associated with these agents their future role to complement treatment regimes is encouraging and warrants further investigation.
Curcumin (Curcuma longa
– Figure ), the principle curcuminoid in turmeric and widely used culinary spice is cytotoxic to cancer cells on a number of levels with a proven synergy when used in combination with chemotherapy/radiotherapy [63
]. Its angioinhibitory action has been substantiated in a number of cancer cell lines including that of the breast where it was found to inhibit two major angiogenic factors, VEGF and b-FGF (basic-fibroblast growth factor) [66
]. Besides this it also impedes tumour cell invasion, a property found to diminish circulating but not established metastases. It does this via
downregulation of matrix metalloproteinases (MMP), most notably MMP-2 & MMP-9 – responsible for the invasive growth property of tumours [68
]. In Ehrlich ascites tumour (EAT) cells a time-dependent inhibition of VEGF and key growth factor angiopoietin was observed, combined with an anti-proliferative effect on HUVECs, this being attributed directly to VEGF and NF-κB inhibition [71
]. Other reported actions of curcumin include inhibition of epidermal growth factor receptor (EGFR) and intracellular signalling tyrosine kinases, the latter of which are known to promote angiogenesis through gene activation of cyclooxygenase-2, IL-2 and MMPs [73
]. Derivatives of curcumin have also being investigated with preliminary findings pointing towards an increase in antitumor activity, although further corroborative studies are necessary to confirm these findings [76
TCM often possess quite distinct and specialised modes of action, and consequently tumours normally resistant to conventional chemotherapy are reported to be more susceptible to TCM therapy [79
]. They have demonstrable and often direct inhibitory effects on tumour cell growth and proliferation, affecting different stages of the cell growth cycle and mitotic phase [80
]. Herbal compounds such as paclitaxel (Taxol®
) and its derivatives suppress microtubule depolymerization, thus terminating cell mitosis [81
]. As a result these, and compounds including harringtonine (Cephalotaxus hainanensis
) and camptothecin (Camptotheca acuminata
) with similar mechanisms of action are already commonly used in the clinic as anticancer agents for a variety of cancers [82
]. The mechanism of action of camptothecin (Camptotheca acuminata
) being to inhibit DNA topoisomerase I, consequently affecting DNA replication; paclitaxel is a mitotic spindle inhibitor (spindle poison), which can also bind with tubulin and prevent the normal physiological process of microtubule depolymerization.
Anticancer properties of the TCM elemene (Rhizoma Zedoariae
) and oridonin (Rabdosia rubescens
) lend themselves to being co-administered with conventional chemotherapeutic agents (e.g. doxorubicin and 5-fluorouracil (5-FU)) to impart a synergistic anti-tumour effect. Combining elemene (Rhizoma Zedoariae
) with the pyrimidine base analogue 5-FU, resulted in significantly higher tumour growth inhibitive effects [83
]. The anti-tumour activity of another TCM, 'half-flag' (Pteris semipinnata L.
– Figure ) was also significant, being shown to inhibit DNA production in HL-60 cells by 41% when combined with 5-FU, compared to only 10% in cells treated with the TCM alone. Half-flag also improved the anticancer efficiency of several other chemotherapeutic drugs when used concomitantly [84
Plant of Pteris semipinnata L. ('half-flag').
Similarly, derivatives of the herbal compound berbamine (Berberis amurensis
), namely EBB (O
-(4-ethoxyl-butyl)-berbamine) when combined with cyclophosphamide and mitomycin-C respectively enhanced the antitumor capacity, while also significantly improving patients' quality of life [85
]. Zhang and co-workers tested 20 natural flavonoid compounds in breast cancer cell lines discovering they assist in the intracellular accumulation of anthracycline drugs while also reversing anthracene resistance [86
]. Kim SW et al
., reported that ginsenoside-Rg3
(Panax ginsenoside Rg3
) promotes Rhodamine-123 accumulation in vincristine-resistant KBV20C human fibroblast cancer cells, reversing vincristine resistance acquired by a variety of cells [88
The discovery that single components within TCM have the potential to overcome multidrug resistance developed by tumour cells opens the door to new avenues of multi-drug/TCM therapy. These findings justify and moreover pave the way for them to be used alongside conventional drugs, where significant resistance to therapy has already developed.
Although only one clinical trial using TCM was reported up until 2001 it was poorly controlled and any conclusions drawn were deemed unreliable, it is noteworthy however that given the very recent attention being received by TCM a re-analysis study has since been conducted [89
]. This raises the call for more well-defined, robust and regulated clinical trials on TCM to ensure reliable data is generated which would enable regulatory authorities and clinicians alike to make well-informed decisions when considering their incorporation into western formularies.