Dissection of mechanisms of Chinese medicinal formula Realgar- Indigo naturalis as an effective treatment for promyelocytic leukemia

Abstract

To enhance therapeutic efficacy and reduce adverse effects, practitioners of traditional Chinese medicine (TCM) prescribe a combination of plant species/minerals, called formulae, based on clinical experience. Nearly 100,000 formulae have been recorded, but the working mechanisms of most remain unknown. In trying to address the possible beneficial effects of formulae with current biomedical approaches, we use Realgar-Indigo naturalis formula (RIF), which has been proven to be very effective in treating human acute promyelocytic leukemia (APL) as a model. The main components of RIF are realgar, Indigo naturalis, and Salvia miltiorrhiza, with tetraarsenic tetrasulfide (A), indirubin (I), and tanshinone IIA (T) as major active ingredients, respectively. Here, we report that the ATI combination yields synergy in the treatment of a murine APL model in vivo and in the induction of APL cell differentiation in vitro. ATI causes intensified ubiquitination/degradation of promyelocytic leukemia (PML)-retinoic acid receptor ␣ (RAR␣) oncoprotein, stronger reprogramming of myeloid differentiation regulators, and enhanced G1/G0 arrest in APL cells through hitting multiple targets compared with the effects of mono-or biagents. Furthermore, ATI intensifies the expression of Aquaglyceroporin 9 and facilitates the transportation of A into APL cells, which in turn enhances A-mediated PML-RAR␣ degradation and therapeutic efficacy. Our data also indicate A as the principal component of the formula, whereas T and I serve as adjuvant ingredients. We therefore suggest that dissecting the mode of action of clinically effective formulae at the molecular, cellular, and organism levels may be a good strategy in exploring the value of traditional medicine.traditional chinese medicine ͉ active ingredient ͉ tetraarsenic tetrasulfide ͉ synergism ͉ systems biology T he complexity of medicine suggests that treatment protocols should be carefully designed, and the construction of a prescription is an art in fighting disease. Increasing evidence demonstrates that, in treating illnesses, including cancer (1) and HIV/AIDS (2), treatment regimens containing multiple drugs with distinct but related mechanisms can usually amplify the therapeutic efficacies of each agent, leading to maximal therapeutic efficacy with minimal adverse effects. Interestingly, combination therapy has been advocated for Ͼ2,500 years by prescriptions called formulae (3, 4) in traditional Chinese medicine (TCM), a unique medical system assisting the ancient Chinese in dealing with disease. Typically, formulae consist of several types of medicinal herbs or minerals, in which one represents the principal component, and others serve as adjuvant ones to assist the effects or facilitate the delivery of the principal component (3, 4). It is believed that, at least in some formulae, multiple components could hit multiple targets and exert synergistic therapeutic efficacies (3, 4). However, essential compounds have not been identified in most formulae, whereas precise mechanisms of form...

Pin1 expression contributes to lung cancer prognosis and carcinogenesis

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Functional divergence of diterpene syntheses in the medicinal plant Salvia miltiorrhiza Bunge

“…These are highly bioactive. For example, tanshinone IIA exerts vasorelaxative activity, has antiarrhythmic effects, provides protection against ischemia reperfusion injury Gao et al, 2008;Sun et al, 2008), and exhibits anticancer activities (Efferth et al, 2008;Lee et al, 2008;Wang et al, 2008;Gong et al, 2011). In addition, tanshinones have been reported to have a broad spectrum of antimicrobial activities against various plant pathogens, including rice (Oryza sativa) blast fungus Magnaporthe oryzae (Zhao et al, 2011).…”

Retrospective analysis of 119 cases of pediatric acute promyelocytic leukemia: Comparisons of four treatment regimes

“…Wang et al (27) reported that RIF, when used in a murine APL model, promoted ubiquitination and degradation of the PML/RARα oncoprotein by inducing expression and transportation of aquaglyceroporin-9 which degraded PML/RARα. It also enhanced G1/G0 arrest of APL cells by regulating multiple targets of the cell cycle.…”