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Bioinorganic Chemistry and Chemical Biology

 

¾¾ Mechanistic investigation of anticancer metallodrugs

 

 

Tetrathiomolybdate Induces Dimerization of the Metal-binding Domain of ATPase and Inhibits Platination of the Protein

 

Nature Communications, 2019, 10, 186

The copper efflux protein ATPase is associated with the cisplatin resistance. Tetrathiomolybdate (TM) is a drug used for the treatment of Wilson's disease by targeting ATP7B (WLN). We found that TM induces dimerization of the metal-binding domain of ATP7B (WLN4) through a unique sulfur-bridged Mo2S6O2 cluster. The binding of Mo to cysteine residues of WLN4 inhibits platination of the protein. These results reveal the molecular mechanism how TM attenuates the cisplatin resistance mediated by copper efflux proteins.

 

 

Arsenic trioxide preferentially binds to the ring finger protein PML: understanding target selection of the drug

Arsenic trioxide (ATO) is used in clinic for the treatment of acute promyelocytic leukemia (APL) by targeting the protein PML. We found that ATO preferentially binds to the ring-finger domain of PML in the proteins mixture with zinc-finger domains. This result suggests a strategy of novel anti-APL drug design by selective targeting to PML. Based on this hypothesis, we found a new anti-APL ruthenium agent (see following the work).

 

Metallomics, 2018,10, 1564-1569

 

 

 

 

A dual functional ruthenium arene complex induces differentiation and apoptosis of acute promyelocytic leukemia cells

 

Chem. Sci., doi: 10.1039/C9SC03110C

Based on above the hypothesis, we identified a Ru(II) arene complex, [(¦Ç6-p-bip)Ru(en)Cl][PF6] (Ru-1) that can selectively react with PML. This reaction leads to the zinc-release and protein unfolding. Consequently, the degradation of the fusion protein PML-RAR¦Á occurs, which causes the differentiation of APL cells. In addition, Ru-1 can also bind to DNA and trigger apoptosis of APL cells. Therefore, Ru-1 acts as a dual functional agent that inhibits the growth of APL cells and induces the cell differentiation. On the contrary, the other non-selective Ru(II) compound, though also highly reactive to PML, does not exhibit anti-APL activity.

 

 

 

Cisplatin Binds to Human Copper Chaperone Cox17: the Mechanistic Implication of Drug Delivery to Mitochondria

 

 

Chem. Commun. 2014, 50, 2667¨C2669

Biochem. J., 2015, 472(2) 217¨C223

We found that the human copper chaperone Cox17 facilitates the delivery of cisplatin to mitochondria. The platinum accumulation in mitochondria is clearly enhanced by the overexpression of Cox17, and is significantly reduced by silencing the Cox17 gene. In addition, the expression of Cox17 and its transport to mitochondria contribute to the cytotoxicity of the drug. In vitro studies show that cisplatin binds to Cox17 at the copper coordination residues, and the platination of Cox17 leads to the copper release from the protein. Although the drug inactive transplatin can also react with Cox17, this reaction is highly suppressed by glutathione (GSH), the most abundant cellular reducing agent. On the contrary, the presence of GSH enhances the reactivity of cisplatin to Cox17. In addition, the pre-formed cisplatin/GSH adducts are more readily to react with Cox17, and cisplatin can transfer from glutathione to Cox17. These results indicate that Cox17 could contribute to the platinum drug transport to mitochondria, and glutathione plays crucial roles in modulating the reactivity of various platinum complexes.

 

 

 

¾¾ Design of novel anticancer metallodrugs

 

 

Aspirin Ligation Enhances Cisplatin Efficacy by Altering the Cellular Response

˵Ã÷: E:\Paper_Working\ChengQinqin\Asplatin\Angew_Asplatin\TOC4.tif

 

Chem. Commun., 2014, 50(56),7427¨C7430,

Metallomics, 2016, 8, 672-678

A novel conjugate of platinum (IV) prodrug has been designed and synthesized by the ligation of aspirin to cisplatin, to generate c,c,t-[PtCl2(NH3)2(OH)(aspirin)] (asplatin). Asplatin exhibits significant cytotoxicity to tumor cells, up to 10 times more effective than cisplatin. In addition, asplatin almost fully overcomes the drug resistance of the cisplatin resistant cells. Asplatin is highly accumulated in cancer cells; upon the reduction with cellular ascorbic acid, asplatin is activated and binds to DNA more efficiently than cisplatin. Meanwhile, the aspirin released from asplatin also modulate the cellular response to the platinum agent. Mechanistic studies reveal that the aspirin ligand promotes the apoptosis via the BCL-2 associated mitochondrial pathway, which greatly sensitizes the tumor cells to the cisplatin converted from asplatin. Therefore, the ligation of aspirin to the platinum drug exhibits the great synergistic effect in the low micromolar range. The in vivo experiment shows that asplatin exerts a significant inhibitory effect on tumor growth with lower systemic toxicity compared with cisplatin. This result offers a novel strategy to enhance sensitivity of platinum drugs by ligation of the anti-inflammation drug aspirin. [Highlighted in Chemistry World]

 

 

 

¾¾ Drug delivery

 

 

Modular design of nanobody-drug conjugates for targeted-delivery of platinum anticancer drugs with an MRI contrast agent

 

Chem. Commun., 2019, 55, 5175-5178

Targeted delivery is highly desirable in cancer chemotherapy, particularly for cisplatin. We developed a multifunctional nanobody-drug conjugate (NDC) for targeted delivery of platinum(IV) prodrug and MRI contrast agent. NDC can be specifically internalized into EGFR positive cancer cells. Therefore, the drug accumulation is increased in EGFR positive tumor and decreased in major orangs, resulting in higher therapeutic effect and lower side-effects in comparison to the treatment of cisplatin. The fusion of anti-albumin nanobody improves the pharmacokinetic properties of NDC, which further enhances the drug efficacy. In addition, the Gd-binding domain enables in situ detection of the drug distribution in vivo.

 

 

Oral Delivery of Platinum Anticancer Drug Using Lipid Assisted Polymeric Nanoparticles

 

Chem. Commun., 2015, 51, 17536¨C17539

 

Oral administration is highly desirable in chemotherapy, particularly for drugs with severe side-effects, eg. platinum anticancer drugs. Although Pt(II) antitumor drugs can be treated only via intravenous injection, Pt(IV) complexes have shown high oral bioavailability. However, the undesired reduction limits the effectiveness of Pt(IV) agents. Here, we present a nano-delivery platform for the oral administration of Pt(IV) prodrug using the lipid assisted polymeric nanoparticles. The self-assembled cholesterol-asplatin-incorporated nanoparticles (SCANs) exhibit enhanced cellular uptake and sustained drug release. SCANs exhibit higher inhibitory efficiency compared with free cisplatin on multiple cancer cells, including cisplatin resistant cells. Pharmacokinetic study reveals that SCANs demonstrate significantly improved oral bioavailability with the prolonged drug release time and the postponed drug clearance in comparison to free Pt(IV) prodrugs. In vivo assay shows that the oral administration of SCANs effectively inhibits the tumor growth with significantly lower nephrotoxicity and systemic toxicity compared with intravenous treatment of cisplatin. [Highlighted in Chemistry World]

 

 

Charge-Selective Delivery of Proteins Using Mesoporous Silica Nanoparticles Fused with Lipid Bilayers

 

ACS Appl. Mater. Interfaces, 2019, 11, 3645-3653

 

We developed a platform for efficient protein delivery using mesoporous silica nanoparticles (MSN and MSN). The cargo proteins, based on the surface charges, can be selectively loaded in very high efficiency. The lipid fusion significantly increases the stability of the nano-system in physiological condition, and the MSN-LP protocell can efficiently deliver proteins into cells. Proteins can maintain their functions after delivery into cells.

 

 

 

 

Human Serum Albumin Conjugated Nanoparticles for pH and Redox-Responsive Delivery of a Prodrug of Cisplatin

 

 

 

Chem. Eur. J. 2015, 21(46), 16547¨C16554

A highly biocompatible, pH and redox dual-responsive delivery system is prepared using the hybrid nanoparticles of human serum albumin (HSA) and calcium phosphate (CaP) for the Pt(IV) prodrug of cisplatin. This conjugate is very stable under the extracellular conditions, so that it protects the Pt(IV) prodrug in HSA. Upon reaching the acidic and hypoxia environment, the platinum drug is released in its active form and is able to bind to the target DNA. Interestingly, this delivery system demonstrates enhanced cytotoxicity to tumor cells, but not to normal cells.

 

 

 

¾¾ Mechanistic investigation of metalloproteins

 

 

Cuprous binding promotes interaction of copper transport protein hCTR1 with cell membranes

 

Chem. Commun., 2019, 55, 11107-11110

Human copper transporter (hCTR1) is a plasma membrane protein that facilitates the cellular uptake of cuprous ions. The extracellular N-terminal metal binding domain (MBD) of hCTR1 is proposed to capture copper ions and transfer them into cells via coordination transfer. We found that Cu(I) ions bind to the N-terminal MBD of hCTR1 to form a Cu(His)2(Met)2 coordination and induce its conformational change. This alteration promotes the interaction of N-terminal MBD with cell membranes, which is confirmed on DPPC liposomes and on living cells as well. Confocal fluorescence images clearly showed that, upon Cu(I) coordination, hCTR11-46 binds to the membrane of cells. These results reveal that copper binding triggers the conformation change of N-terminal MBD of hCTR1 and leads to the membrane interaction, which can be a crucial step to initiate the cellular uptake of copper ions by hCTR1.

 

 

 

Copper-Finger Protein of Sp1: the Molecular Basis of Copper Sensing

 

Metallomics, 2017, 9, 1169-1175

The expression of copper transport protein hCtr1 is transcriptionally regulated by specifity protein 1 (Sp1) in response to the cellular copper level. We found that Sp1 demonstrates high binding affinity to cuprous ions, even stronger than Cu-Atox1 binding. Cu(I) can displace Zn(II) in Sp1, resulting in a well-folded ¡®Copper-Finger-Protein¡¯ (CFP). Although only very little structural alteration occurs upon the copper binding, CFP cannot recognize the promoter of hCtr1, therefore copper binding interrupts the transcription. This result indicates that, in addition to apo-to-holo alteration, the metal substitution can also lead to the transcriptional switch in metal sensing.

 

 

 

 

 

 

 

 

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