Mechanistic elucidation of Chinese medicinal formula
Realgar-Indigo naturalis as an effective treatment for promyelocytic leukemia
In March 2008, Prof. Chen Zhu (Minister of Health) and his research group published an article entitled “Dissection of mechanisms of Chinese medicinal formula Realgar-Indigo naturalis as an effective treatment for promyelocytic leukemia” on the Proceedings of the National Academy of Sciences (PNAS). It was probably the first systematic analysis conducted to unravel the efficacy and underlying working mechanisms of Chinese medicinal formula-Realgar Indigo naturalis (RIF) for treatment of acute promyelocytic leukemia (APL). Through current biochemical approaches, the modes of actions of clinically effective Realgar-Indigo naturalis formula: “multiple components could hit multiple targets and exert effects of mutual reinforcement” have been demonstrated at molecular, cellular and organism levels. The rationale of TCM design: “Principal”, “Minister”, “Assistant” and “Servant” have also been illustrated using modern biomedical approaches.
Rationale of combination therapy and formula design
Prof. Chen has pioneered extensive research in combining all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) as a synergistic chemotherapy for APL. ATRA and ATO have been reported to induce degradation of promyelocytic leukemia (PML)-retinoic acid receptor alpha (RARα) that finally facilitated APL cell differentiation and apoptosis. The clinical efficacy of ATRA/ATO combined therapy has been reported with 4-year disease-free survival of more than 90% in APL patients.
As early as 1980s, the pathogenesis of APL still remained unclear, Prof. Huang Shi Lin and a group of experts at TCM Hematology Institute of People's Liberation Army designed a TCM-theory guided Realgar Indigo naturalis formula comprising of Realgar, Indigo naturalis, Salvia miltiorrhiza and Radix psudostellariae in accordance to symptoms and characteristics of APL patients. With collective efforts on combination therapy, APL will hopefully be the first curable acute myeloid leukemia. It has been documented that APL patients with RIF prescription achieved a 5-year overall survival rate of 87% in multicenter clinical trials. Despite its clinical efficacy, the molecular basis of RIF for APL treatment remained unresolved.
Mechanistic elucidation of TCM formula
Prof. Chen and his research group are the one who provide convincing explanation on the molecular mechanism of RIF at biochemical level. Tetraarsenic tetrasulfate (A), indirubin (I) and tanshinone IIA (T) are major active ingredients of Realgar, Indigo naturalis and Salvia miltiorrhiza respectively. Tetraarsenic tetrasulfate is regarded as the “Principal” element which induces ubiquitination and degradation of PML-RARα oncoprotein and partly restore normal myeloid cell transcription leading to terminal APL cell differentiation. Indirubin and tanshinone IIA serve as adjuvant components to intensify tetraarsenic tetrasulfate-induced ubiquitination and degradation of PML-RARα, strengthen reprogramming of myeloid differentiation regulators and enhance G1/G0 arrest in APL cells. As demonstrated in murine APL model, Indigo naturalis serves as “Assistant” to alleviate toxic and adverse effect possessed by the Principal: Realgar. Both indirubin and tanshinone IIA act as “Delivering servants” to facilitate delivery of Principal element (Realgar) to the site of disease. Indirubin and tanshinone IIA increase cellular uptake of arsenic by inducing up-regulation of Aquaglyceroporin 9 (AQP9) which is a transmembrane protein governing arsenic uptake and cellular sensitivity of arsenic. Collectively, the ATI components in Realgar Indigo naturalis formula hit multiple targets and work together in a synergistic mode.
Breakthrough of research methodology in multi-component CM formula design and mechanistic study
Chen’s research group have successfully elucidated the multiple components/multiple targets working mechanisms of RIF with current biomedical approaches and illustrated the rationale of formula design. Most researchers regard dissociation of TCM formula into smaller pieces for downstream research as difficult tasks since the innate efficacy may be lost once the formula was broken into discrete pieces. Given the complexity for dissecting mode of action of numerous clinically proven formulae, it is suggested to begin with those accompanied with precise efficacy as well as known bioactive components and structures. Prof. Chen remarked that choosing to study Realgar-Indigo naturalis formula is the first key step leading to fruitful research findings since the three major components: tetraarsenic tetrasulfate, indirubin and tanshinone IIA have already been well-studied. With modern pharmaco-chemical methods, major bioactives in RIF have been dissociated, combined and authenticated. As a result, the actual working mechanisms and sites of action possessed by RIF can be fully dissected at molecular and cellular levels.
Consistency in functional and mechanistic recognition of each bioactive component has been derived from either molecular research findings or perceptions of TCM practitioners. Prof. Chen’s research findings have attracted extensive positive comments from scientific academia worldwide. A comment entitled “Traditional Chinese medicine: Ancient formula in modern times” has been published in Nature China, with special emphasis on how major components of an ancient Chinese medicinal formula act in a harmony to cure disease and its significance for bridging the gap between Traditional Chinese medicine and Modern Western medicine. Besides, “SciBX: Science-Business eXchange”, a joint publication platform organized by Nature Publishing Group and BioCentury Publications Inc., has also reported these research findings.
Embracing tradition and innovation
Prof. Chen attributes his success primarily to the choice of TCM formula. The clinical efficacy of RIF in treating promyelocytic leukemia has been proven in multiple clinical centers which provided solid foundation for further downstream studies. His prominent research findings can also be attributed to the availability of highly purified bioactive compounds as well as well-established cell culture and animal APL models. Enrichment of TCM theoretical system and applicability are the blueprints for TCM development. All in all, embracing tradition and innovation is advocated. Prof. Chen is in favor of an open mind for TCM modernization. He also recommended that research should embrace modern technology and multi-disciplinary approach. TCM combination therapy, based on nearly 100,000 formulae, has been advocated for more than 2500 years. Western medicine practitioners have gradually recognized the advantages of combination therapy in recent years. Although TCM formulae have achieved clinical efficacies, not all essential components have been identified and their underlying working mechanisms have not yet been explained convincingly at biochemical level. These collectively hinder the modernization of TCM and their application. Current advances in system biology and biomedical sciences will offer opportunities and platforms to bridge and integrate Western and Eastern medicines, and pave the way towards modernization of TCM. Through tradition and innovation, novel or modern medicine will emerge in a better form from Chinese and Western medicine.
Sources:
Nature China http://www.nature.com/nchina/2008/080326/full/nchina.2008.64.html
Proceedings of the National Academy of Sciences (PNAS) www.pnas.org/content/105/12/4826
ScienceNet-Sciences Times http://www.sciencenet.cn/
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