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Zhao C.,Guangzhou Medical UniversityGuangdong | Chen X.,Guangzhou Medical UniversityGuangdong | Zang D.,Guangzhou Medical UniversityGuangdong | Lan X.,Guangzhou Medical UniversityGuangdong | And 17 more authors.
Biochemical Pharmacology | Year: 2016

DNA is the well-known molecular target of current platinum-based anticancer drugs; consequently, their clinical use is severely restricted by their systemic toxicities and drug resistance originating from non-selective DNA damage. Various strategies have been developed to circumvent the shortcomings of platinum-based chemotherapy but the inherent problem remains unsolved. Here we report that platinum pyrithione (PtPT), a chemically well-characterized synthetic complex of platinum, inhibits proteasome function and thereby exhibits greater and more selective cytotoxicity to multiple cancer cells than cisplatin, without showing discernible DNA damage both in vitro and in vivo. Moreover, unlike the classical proteasome inhibitor bortezomib/Velcade which inhibits the proteasome via blocking the peptidase activity of 20S proteasomes, PtPT primarily deactivates 26S proteasome-associated deubiquitinases USP14 and UCHL5. Furthermore, PtPT can selectively induce cytotoxicity and proteasome inhibition in cancer cells from leukemia patients but not peripheral blood mononuclear cells from healthy humans. In nude mice, PtPT also remarkably inhibited tumor xenograft growth, without showing the adverse effects that were induced by cisplatin. Hence, we have discovered a new platinum-based anti-tumor agent PtPT which targets 26S proteasome-associated deubiquitinases rather than DNA in the cell and thereby exerts safer and more potent anti-tumor effects, identifying a highly translatable new platinum-based anti-cancer strategy. © 2016


Zhu J.,Henan University | Chen L.,Henan University | Dong Y.,Key Laboratory of Natural Drug and Immune Engineering of Henan Province | Li J.,Lanzhou University | And 2 more authors.
Spectrochimica Acta - Part A: Molecular and Biomolecular Spectroscopy | Year: 2014

In this work, the interaction of 5-Hydroxymethyl-2-furfural (5-HMF) with calf thymus DNA (ctDNA) under simulated physiological conditions (Tris-HCl buffer of pH 7.40), was explored by UV absorption spectroscopy, fluorescence spectroscopy and molecular modeling method, using ethidium bromide (EB) as a fluorescence probe of DNA. The fluorescence quenching mechanism of EB-ctDNA by 5-HMF was confirmed to be a static quenching, which derived from the formation of a new complex. The binding constants of 5-HMF with DNA in the presence of EB were calculated to be 2.17 × 103, 4.24 × 103 and 6.95 × 103 L mol-1 at 300, 305 and 310 K, respectively. The calculated thermodynamic parameters, enthalpy change ΔH and entropy change ΔS, suggested that both hydrophobic interactions and hydrogen bonds played a predominant role in the binding of 5-HMF to DNA. According to the UV absorption spectroscopy and melting temperature (T m) curve results, the binding mode of 5-HMF with DNA was indicative of a non-intercalative binding, which was supposed to be a groove binding. The molecular modeling results showed that 5-HMF could bind into the hydrophobic region of ctDNA and supported the conclusions obtained from the above experiments. © 2013 Elsevier B.V. All rights reserved.


Zhu J.,Henan University | Wu L.,Henan University | Wu L.,Key Laboratory of Natural Drug and Immune Engineering of Henan Province | Zhang Q.,Henan University | And 3 more authors.
Spectrochimica Acta - Part A: Molecular and Biomolecular Spectroscopy | Year: 2012

The interaction between Daphnin with human serum albumin has been studied for the first time by spectroscopic methods including fluorescence quenching technology, circular dichroism (CD) spectroscopy and Fourier transform infrared (FT-IR) spectroscopy under simulative physiological conditions. The results of fluorescence titration revealed that Daphnin can quench the intrinsic fluorescence of HSA by static quenching and there is a single class of binding site on HSA. In addition, the studies of CD spectroscopy and FT-IR spectroscopy showed that the protein secondary structure changed with increases of α-helices at the drug to protein molar ratio of 2. Furthermore, the thermodynamic functions ΔH 0 and ΔS 0 for the reaction were calculated to be 11.626 kJ mol -1 and 118.843 J mol -1 K -1 according to Van't Hoff equation. The thermodynamic parameters (ΔH 0 and ΔS 0) and the molecular modeling study indicated that hydrophobic force played an important role to stabilize the Daphnin-HSA complex, and Daphnin could bind within the subdomain IIA of the HSA. © 2012 Elsevier B.V. All rights reserved.

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