Polycationic calixarene PTX013, a potent cytotoxic agent against tumors and drug resistant cancer

Dings, Ruud P.M.; Levine, Joseph; Brown, Susan G.; Astorgues‐Xerri, Lucile; MacDonald, John R.; Hoye, Thomas R.; Raymond, Éric; Mayo, Kevin H.

doi:10.1007/s10637-013-9932-0

Cited by 45 publications

(31 citation statements)

References 21 publications

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“…[116] The peptidomimetics were also further modified and their in vitro and in vivo efficacy was further improved showing over 100-fold higher effect in vitro than the original topomimetics against certain endothelial cells such as SCK and A549. [125] However, the compounds showed dose-dependent toxicity in mice at high doses which had not been reported for an anginex-based therapy before. [125] Overall, anginex and its mimetics are very potent antiangiogenics that have the ability to localise to angiogenically activated endothelial cells and display cytotoxicity to these cells, resulting in decreased vascularisation and decreased tumour growth.…”

Section: Peptide-based Inhibitorsmentioning

confidence: 84%

“…[125] However, the compounds showed dose-dependent toxicity in mice at high doses which had not been reported for an anginex-based therapy before. [125] Overall, anginex and its mimetics are very potent antiangiogenics that have the ability to localise to angiogenically activated endothelial cells and display cytotoxicity to these cells, resulting in decreased vascularisation and decreased tumour growth. The role of galectin-anginex interactions in the anti-angiogenic effect is debatable and further studies are necessary to confirm whether the compounds are truly inhibitors or activators of galectins.…”

Section: Peptide-based Inhibitorsmentioning

confidence: 84%

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Inhibitors of Galectins and Implications for Structure-Based Design of Galectin-Specific Therapeutics

2014

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Galectins are a family of galactoside-specific lectins that are involved in a myriad of metabolic and disease processes. Due to roles in cancer and inflammatory and heart diseases, galectins are attractive targets for drug development. Over the last two decades, various strategies have been used to inhibit galectins, including polysaccharide-based therapeutics, multivalent display of saccharides, peptides, peptidomimetics, and saccharide-modifications. Primarily due to galectin carbohydrate binding sites having high sequence identities, the design and development of selective inhibitors targeting particular galectins, thereby addressing specific disease states, is challenging. Furthermore, the use of different inhibition assays by research groups has hindered systematic assessment of the relative selectivity and affinity of inhibitors. This review summarises the status of current inhibitors, strategies, and novel scaffolds that exploit subtle differences in galectin structures that, in conjunction with increasing available data on multiple galectins, is enabling the feasible design of effective and specific inhibitors of galectins. small-molecule crystallography, University of London, UK) undertook post-doctoral research in protein X-ray crystallography and drug-design in academia and industry within Canada, USA, Switzerland and Australia. In 2002 Helen established a protein X-ray crystallography structural biology group at the Institute for Glycomics, Griffith University. As recognition of her international contribution to structural biology and chemistry she was admitted as fellow of the Royal Society of Chemistry (FRSC) in 2006. Her research involves determination of atomic protein structure, analysis of protein-ligand interactions and application of this information in understanding protein function and for structure based drug-design. Her research group has a major focus on lectins critical to disease progression including her research program on galectins that have importance in serious conditions including cancer. Khuchtumur Bum-Erdene completed his Bachelors degree in Chemistry (

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Section: Peptide-based Inhibitorsmentioning

confidence: 84%

Section: Peptide-based Inhibitorsmentioning

confidence: 84%

Inhibitors of Galectins and Implications for Structure-Based Design of Galectin-Specific Therapeutics

2014

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“…Cancer progression has been suggested to include the loss of cell cycle checkpoint controls that regulate passage through the cell cycle (Pelizzarorocha et al, 2013;Ji et al, 2017). According to the literatures, Dings and co-workers (Dings et al, 2013) have revealed that calixarene amine derivative PTX013 had good cytotoxicity to cancer cells and blockades the cell cycle of SQ20B at G0/G1 phase. In addition, Pelizzarorocha et al (2013) found that tert-butyl calix[6]arenes can cause cell cycle arrest in G0/G1 phase by down-regulating key proteins, such as PIM1, CDK2, and CDK4.…”

Section: Flow Cytometry For Mcf-7 Cell Cycle and Apoptosis Analysismentioning

confidence: 99%

Structural Design, Synthesis, and Preliminary Biological Evaluation of Novel Dihomooxacalix[4]arene-Based Anti-tumor Agents

Wang

Han

et al. 2019

Front. Chem.

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Calixarene and its derivatives have extensively served as promising anti-tumor agents. Previously, we have synthesized a series of calix[n]arene polyhydroxyamine derivatives (n = 4, 6, 8) and found that 5,11,17,23-tetra-tert-butyl-25,27-bis [N-(2-hydroxyethyl)aminocarbonylmethoxyl] calix[4]arene (CLX-4) displayed significant effect toward SKOV3, A549, SW1990, HeLa, Raji, and MDA-MB-231 cancer cells. In the present work, we find a replacement of calix[4]arene bone and synthesized 19 novel structurally related dihomooxacalix[4]arene amide derivatives 4A−4S to optimize its efficacy. Their abilities to induce cytotoxicity in human lung carcinoma (A549) cells, breast cancer (MCF-7) cells, cervical cancer (HeLa) cells, hepatocellular carcinoma (HepG2) cells, as well as human umbilical vein endothelial (HUVEC) cells are evaluated in vitro. Encouraging results show that the majority of dihomooxacalix[4]arene amide derivatives are effective at inhibiting A549 cell proliferation with the corresponding IC 50 ranging from 0.6 to 20.1 µM. In particular, compounds 4A, 4D, and 4L explore markedly increased potency (IC 50 value is 2.0 ± 0.5 µM, 0.7 ± 0.1 µM, and 1.7 ± 0.4 µM) over the cytotoxicity profiles of control CLX-4, whose IC 50 value is 2.8 ± 0.3 µM. More interestingly, 4A also demonstrates the perfect cytotoxic effect against MCF-7, HeLa, and HepG2 cells with IC 50 values of 1.0 ± 0.1 µM, 0.8 ± 0.2 µM, and 2.7 ± 0.4 µM. In addition, the results proved that our synthesized 4A has much lower toxicity (41%) to normal cells at a concentration of 10 µM than that of 4D (90%). To reveal the mechanisms, the key indicators including the cell cycle and apoptosis are observed by the flow cytometry analysis in MCF-7 cells. The results demonstrate that both 4A and 4D can induce the MCF-7 cell cycle arrest in G0/G1 phase and cell apoptosis. Therefore, our finding proves that the dihomooxacalix[4]arene amide derivatives are convenient platforms for potential supramolecular anticancer agents.

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“…Ongoing clinical trials aim to reveal the therapeutic benefit of targeting galectin‐1 in cancer patients . In addition, continuing efforts are undertaken to develop novel galectin‐1‐targeting molecules for diagnostic and therapeutic purposes . In this article, we used a rational approach to generate antibodies with pre‐defined epitope specificity and selectivity for galectin‐1.…”

Section: Introductionmentioning

confidence: 99%

“…11 In addition, continuing efforts are undertaken to develop novel galectin-1-targeting molecules for diagnostic and therapeutic purposes. 24,25 In this article, we used a rational approach to generate antibodies with pre-defined epitope specificity and selectivity for galectin-1. We demonstrate that with this approach we were able to generate antibodies that are specific for galectin-1 and reactive in multiple species, making them excellent candidates for tissue analysis in experimental and clinical setups.…”

Section: Introductionmentioning

confidence: 99%

A key role for galectin‐1 in sprouting angiogenesis revealed by novel rationally designed antibodies

Beijnum

Thijssen

Läppchen

et al. 2016

Intl Journal of Cancer

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Galectins are carbohydrate binding proteins that function in many key cellular processes. We have previously demonstrated that galectins are essential for tumor angiogenesis and their expression is associated with disease progression. Targeting galectins is therefore a potential anti-angiogenic and anti-cancer strategy. Here, we used a rational approach to generate antibodies against a specific member of this conserved protein family, i.e. galectin-1. We characterized two novel mouse monoclonal antibodies that specifically react with galectin-1 in human, mouse and chicken. We demonstrate that these antibodies are excellent tools to study galectin-1 expression and function in a broad array of biological systems. In a potential diagnostic application, radiolabeled antibodies showed specific targeting of galectin-1 positive tumors. In a therapeutic setting, the antibodies inhibited sprouting angiogenesis in vitro and in vivo, underscoring the key function of galectin-1 in this process.

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Polycationic calixarene PTX013, a potent cytotoxic agent against tumors and drug resistant cancer

Cited by 45 publications

References 21 publications

Inhibitors of Galectins and Implications for Structure-Based Design of Galectin-Specific Therapeutics

Inhibitors of Galectins and Implications for Structure-Based Design of Galectin-Specific Therapeutics

Structural Design, Synthesis, and Preliminary Biological Evaluation of Novel Dihomooxacalix[4]arene-Based Anti-tumor Agents

A key role for galectin‐1 in sprouting angiogenesis revealed by novel rationally designed antibodies

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