TY - JOUR
T1 - Arsenoplatin-1 Is a Dual Pharmacophore Anticancer Agent
AU - Miodragović, Denana
AU - Merlino, Antonello
AU - Swindell, Elden P.
AU - Bogachkov, Abraham
AU - Ahn, Richard W.
AU - Abuhadba, Sara
AU - Ferraro, Giarita
AU - Marzo, Tiziano
AU - Mazar, Andrew P.
AU - Messori, Luigi
AU - O'Halloran, Thomas V.
N1 - Funding Information:
T.V.O. and Đ.M. acknowledge support from the National Institute of Health: U01CA15146, 1U54CA193419, and U54CA202995-03 (ChicagoCHEC). L.M. and T.M. gratefully acknowledge Beneficentia Stiftung, ITT (Instituto Toscano Tumori), Ente Cassa Risparmio Firenze (ECR), and AIRC for funding the projects (IG-16049) and “Advanced Mass Spectrometry Tools for Cancer Research: Novel Applications in Proteomics, Metabolomics and Nanomedicine” (Multiuser equipment Program 2016, ref code 19650). COST Action CM1105 and CIRCMSB are also acknowledged. T.M. thanks AIRC-FIRC (Fondazione Italiana per la Ricerca sul Cancro, 3-years Fellowship for Italy Project Code: 18044). We wish to thank Dr. Nenad Juranic (Mayo Clinic) for sharing his expertise with NMR. We thank Dr. Alessandro Pratesi (University of Florence) for the support with ESI-MS experiments and simulations.
Publisher Copyright:
© 2019 American Chemical Society.
PY - 2019/4/24
Y1 - 2019/4/24
N2 - Arsenoplatins are adducts of two chemically important anticancer drugs, cisplatin and arsenic trioxide, that have a Pt(II) bond to an As(III) hydroxide center. Screens of the NCI-60 human tumor cell lines reveal that arsenoplatin-1 (AP-1), [Pt(μ-NHC(CH3)O)2ClAs(OH)2], the first representative of this novel class of anticancer agents, displays a superior activity profile relative to the parent drugs As2O3 or cisplatin in a majority of cancer cell lines tested. These activity profiles are important because the success of arsenic trioxide in blood cancers (such as APL) has not been seen in solid tumors due to the rapid clearance of arsenous acid from the body. To understand the biological chemistry of these compounds, we evaluated interactions of AP-1 with the two important classes of biomolecules - proteins and DNA. The first structural studies of AP-1 bound to model proteins reveal that platinum(II) binds the Nμ of His in a manner that preserves the Pt-As bond. We find that AP-1 readily enters cells and binds to DNA with an intact Pt-As bond (Pt:As ratio of 1). At longer incubation times, however, the Pt:As ratio in DNA samples increases, suggesting that the Pt-As bond breaks and releases the As(OH)2 moiety. We conclude that arsenoplatin-1 has the potential to deliver both Pt and As species to a variety of hematological and solid cancers.
AB - Arsenoplatins are adducts of two chemically important anticancer drugs, cisplatin and arsenic trioxide, that have a Pt(II) bond to an As(III) hydroxide center. Screens of the NCI-60 human tumor cell lines reveal that arsenoplatin-1 (AP-1), [Pt(μ-NHC(CH3)O)2ClAs(OH)2], the first representative of this novel class of anticancer agents, displays a superior activity profile relative to the parent drugs As2O3 or cisplatin in a majority of cancer cell lines tested. These activity profiles are important because the success of arsenic trioxide in blood cancers (such as APL) has not been seen in solid tumors due to the rapid clearance of arsenous acid from the body. To understand the biological chemistry of these compounds, we evaluated interactions of AP-1 with the two important classes of biomolecules - proteins and DNA. The first structural studies of AP-1 bound to model proteins reveal that platinum(II) binds the Nμ of His in a manner that preserves the Pt-As bond. We find that AP-1 readily enters cells and binds to DNA with an intact Pt-As bond (Pt:As ratio of 1). At longer incubation times, however, the Pt:As ratio in DNA samples increases, suggesting that the Pt-As bond breaks and releases the As(OH)2 moiety. We conclude that arsenoplatin-1 has the potential to deliver both Pt and As species to a variety of hematological and solid cancers.
UR - http://www.scopus.com/inward/record.url?scp=85064979823&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85064979823&partnerID=8YFLogxK
U2 - 10.1021/jacs.8b13681
DO - 10.1021/jacs.8b13681
M3 - Article
C2 - 30943017
AN - SCOPUS:85064979823
SN - 0002-7863
VL - 141
SP - 6453
EP - 6457
JO - Journal of the American Chemical Society
JF - Journal of the American Chemical Society
IS - 16
ER -