Disulfiram when combined with copper enhances the therapeutic effects of temozolomide for the treatment of Glioblastoma
It would certainly be worth considering the use of DSF-Cu in the neoadjuvant and adjuvant setting both in newly diagnosed and recurrent patients since based on the newly described mechanism-of-action, namely inhibiting DNA repair, DSF-Cu may act as a radiation
sensitizer at the time of radiation therapy. Moreover, we believe that our observations are not
limited to repurposing DSF solely for glioma but could be used when combined with a copper
supplement in a number of cancers for which resistance to DNA damaging agents is commonly
observed and in situations when targeting DNA repair coupled with proteasome inhibition
demonstrates therapeutic benefit such as in multiple myeloma.
Ni(II), Cu(II), and Zn(II) Diethyldithiocarbamate Complexes Show Various Activities Against the Proteasome in Breast Cancer Cells
A series of three complexes with diethyldithiocarbamate ligand and three different metals (Ni, Cu, Zn) was prepared, confirmed by X-ray crystallography, and tested in human breast cancer MDA-MB-231 cells. Zinc and copper complexes, but not nickel complex, were found to be more active against cellular 26S proteasome than against purified 20S proteasome core particle. One of the possible explanations is inhibition of JAMM domain in the 19S proteasome lid.
Targeting copper in cancer therapy: 'Copper That Cancer'.
Many cancer types exhibit increased intratumoral copper and/or altered systemic copper distribution. The realization that copper serves as a limiting factor for multiple aspects of tumor progression, including growth, angiogenesis and metastasis, has prompted the development of copper-specific chelators as therapies to inhibit these processes. Another therapeutic approach utilizes specific ionophores that deliver copper to cells to increase intracellular copper levels. The therapeutic window between normal and cancerous cells when intracellular copper is forcibly increased, is the premise for the development of copper-ionophores endowed with anticancer properties.
Turning Tumor-Promoting Copper into an Anti-Cancer Weapon via High-Throughput Chemistry
Cancer tissues have a high level of copper that participate in cellular processes such as angiogenesis to promote cancer development. Organic compounds that bind copper provide useful tools to convert cancer-promoting copper to cancer-fighting agents. These copper complexes can serve as anti-angiogenesis agents or ROS generators to inhibit tumor growth. These agents can also target cellular proteins such as the proteasome to inhibit cancer cell proliferation. Taken together, medicinal chemistry, computation modeling, and combinatorial chemistry can provide powerful tools to explore chemical space and structure-activity relationships in order to optimize and develop more potent and specific anticancer copper ligands.
Advances in Copper Complexes as Anticancer Agents
The advent of targeted therapies, i.e., small molecules or antibodies that interfere with signaling proteins involved in the etiology of cancer, revolutionized the treatment of tumors with an addiction to specific oncogenes (e.g., ALK in lung cancer, Bcr-Abl in chronic myeloid leukemia, KIT in GIST, EGFR in lung cancer, HER2 in breast cancer or MET in liver tumors). However, for many cancers, the progressionfree survival of patients treated with targeted therapy is less than one year, which justify for a regain of interest in cytotoxic agents including metallodrugs. Indeed, the prevalent success of cisplatin in the treatment of various types of cancers has placed organometallic compounds on the forefront in the development of anticancer drugs.
In this quest, copper derivatives hold promising opportunities due to opportunities provided by the hypoxic environment that is a hallmark of cancer cells coupled with the ability of copper complexes to catalyze the formation of Reactive Oxygen and Nitrogen species (ROS and RNS).
Design, Syntheses, Characterization, and Cytotoxicity Studies of Novel Heterobinuclear Oxindolimine Copper(II)-Platinum(II) Complexes
The design and syntheses of two new mononuclear oxindolimine-copper(II) (1 and 2) and corresponding hetero binuclear oxindolimine Cu(II)Pt(II) complexes (3 and 4), are described. Finally, the cytotoxicity of each complex was tested toward different tumor cells, in comparison to cisplatin, and low values of IC 50 in the range 0.6 to 4.0μM were obtained, after 24 or 48h incubation at 37°C. The obtained results indicate that such complexes can be promising alternative antitumor agents.
Sonochemical Synthesis and Characterization of the Copper(II) Nanocomplex: DNA- and BSA-Binding, Cell Imaging, and Cytotoxicity Against the Human Carcinoma Cell Lines.
The in vitro cytotoxicity of the complex (solution in DMSO) and nanocomplex (colloid in H2O) against the human carcinoma cell lines (MCF-7 and A-549) was evaluated by MTT assay. The results of in vitro cytotoxicity indicate that the complex and nanocomplex have excellent cytotoxicity activity against MCF-7 and A-549. Results of the microscopic analyses of the cancer cells confirm the results of the cytotoxicity.
A mononuclear Cu(II) complex with 5,6-diphenyl-3-(2-pyridyl)-1,2,4-triazine: Synthesis, crystal structure, DNA- and BSA-binding, molecular modeling, and anticancer activity against MCF-7, A-549, and HT-29 cell lines.
The in vitro cytotoxicity indicate that the complex has excellent anticancer activity against the three human carcinoma cell lines, MCF-7, A-549, and HT-29, with IC50 values of 9.8, 7.80, and 4.50 μM, respectively. The microscopic analyses of the cancer cells demonstrate that the Cu(II) complex apparently induced apoptosis.
DNA binding, DNA cleavage, and cytotoxicity studies of two new copper (II) complexes.
Slow decrease in DNA viscosity indicates partially intercalative binding in addition to hydrogen binding on the surface of DNA. The second binding mode was also confirmed by additional tests: interaction in denaturation condition and acidic pH. Also, these new complexes induced cleavage in pUC18 plasmid DNA as indicated in gel electrophoresis and showed excellent antitumor activity against K562 (human chronic myeloid leukemia) cells.
Dinuclear Copper(I) Complexes Containing Cyclodiphosphazane Derivatives and Pyridyl Ligands: Synthesis, Structural Studies, and Antiproliferative Activity toward Human Cervical and Breast Cancer Cells
Copper(I) complexes containing cyclodiphosphazanes and pyridyl-type ligands show excellent antiproliferative activity toward human cervical and breast cancer cells. One of the copper(I) complexes traps a cluster of four water molecules through hydrogen bonding to form a one-dimensional polymeric sheetlike structure.
Clioquinol and pyrrolidine dithiocarbamate complex with copper to form proteasome inhibitors and apoptosis inducers in human breast cancer cells
A unique feature of cancer cells is to accumulate high concentrations of copper. We believe a potential strategy for cancer chemotherapy could involve the use of organic ligands that act as copper sensors and bind with the elevated copper in cancer cells and tissues. These complexes would act as proteasome inhibitors and apoptosis inducers to tumor cells. Because normal cells contain only trace amounts of copper, the organic ligands should form far fewer complexes with copper in them, thus exposing the normal cells to a minimal dose and reducing toxicity. We propose that treatment with copper-binding compounds such as CQ and PDTC will result in these compounds behaving as tumor 'sensors' using copper as a selection criterion. Therefore, this approach may convert the proangiogenic cofactor copper into a cancer-specific killing agent.