1122-90-3Relevant articles and documents
Arsenic trioxide targets Hsp60, triggering degradation of p53 and survivin
Cheung, Yam Fung,Hu, Xuqiao,Ip, Tiffany Ka-Yan,Koohi-Moghadam, Mohamad,Li, Hongyan,Naranmandura, Hua,Ng, Kwan-Ming,Sun, Hongzhe,Tritton, Daniel N.,Tse, Eric Wai-Choi,Wang, Haibo,Wang, Runming,Wang, Yi,Wang, Yuchuan,Yang, Xinming
, p. 10893 - 10900 (2021)
The mechanisms of action of arsenic trioxide (ATO), a clinically used drug for the treatment of acute promyelocytic leukemia (APL), have been actively studied mainly through characterization of individual putative protein targets. There appear to be no studies at a system level. Herein, we integrate metalloproteomics through a newly developed organoarsenic probe, As-AC (C20H17AsN4O3S2) with quantitative proteomics, allowing 37 arsenic binding and 250 arsenic regulated proteins to be identified in NB4, a human APL cell line. Bioinformatics analysis reveals that ATO disrupts multiple physiological processes, in particular, chaperone-related protein folding and cellular response to stress. Furthermore, we discover heat shock protein 60 (Hsp60) as a vital target of ATO. Through biophysical and cell-based assays, we demonstrate that ATO binds to Hsp60, leading to abolishment of Hsp60 refolding capability. Significantly, the binding of ATO to Hsp60 disrupts the formation of Hsp60-p53 and Hsp60-survivin complexes, resulting in degradation of p53 and survivin. This study provides significant insights into the mechanism of action of ATO at a systemic perspective, and serves as guidance for the rational design of metal-based anticancer drugs. This journal is
Structural Modification of Aminophenylarsenoxides Generates Candidates for Leukemia Treatment via Thioredoxin Reductase Inhibition
Song, Zi-Long,Zhang, Junmin,Xu, Qianhe,Shi, Danfeng,Yao, Xiaojun,Fang, Jianguo
, p. 16132 - 16146 (2021/11/16)
Upregulation of the selenoprotein thioredoxin reductase (TrxR) is of pathological significance in maintaining tumor phenotypes. Thus, TrxR inhibitors are promising cancer therapeutic agents. We prepared different amino-substituted phenylarsine oxides and evaluated their cytotoxicity and inhibition of TrxR. Compared with our reported p-substituted molecule (8), the o-substituted molecule (10) shows improved efficacy (nearly a fourfold increase) to kill leukemia HL-60 cells. Although the compounds 8 and 10 display similar potency to inhibit the purified TrxR, the o-substitution 10 exhibits higher potency than the p-substitution 8 to inhibit the cellular TrxR activity. Molecular docking results demonstrate the favorable weak interactions of the o-amino group with the TrxR C-terminal active site. Efficient inhibition of TrxR consequently induces the oxidative stress-mediated apoptosis of cancer cells. Silence of the TrxR expression sensitizes the cells to the arsenic compound treatment, further supporting the critical involvement of TrxR in the cellular actions of compound 10.
Organoarsenic compound and use thereof
-
, (2019/03/06)
The invention discloses an organoarsenic compound. The organoarsenic compound has the following structural formula as shown in the specification, wherein n is 1 or 2; R, R1, R2, R3, R4 and R5 are respectively and independently amino, R6-CO-NH, R7-CO-O, alkyl, aryl, a heterocyclic substituent, alkoxyl, alkylamino, a halogen atom, nitro, hydroxyl or a hydrogen atom; R6 is alkyl, aminoalkyl or aryl;R7 is alkyl, aminoaryl or aryl. The organoarsenic compound has good inhibitory activity for thioredoxin reductase, has strong cytotoxicity for tumor cell HL-60, and can be used for preparing a thioredoxin reductase inhibitor or an antitumor drug with thioredoxin reductase as a target spot.
