Evidence-based Chinese medicine for cancer therapy
V. Badireenath Konkimalla, Thomas Efferth. Journal of Ethnopharmacology. Volume 116, Issue 2, 5 March 2008, Pages 207–210 http://dx.doi.org/10.1016/j.jep.2007.12.009
Abstract
In contrast to western medicine (WM), traditional Chinese medicine (TCM) does not focus on a single target but on multiple targets involved in a particular disease condition by applying diverse modalities, such as herbal medicine, acupuncture, moxibustion, etc. There is no pre-determined treatment procedure in TCM, and every patient condition is handled individually. Such patient-tailored treatments have a millennia-old tradition in TCM. Illustrative examples of the power of TCM have been documented in cancer research, i.e., camptothecin, homoharringtonine, or arsenic trioxide. On the other hand, one major reason for reluctance of western academia towards TCM is due to the lack of clinical studies of TCM receipts. This situation is changing very recently, and a number of clinical studies were conducted on TCM providing convincing evidence for the first time to gain credibility and reputation outside China. Clinical trials with TCM remedies focus on three major fields in cancer research: (1) improvement of poor treatment response rates towards standard chemo- and radiotherapy, (2) reduction of severe adverse effects of standard cancer therapy, and (3) unwanted interactions of standard therapy with herbal medicines. Efficacy and safety of TCM treatments depend on the quality of TCM products. Appropriate quality assurance and control of TCM products as well as sustainable production methods are pre-conditions for the implementation of TCM in cancer therapy at an international level. In conclusion, the most important question for recognition and implementation of TCM into WM concerns the clinical evidence for the efficacy of TCM and international quality standards for TCM products.
Keywords
Cancer therapy;
Clinical trial;
Meta-analysis;
Molecular pharmacology;
Pharmacognosy;
Traditional Chinese medicine
1. Traditional Chinese medicine (TCM) and western (Allopathic) medicine (WM)
Fig. 1. TCM products are sold on traditional medicinal markets in China since many centuries. Today, they represent a valuable resource for the development of molecular targeted and individualized treatment options for cancer patients.
TCM is often considered as complementary or alternative medicine with a considerable degree of reluctance among western scholars. TCM and WM mainly differ in their basis of approach. TCM follows a holistic approach, where TCM physicians consider the entire human body to design the treatment regimen for their patients. Consequently, TCM in contrary to WM does not focus on a single target but on multiple targets involved in a particular disease condition by applying diverse modalities, such as herbal medicine, acupuncture, moxibustion, etc. There is no pre-determined treatment procedure in TCM. Rather every patient condition is handled individually. At times, different treatment regimens are prescribed to the same patient depending on progress of the disease. Such patient-tailored treatment has a millennia-old tradition in TCM (Fig. 1).
One major reason for reluctance of western academia towards TCM is due to the lack of clinical studies of TCM receipts. The concept of improving the efficacy of treatment options developed during the pre-clinical research is uncommon in TCM. In TCM-based therapy, patient treatment commences without any experimental phase in the laboratory. The western concept of “from the bench to the bedside” does not fit in clinical practice of TCM. Nevertheless, a number of clinical studies were conducted during the past years on TCM to gain credibility and reputation outside China.
During the past few years, TCM has expanded tremendously outside China. In 2006, the export revenue was one billion US$, which is a 31% increase compared to 2005, and the tendency is even rising. China accounts 380,000 licensed TCM physicians. In 2005, 620,000 students attended 32 TCM colleges and universities in China. TCM takes a prominent role in the 11th Five-Year Plan on National Development of Economy and Society (2006–2010) launched by the Chinese government.
An important signal came from the US Food and Drug Administration (FDA) by the approval of herbal mixtures with unknown ingredients, if convincing evidence for their safety and efficacy is provided. This raised the interest of many pharmaceutical companies on herbal medicine all over the world.
On the other hand, illustrative examples of the power of TCM have been documented in cancer research. Natural products isolated from TCM-remedies with exquisite activity against cancer are camptothecin (from Camptotheca acuminata), homoharringtonine (from Cephalotaxus harringtonia), and the mineral arsenic trioxide. In a recent study, it is pointed out that the fraction of natural products and derivatives from them is 47% (Newman and Cragg, 2007). The promise of combinatorial chemistry announced more than a decade ago has not been materialized, and natural products are the far more promising candidates for cancer treatments than purely synthetic compounds. It can be expected that natural products from TCM such as camptothecin, which are already established in the clinic for certain tumor entities, represent only the tip of the ice mountain and that many other highly potent natural products will be uncovered in the years to come. There is a great demand for new drugs, since many cancer patients still cannot be cured from their disease by currently available treatment options. Major problems that have to be taken into account are:
(1) Poor treatment response rates due to the development of resistance of tumor cells towards standard chemo- and radiotherapy.
(2) Severe adverse effects of standard cancer therapy.
(3) Unwanted interactions of standard therapy with herbal medicines.
As a consequence, sufficient levels of drugs frequently cannot be reached in cancer patients to efficiently eradicate tumor cells.
As shown in recent pre-clinical and clinical studies, TCM can indeed influence the efficacy of standard cancer therapy of WM. This sort of analysis provide convincing evidence for the effectiveness of TCM derived treatment principles and represents a pre-condition for the inclusion of these treatment principles of TCM into WM. Hence, an improvement of current treatment options for cancer patients could be reached in the foreseeable future.
2. Improvement of treatment response rates
A meta-analysis on the beneficial effect of Chinese herbal medicine over standard cancer chemotherapy in 26 clinical studies representing 2079 patients showed significantly improved tumor response to chemotherapy and survival of patients at 12, 24, and 26 months using herbal medicine (Shu et al., 2005). Another recent meta-analysis on Astragalus-based Chinese herbs has shown improved response to chemotherapy with reduced therapy-related toxicity by stimulating macrophages and natural killer cell activity, and inhibiting T-helper cell type 2 cytokines (McCulloch et al., 2006). This meta-analysis included 34 randomized clinical trials (n = 2815 patients) under platinum-based chemotherapy against non-small cell lung cancer. In 12 trials (n = 940 patients) a reduced risk of death at 12 months was observed. Improved tumor response to chemotherapy was observed in 30 clinical studies (n = 2472 patients). Injection of the Chinese Ai Di remedy improved life quality in another four trials (n = 257 patients) as measured by Karnovsky index.
3. Reduction of side effects associated with cancer therapy
Acupuncture is widely applied in TCM for treating pain, a prominent side effect encountered during cancer therapy. A recent meta-analysis critically evaluated the value of acupuncture for pain encountered during cancer treatment with 11 randomized controlled trials, two non-randomized trials and 8 case studies (Pan et al., 2000). As a result, acupuncture, electro-acupuncture, and massage therapy significantly relieved pain in cancer patients. Patients with severe chronic obstructive pulmonary disease may also benefit from the use of acupuncture, acupressure, and muscle relaxation with breathing retraining to relieve dyspnea. Another meta-analysis focused on the effect of acupuncture on nausea and vomiting, which are also frequent side effects of cancer chemotherapy on 11 clinical trials representing 1247 patients (Ezzo et al., 2005). Acupuncture-point stimulation, electro-acupuncture, and acupressure reduced incidence of acute vomiting, but not acute or delayed nausea severity as compared to control.
4. Unwanted interactions of standard therapy with herbal medicines
A frequently under-estimated problem for reduced efficacy of chemotherapy is due to the interaction of standard cancer drugs with herbal medicine. A prominent example is Hypericum perforatum (St. John’s Wort) used in treating mild to moderate depression (Singh, 2005). The active compounds hypericin, pseudohypericin, and hyperforin inhibit neurotransmitters serotonin, norepinephrine, and dopamine involved in mood control. The bioactive natural compounds of Hypericum perforatum induce intestinal P-glycoprotein as well as intestinal and hepatic cytochrome P-450 monooxygenase CYP3A4 by activating nuclear steroid/pregnane and xenobiotic receptor (SXR/PXR). This causes Hypericum to reduce distribution and deposition of cancer drugs such as irinotecan, imatinib mesylate, etc. resulting in their decreased plasma concentration. As a consequence, the effectiveness of chemotherapy is diminished resulting in refractoriness of tumors. The magnitude of this problem has been demonstrated in a recent meta-analysis (Mills et al., 2005). A total of 47 clinical trials with 10 different herbal medicines and 5 different traditional herbal decoctions were re-analyzed. Drug interactions with Hypericum perforatum have been found in 16 out of 24 trials. Furthermore, two of five trials found drug interactions with garlic and another trial reported drug interactions with American ginseng.
5. Safety, quality control, and sustainable production
Efficacy and safety of TCM treatments depend on the quality of TCM products. This is still a major drawback of TCM in the past. With reference to toxic effects of few TCM products in the past (Nortier et al., 2000), quality control and safety issues are of major importance. Plant origin and procedure of preparation have to be well defined and documented. The plants have to be well-characterized applying advanced techniques (HPLC fingerprints, random amplified polymorphic DNA analysis, etc.). Safety limits for residual pesticides, heavy metals, mycotoxins, microbial contaminations, and residual solvents have to be determined.
Before valuable principles derived from TCM can be considered to be integrated into WM, several strategies have been realized to assure and control quality of TCM products:
1. Production, processing, and application of herbal products have to be performed under standardized conditions, e.g., Good Agricultural Practice (GAP), Good Manufacturing Practice (GMP), Good Laboratory Practice (GLP), and Good Clinical Practice (GCP).
2. Phytochemical approaches are applied to isolate phytoconstituents from Chinese herbs. This enables the elucidation of molecular and cellular modes of action (Fig. 2) ( [Battistutta et al., 2000], [Stermitz et al., 2000], [Skrzypczak-Jankun et al., 2003], [Efferth, 2007], [Efferth et al., 2007a], [Efferth et al., 2007b] and [Efferth et al., 2007c]). The identification of the active principles in TCM herbs facilitates the acceptance among western scholars. After isolation of bioactive compounds from medical plants, derivatives with improved pharmacological features can be developed by means of combinatorial chemistry. Upon identification of cellular target molecules, in silico screening techniques to calculate binding affinities of compounds of pharmacophores of target proteins can be applied.
Fig. 2. Structural representation of crystal structures of two exemplary natural products from TCM binding to cancer-related target proteins. (A) Emodin (from the rhizomes of Rheum palmatum; red and green ball and sticks representation) complexes to and inhibits the alpha-subunit of protein kinase CK2 crystal structure (in violet ribbon representation) by replacement of ATP from the protein.9 (PDB code: 1F0Q). (B) Epigallocathechin (from the leaves of Camelia sinensis; red and green ball and sticks representation) binds to lipoxygenase-3 (in yellow ribbon representation) thereby inhibiting the protein’s function.10 (PDB code: 1JNQ). The PDB coordinates of the crystal structures were retrieved from the protein data bank (PDB; http://www.rcsb.org) and figures were generated using PyMol software (http://pymol.sourceforge.net).
3. Most TCM remedies are mixtures of diverse herbs. The idea of “reverse phytochemistry” is to isolate active compounds from different herbs of the mixture and combine them to novel composite products. Thereby, the inactive or toxic herbal constituents are excluded and synergistic actions are exploited. The molecular mode of action of such a synergy has been exemplarily demonstrated for berberine and 5-methoxyhydnocarpine (Stermitz et al., 2000).
4. A related strategy is the measurement of plasma levels of natural products from herbal medicines. Since many constituents are not absorbed by the body, it makes sense to use only those active compounds taken up by the blood circulation for preparing composite TCM products.
5. Bioactive ingredients are generally present in low quantities in plants. Moreover, a sustainable production of TCM products cannot be guaranteed with herbs grown in the wild. Therefore, the genes encoding enzymes involved in the biosynthesis of natural products can be cloned into bacteria (Escherichia coli) or yeast (Saccharomyces cerevisiae) to scale up production. Another strategy is to genetically engineer the nutritional food. This approach can be used for both prevention and treatment of diseases.
6. Conclusion
The most important question for recognition and implementation of TCM into WM concerns the clinical evidence for the efficacy of TCM and international quality standards for TCM products. It will be decisive in the years to come to continue and expand measures for the clinical activity both of isolated natural products and herbal mixtures derived from TCM. Evidence-based approaches in the clinic have to be supplemented by experimental studies to unravel cellular and molecular modes of action of those TCM treatments. Appropriate quality assurance and control of TCM products as well as sustainable production methods are pre-conditions for the implementation of TCM in cancer therapy at an international level. TCM certainly bear a considerable potential for the improvement of cancer therapy. The challenge is to identify the “gems” in TCM and to implement them into WM for the sake of cancer patients.
Acknowledgement
This paper was funded by a grant of the Dietmar Hopp Stiftung, Germany.
References
Battistutta et al., 2000 R. Battistutta, S. Sarno, E. De Moliner, E. Papinutto, G. Zanotti, L.A. Pinna. The replacement of ATP by the competitive inhibitor emodin induces conformational modifications in the catalytic site of protein kinase CK2. Journal of Biological Chemistry, 275 (2000), pp. 29618–29622
Efferth, 2007. T.W. Efferth. Schwabe Award 2006: antiplasmodial and antitumor activity of artemisinin—from bench to bedside. Planta Medica, 73 (2007), pp. 299–309
Efferth et al., 2007a. T. Efferth, Y.J. Fu, Y.G. Zu, G. Schwarz, V.S. Konkimalla, M. Wink. Molecular target-guided tumor therapy with natural products derived from traditional Chinese medicine. Current Medicinal Chemistry, 14 (2007), pp. 2024–2032
Efferth et al., 2007b. T. Efferth, P.C. Li, V.S. Konkimalla, B. Kaina. From traditional Chinese medicine to rational cancer therapy. Trends in Molecular Medicine, 13 (2007), pp. 353–361
Efferth et al., 2007c. T. Efferth, H. Miyachi, H. Bartsch. Pharmacogenomics of a traditional Japanese herbal medicine (Kampo) for cancer therapy. Cancer Genomics and Proteomics, 4 (2007), pp. 81–91
Ezzo et al., 2005. J. Ezzo, A. Vickers, M.A. Richardson et al. Acupuncture-point stimulation for chemotherapy-induced nausea and vomiting. Journal of Clinical Oncology, 23 (2005), pp. 7188–7198
McCulloch et al., 2006. M. McCulloch, C. See, X.J. Shu et al. Astragalus-based Chinese herbs and platinum-based chemotherapy for advanced non-small-cell lung cancer: meta-analysis of randomized trials. Journal of Clinical Oncology, 24 (2006), pp. 419–430
Mills et al., 2005. E. Mills, P. Wu, B.C. Johnston, K. Gallicano, M. Clarke, G. Guyatt. Natural health product-drug interactions: a systematic review of clinical trials. Therapeutic Drug Monitoring, 27 (2005), pp. 549–557
Newman and Cragg, 2007. D.J. Newman, G.M. Cragg. Natural products as sources of new drugs over the last 25 years. Journal of Natural Products, 70 (2007), pp. 461–477
Nortier et al., 2000. J.L. Nortier, M.C. Martinez, H.H. Schmeiser et al. Urothelial carcinoma associated with the use of a Chinese herb (Aristolochia fangchi). The New England Journal of Medicine, 342 (2000), pp. 1686–1692
Pan et al., 2000. C.X. Pan, R.S. Morrison, J. Ness, A. Fugh-Berman, R.M. Leipzig. Complementary and alternative medicine in the management of pain, dyspnea, and nausea and vomiting near the end of life. A systematic review. Journal of Pain and Symptom Management, 20 (2000), pp. 374–387
Shu et al., 2005. X. Shu, M. McCulloch, H. Xiao, M. Broffman, J. Gao. Chinese herbal medicine and chemotherapy in the treatment of hepatocellular carcinoma: a meta-analysis of randomized controlled trials. Integrative Cancer Therapy, 4 (2005), pp. 219–229
Singh, 2005. Y.N. Singh. Potential for interaction of kava and St. John’s wort with drugs. Journal of Ethnopharmacology, 100 (2005), pp. 108–113
Skrzypczak-Jankun et al., 2003. E. Skrzypczak-Jankun, K. Zhou, J. Jankun. Inhibition of lipoxygenase by (−)-epigallocatechin gallate: X-ray analysis at 2,1 A reveals degradation of EGCG and shows soybean LOX-3 complex with EGC instead. International Journal of Molecular Medicine, 12 (2003), pp. 415–420
Stermitz et al., 2000. F.R. Stermitz, P. Loren