Dissection of mechanisms of Chinese medicinal formula Realgar-Indigo naturalis as an effective treatment for promyelocytic leukemia.
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 alpha (RARalpha) oncoprotein, stronger reprogramming of myeloid differentiation regulators, and enhanced G(1)/G(0) 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-RARalpha 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.
Wang
Lan
L
State Key Laboratory of Medical Genomics and Shanghai Institute of Hematology, Rui Jin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 197 Rui Jin Road II, Shanghai 200025, China.
Zhou
Guang-Biao
GB
Liu
Ping
P
Song
Jun-Hong
JH
Liang
Yang
Y
Yan
Xiao-Jing
XJ
Xu
Fang
F
Wang
Bing-Shun
BS
Mao
Jian-Hua
JH
Shen
Zhi-Xiang
ZX
Chen
Sai-Juan
SJ
Chen
Zhu
Z
D000818:Animals; D020346:Aquaporins / Q000235:genetics / Q000378:metabolism; D001152:Arsenicals / Q000494:pharmacology / Q000627:therapeutic use*; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004357:Drug Synergism; D004365:Drugs, Chinese Herbal / Q000494:pharmacology / Q000627:therapeutic use*; D016193:G1 Phase / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008516:Medicine, Chinese Traditional; D051379:Mice; D015514:Oncogene Proteins, Fusion / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D016192:Resting Phase, Cell Cycle / Q000187:drug effects; D013440:Sulfides / Q000494:pharmacology / Q000627:therapeutic use*; D014158:Transcription, Genetic / Q000187:drug effects; D054875:Ubiquitination / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
C109669:AQP9 protein, human; D020346:Aquaporins; D001152:Arsenicals; D004365:Drugs, Chinese Herbal; D015514:Oncogene Proteins, Fusion; D013440:Sulfides; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; C528183:realgar-indigo naturalis; C058317:arsenic disulfide