New uses for old copper-binding drugs: converting the pro-angiogenic copper to a specific cancer cell death inducer

Chen, Di; Dou, Q. Ping

doi:10.1517/14728222.12.6.739

Cited by 61 publications

(51 citation statements)

References 90 publications

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“…To address enormous unmet medical needs, there have been recent efforts in "repurposing" drugs (14,15,45,55) from other therapies even for neglected parasitic diseases (5,8,19,27,34,38,39). The current therapeutic drugs for Chagas' (13).…”

Section: Discussionmentioning

confidence: 99%

Image-Based High-Throughput Drug Screening Targeting the Intracellular Stage of Trypanosoma cruzi , the Agent of Chagas' Disease

Engel¹,

Ang

Chen

et al. 2010

Antimicrob Agents Chemother

101

114

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Chagas' disease, caused by infection with the parasite Trypanosoma cruzi, is the major cause of heart failure in Latin America. Classic clinical manifestations result from the infection of heart muscle cells leading to progressive cardiomyopathy. To ameliorate disease, chemotherapy must eradicate the parasite. Current drugs are ineffective and toxic, and new therapy is a critical need. To expedite drug screening for this neglected disease, we have developed and validated a cell-based, high-throughput assay that can be used with a variety of untransfected T. cruzi isolates and host cells and that simultaneously measures efficacy against the intracellular amastigote stage and toxicity to host cells. T. cruzi-infected muscle cells were incubated in 96-well plates with test compounds. Assay plates were automatically imaged and analyzed based on size differences between the DAPI (4,6-diamidino-2-phenylindole)-stained host cell nuclei and parasite kinetoplasts. A reduction in the ratio of T. cruzi per host cell provided a quantitative measure of parasite growth inhibition, while a decrease in count of the host nuclei indicated compound toxicity. The assay was used to screen a library of clinically approved drugs and identified 55 compounds with activity against T. cruzi. The flexible assay design allows the use of various parasite strains, including clinical isolates with different biological characteristics (e.g., tissue tropism and drug sensitivity), and a broad range of host cells and may even be adapted to screen for inhibitors against other intracellular pathogens. This high-throughput assay will have an important impact in antiparasitic drug discovery.

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Section: Discussionmentioning

confidence: 99%

Image-Based High-Throughput Drug Screening Targeting the Intracellular Stage of Trypanosoma cruzi , the Agent of Chagas' Disease

Engel¹,

Ang

Chen

et al. 2010

Antimicrob Agents Chemother

101

114

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“…For instance, the list (Tables 1, 2) contains multiple compounds sharing common activities or properties, such as heavymetal chelators, DNA-replication inhibitors, microtubules inhibitors, dihydrofolate reductase inhibitors, and protein synthesis inhibitors. In fact, many of these drugs as well as menadione [37] are potential generators of reactive oxygen species (ROS) [38][39][40][41][42]. The four top-ranking drugs, however, could up-regulate RECK in SW480 which carries a mutant p53 gene [43] (Fig.…”

Section: Discussionmentioning

confidence: 99%

A novel screen using the Reck tumor suppressor gene promoter detects both conventional and metastasis-suppressing anticancer drugs

et al. 2010

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AbstrAct:The membrane-anchored matrix metalloproteinase-regulator RECK is often downregulated in various types of cancers; the levels of residual RECK in resected tumors often correlate with better prognosis. Forced expression of RECK in cancer cells suppresses tumor angiogenesis, invasion, and metastasis in xenograft models. RECK is therefore a promising marker for benignancy and a potential effector in cancer therapy. We established a cell line containing two transgene systems: (1) the secreted alkaline phosphatase (SEAP) gene fused to Reck promoter and (2) the HRAS 12V oncogene driven by the Tet-off promoter system. This cell line exhibits transformed phenotype in regular medium and flat morphology with increased SEAP activity in the presence of doxycycline, allowing the assessment of RECK-inducing activity of chemicals in the contexts of both transformed and untransformed cells. Our pilot experiments with 880 known bioactive compounds detected 34 compounds that activate RECK promoter; among these, 10 were authentic anticancer drugs. Four selected compounds up-regulated endogenous RECK protein in several human cancer cell lines. The top-ranking compound, disulfiram, strongly suppressed spontaneous lung-metastasis of human fibrosarcoma cells in nude mice. Our data demonstrate the value of this screen in discovering effective cancer therapeutics.

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“…These two chelators, already utilized for the treatment of AD and bacterial and fungal infections, respectively, offer the attracting perspective to discover new applications of existing drugs having pharmacological and safety profiles already defined with the ultimate goal to shorten the way toward clinical trials. 155 Additional tests in Jurkat T cells established that such mixtures had selectivity toward tumor or transformed cells. This behavior has been related to the different high copper load in tumor cells vs. low copper load in normal cells.…”

Section: B ''Copper Mixtures'' As Proteasome Inhibitorsmentioning

confidence: 99%

Copper in diseases and treatments, and copper‐based anticancer strategies

Tisato¹,

Marzano

Porchia³

et al. 2009

Medicinal Research Reviews

455

420

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Copper is found in all living organisms and is a crucial trace element in redox chemistry, growth and development. It is important for the function of several enzymes and proteins involved in energy metabolism, respiration, and DNA synthesis, notably cytochrome oxidase, superoxide dismutase, ascorbate oxidase, and tyrosinase. The major functions of copper-biological molecules involve oxidation-reduction reactions in which they react directly with molecular oxygen to produce free radicals. Therefore, copper requires tightly regulated homeostatic mechanisms to ensure adequate supplies without any toxic effects. Overload or deficiency of copper is associated, respectively, with Wilson disease (WD) and Menkes disease (MD), which are of genetic origin. Researches on Menkes and Wilson disorders have provided useful insights in the field of copper homeostasis and in particular into the understanding of intracellular trafficking and distribution of copper at molecular levels. Therapies based on metal supplementation with copper histidine or removal of copper excess by means of specific copper chelators are currently effective in treating MD and WD, respectively. Copper chelation therapy is now attracting much attention for the investigation and treatment of various neurodegenerative disorders such as Alzheimer, Parkinson and CreutzfeldtJakob. An excess of copper appears to be an essential co-factor for angiogenesis. Moreover, elevated levels of copper have been found in many types of human cancers, including prostate, breast, colon, lung, and brain. On these basis, the employment of copper chelators has been reported to be of therapeutic value in the treatment of several types of cancers as anti-angiogenic molecules. More recently, mixtures of copper chelators with copper salts have been found to act as efficient proteasome inhibitors and apoptosis inducers, specifically in cancer cells. Moreover, following the worldwide success of platinum(II) compounds in cancer chemotherapy, several families of individual copper complexes have been studied as potential antitumor agents. These investigations, revealing the occurrence of mechanisms of action quite different from platinum drugs, head toward the development of new anticancer metallodrugs with improved specificity and decreased toxic side effects.

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New uses for old copper-binding drugs: converting the pro-angiogenic copper to a specific cancer cell death inducer

Cited by 61 publications

References 90 publications

Image-Based High-Throughput Drug Screening Targeting the Intracellular Stage of Trypanosoma cruzi , the Agent of Chagas' Disease

Image-Based High-Throughput Drug Screening Targeting the Intracellular Stage of Trypanosoma cruzi , the Agent of Chagas' Disease

A novel screen using the Reck tumor suppressor gene promoter detects both conventional and metastasis-suppressing anticancer drugs

Copper in diseases and treatments, and copper‐based anticancer strategies

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