This interview is under strict embargo until Friday, 9 April 2 a.m. Beijing time (Thursday, 8 April 2 p.m. U.S. Eastern time)
Drs. Xiao-Jing Yan, a postdoc, and Xiao-Wei Zhang, a faculty member, at State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital affiliated with Shanghai Jiao Tong University School of Medicine, worked under the guidance of their mentors Profs. Zhu Chen and Sai-Juan Chen. The researchers found that arsenic trioxide (As2O3) can directly bind to PML-RARα oncoprotein in acute promyelocytic leukemia (APL) and induce its degradation, thus elucidating the molecular mechanism of the successful target therapy of As2O3 for APL. This work will be published in Science magazine on April 9.
What are the chief findings in your research paper?
Arsenic trioxide (As2O3) is an effective drug for treatment of acute promyelocytic leukemia (APL). As2O3 and all-trans retinoid acid (ATRA) combination as a synergistic therapy in taming APL has made this disease to be highly curable. In this study, we found that the PML-RARα oncoprotein, which plays a crucial role in the pathogenesis of APL, is the direct target of arsenic. Arsenic binds to RBCC domain in the PML moiety of PML-RARα, induces the structural change and polymerization of this oncoprotein, which facilitates its small ubiquitin-like protein modifier (SUMO) modification and consequential degradation.
How does arsenic trioxide combat cancer in patients with acute promyelocytic leukemia (APL)?
In Traditional Chinese Medicine (TCM), arsenic is applied to only severe diseases with the principle "taming an evil with a toxic agent". The PML-RARα oncoprotein in leukemia cells of APL patients results in a clonal expansion of malignant cells, which are blocked at the promyelocyte stage of granulocytic differentiation. In the 1990s, a group under Prof. Chen in Shanghai Institute of Hematology (SIH) discovered the dual effects of arsenic trioxide on APL cells-apoptosis and differentiation. Our studies have explained the molecular mechanisms of action of As2O3 on APL cells. We found that arsenic binds directly to PML-RARα oncoprotein and induces its degradation, which abrogates the growth and survival advantages of leukemia cells, resulting in the remission of the APL patients.
What are the clinical implications of your work?
Though the powerful efficacy of arsenic trioxide in the treatment of APL has already been proved, it is only used as a second-line drug in some countries due to its obscure mechanisms. Our studies discovered the molecular mechanisms of arsenic trioxide by showing that arsenic, like ATRA, could directly target the key oncoprotein PML-RARα. However, As2O3 and ATRA target different moieties of the oncoprotein through distinct mechanisms, and thus have a synergistic effect on APL treatment, as demonstrated in a large scale of clinical trials for newly diagnosed APL, with only minor side effects. The translational approach (from bedside to bench and vice versa) in this study can be extended to the treatment of other types of cancers.
Do you see a similar clinical role for other traditional Chinese medicines?
Yes, the anti-cancer effects of some other TCM have also been detected, such as Homoharringtonine, a plant alkaloid extracted from the unique Cephalotaxus fortunei in China. The homoharringtonine-based regimen has shown better efficacy on the patients with acute myelocytic leukemia (AML) than control chemotherapy in our ongoing clinical trials.
Of note, Realgar-Indigo naturalis formula (RIF), which has been proved to be very effective in treating APL, is designed based on the TCM principles of combination of different components, in which one represents the principal component (similar to Emperor), and others serve as adjuvant ones (respectively similar to Minister, Assistant and Delivering Servant) to assist the effects or facilitate the delivery of the principal component. The main components of RIF are realgar, Indigo naturalis, and S. miltiorrhiza, with tetraarsenic terasulfide (A), indirubin (I) and tanshinone IIA (T) as major active ingredients, respectively. It was found several years ago by the researchers from SIH that the ATI combination yields a very strong synergistic effect, and thus could induce differentiation and apoptosis of leukemic cells.
What is the next step for your research?
First, in our studies we found that arsenic binds PML-RARα through RBCC domain, but has no similar effect on a few other RBCC family proteins. The selective binding of arsenic on PML-RARα oncoprotein and wild-type PML merits further studies. Second, according to the historical records some other TCM may also have anti-cancer effects. We hope to identify some active ingredients from the effective TCM and find their molecular targets and related mechanisms of action, and finally to apply the breakthroughs from the lab to the clinical treatments for patients with other types of leukemia.
These are Dr. Xiao-Jing Yan and Dr. Xiao-Wei Zhang's written remarks. Please refer to the video interview for exact quotes.
Related Research Papers
Arsenic Trioxide Controls the Fate of the PML-RARalpha Oncoprotein by Directly Binding PML