Anticancer metallohelices: nanomolar potency and high selectivity

Kaner, Rebecca A.; Allison, Simon J.; Faulkner, Alan D.; Phillips, Roger M.; Roper, David I.; Shepherd, Samantha L.; Simpson, Daniel H.; Waterfield, Nicholas R.; Scott, Peter

doi:10.1039/c5sc03677a

Cited by 52 publications

(44 citation statements)

References 44 publications

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“…In addition, the Annexin V-FITC/PI double-labeled flow cytometry analysis revealed that the apoptotic rates of U2OS and 143B cells concentration-dependently increased with cinobufagin treatment. In consistent with our results, previous literature reports have shown that cinobufagin induces apoptosis in a variety of human tumor cells [9, 10, 12, 13, 15, 16]. Thus, these data indicate that the induction of apoptosis is the main cause of the tumor cell growth inhibition by cinobufagin.…”

Section: Discussionsupporting

confidence: 93%

Cinobufagin Induces Apoptosis in Osteosarcoma Cells Via the Mitochondria-Mediated Apoptotic Pathway

Dai

Zheng

Guo

et al. 2018

Cell Physiol Biochem

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Background/Aims: Osteosarcoma is a common primary malignant bone tumor that mainly occurs in childhood and adolescence. Despite developments in the diagnosis and treatment of osteosarcoma, the prognosis is still very poor. Cinobufagin is an active component in the anti-tumor Chinese medicine called “Chan Su”, and we previously revealed that cinobufagin induced apoptosis and reduced the viability of osteosarcoma cells; however, the underlying mechanism remains to be elucidated. Herein, the present study was undertaken to illuminate the molecular mechanism of cinobufagin-induced apoptosis of osteosarcoma cell. Methods: U2OS and 143B cells were treated with different concentrations of cinobufagin. Cell viability, colony formation ability and morphological changes were assessed by a CCK-8 assay, a clonogenic assay and light microscopy, respectively. Cell apoptosis was detected by Hoechst 33258 and Annexin V-FITC/PI staining. Reactive oxygen species (ROS) and mitochondrial membrane potential (ΔΨm) were determined by flow cytometry. Glutathione (GSH) levels were detected by a GSH and GSSG assay kit. The levels of apoptosis-related proteins were determined by western blotting, and 143B cells were introduced to establish a xenograft tumor model. The effect of cinobufagin on osteosarcoma was further investigated in vivo. Results: Our results showed that cinobufagin significantly reduced the viability of U2OS and 143B cells in vitro in a dose-and time-dependent manner. In addition, cinobufagin-induced apoptosis in U2OS and 143B cells was concentration-dependent. Moreover, we found that cinobufagin treatment increased the level of intracellular ROS, decreased ΔΨm, reduced GSH and inhibited GSH reductase (GR). The effects of cinobufagin on cell proliferation, apoptosis, ROS generation and ΔΨm loss were dramatically reversed when the cells were pretreated with the thiol-antioxidants NAC or GSH. Moreover, cinobufagin treatment increased the expression of the pro-apoptotic protein Bax and decreased the expression of the anti-apoptitic protein Bcl-2, thus altering the ratio of Bax to Bcl-2. Furthermore, Cinobufagin treatment caused cytochrome c release from the mitochondria to cytoplasm, thus increasing the protein levels of cleaved-caspase family members to induce apoptosis. Ac-DEVD-CHO or Z-LEHD-FMK significantly reduced cinobufagin-induced apoptosis. Finally, a subcutaneous xenograft animal study verified that cinobufagin also significantly suppressed osteosarcoma growth in vivo. Conclusions: Our present data demonstrated that cinobufagin triggered cell apoptosis in osteosarcoma cells via the intrinsic mitochondria-dependent apoptosis pathway by the accumulation of ROS and the loss of ΔΨm. In an in vivo subcutaneous xenograft model, cinobufagin exhibited excellent tumor inhibitory effects. These results suggest that cinobufagin might potentially be further developed as an anti-tumor candidate for treating osteosarcoma patients in the clinic.

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Section: Discussionsupporting

confidence: 93%

Cinobufagin Induces Apoptosis in Osteosarcoma Cells Via the Mitochondria-Mediated Apoptotic Pathway

Dai

Zheng

Guo

et al. 2018

Cell Physiol Biochem

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“…[5][6][7] In particular,h elicates have been shown to be potential drugs for cancer treatment. [8,9] Their anticancer properties result from their intrinsic chiral nature and topological features (size and charge), whichallow the specific recognition of DNA and noncovalentb inding. Pioneering studies of Hannon demonstrated that helicate complexes interactw ith DNA in new and distinctive ways, where the external surfaces of the heli-cates recognize unusualD NA junction structures, and induce remarkable intramolecular DNA coilinge ffects.…”

Section: Introductionmentioning

confidence: 99%

Steric and Electronic Factors Affecting the Conformation of Bimetallic Cu^I Complexes: Effect of the Aliphatic Spacer of Tetracoordinating Schiff‐Base Ligands

Díaz

Llanos

Arce

et al. 2018

Chemistry A European J

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A family of six homoleptic [Cu (L )] (ClO ) and six heteroleptic [Cu (L )(PPh ) ] (ClO ) bimetallic complexes, in which L are bis-Schiff base ligands with alkyl spacers of variable length (n=2-7 -CH -), were prepared to evaluate the role of the spacer on the formation of helicates or mesocates. In the homoleptic series, spectroscopic and theoretical studies indicate that preferences for a conformation are based on energetic parameters, mainly, the establishment of noncovalent interactions. The odd-even nature of the spacers preconditions the superposition of the aromatic rings to allow the juxtaposition necessary for noncovalent interactions, whereas the increase of the length reduces the strength of such interactions. Consequently, complexes with even-spacers of short length were identified as helicates in solution, [Cu (L )] (n=2, 4). Complexes [Cu (L )] (n=3-7) dissociate in solution to produce the monometallic complexes in equilibrium, [Cu (L )] . The stability of the bimetallic species is discussed in terms of their conformations. The set of heteroleptic complexes was prepared to evaluate the reach of the "odd-even rule" in the solid, which is based on the "zig-zag" arrangements of the spacers. Based on crystallographic information, "S-" and "C"-type conformations of L are related to even and odd spacers, respectively. This trend is considered in addition to other factors to explain preferences for either a mesocate or helicate conformation in the homoleptic series.

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“…from achiral bis‐bidendate building blocks, and trinuclear triple‐stranded homo‐ and heterometallic helicates were reported by Ghosh and co‐workers . Metallohelices exhibiting anticancer activity with nanomolar potency were reported by Kaner et al . We have explored the coordination behavior of metal ions with heterocyclic nucleobases to synthesize complex supramolecular motifs with interesting photophysical properties such as fluorescent gold nanoclusters for cell nuclei imaging and luminescent silver complexes …”

Section: Figurementioning

confidence: 98%

Luminescent Silver–Purine Double Helicate: Synthesis, Self‐Assembly and Antibacterial Action

et al. 2016

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How would you describe your research? We have designed al uminescent silver-purine helical coordination complex and studied its antibacterial activity against both Gram-positive and Gram-negative bacteria. The MIC values indicate that the complex exhibits significantly better activity against Gram-negative bacteria, especially against E. coli.L uminescent properties of this complex were used to study its bacterial cell uptake with the help of fluorescence and scanning electron microscopy methods. This study suggests that silver-purine double helical complexes could be used as potential antibacterial agents.

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Anticancer metallohelices: nanomolar potency and high selectivity

Abstract: New optically pure helicate-like architectures are extremely active against cancer cell lines, with IC50 values as low as 40 nM, but nearly three orders of magnitude less active against healthy cells. There is also low toxicity to microbes and amoeba.

Cited by 52 publications

References 44 publications

Cinobufagin Induces Apoptosis in Osteosarcoma Cells Via the Mitochondria-Mediated Apoptotic Pathway

Cinobufagin Induces Apoptosis in Osteosarcoma Cells Via the Mitochondria-Mediated Apoptotic Pathway

Steric and Electronic Factors Affecting the Conformation of Bimetallic Cu^I Complexes: Effect of the Aliphatic Spacer of Tetracoordinating Schiff‐Base Ligands

Luminescent Silver–Purine Double Helicate: Synthesis, Self‐Assembly and Antibacterial Action

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Anticancer metallohelices: nanomolar potency and high selectivity

Abstract: New optically pure helicate-like architectures are extremely active against cancer cell lines, with IC50 values as low as 40 nM, but nearly three orders of magnitude less active against healthy cells. There is also low toxicity to microbes and amoeba.

Cited by 52 publications

References 44 publications

Cinobufagin Induces Apoptosis in Osteosarcoma Cells Via the Mitochondria-Mediated Apoptotic Pathway

Cinobufagin Induces Apoptosis in Osteosarcoma Cells Via the Mitochondria-Mediated Apoptotic Pathway

Steric and Electronic Factors Affecting the Conformation of Bimetallic CuI Complexes: Effect of the Aliphatic Spacer of Tetracoordinating Schiff‐Base Ligands

Luminescent Silver–Purine Double Helicate: Synthesis, Self‐Assembly and Antibacterial Action

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Product

Resources

About

Steric and Electronic Factors Affecting the Conformation of Bimetallic Cu^I Complexes: Effect of the Aliphatic Spacer of Tetracoordinating Schiff‐Base Ligands