Structures of cisplatin, carboplatin, disulfiram and copper gluconate. Cisplatin has been used for decades to successfully treat testicular cancer. Carboplatin is a second-generation platinum drug that has been used in combination with bortezomib in clinical trials. Disulfiram is a copper chelator and is currently in clinical trials in combination with copper gluconate 

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... (tetraethylthiuram disulfide, DSF) ( Figure 3) is an irreversible inhibitor of aldehyde de- hydrogenase, and is one of only two US FDA-approved drugs for the treatment of alcoholism [177][178][179]. DSF contains an R1R2NC (S)SR3 functional group, with sulfhydryl groups that can react with Cu(II) [180]. This DSF-Cu reaction was confirmed by color-change experiment when DSF and CuCl 2 were mixed at a 1:1 ratio [181]. While DSF is not able to interact with other bioavailable metals such as Fe (II or III) or Mn (III) [180], studies have shown that DSF is able to bind Zn(II). One report demon- strated that Zn(II) supplementation potentiated DSF treatment in melanoma and hepatic cancer [182] and our lab has found that DSF-Zn complex can inhibit the proteasome, albeit at a weaker potency than DSF-Cu. Importantly, studies have also shown that during its absorption into the gastrointestinal system, DSF is promptly converted to its copper complex [177]. We have reported that DSF when complexed with Cu could potently inhibit both purified 20S prote- asome (IC 50 = 7.5 µM) and intact 26S proteasome in MDA-MB-231 breast cancer cell lysates (20 µM). Inhibition of CT-like activity by > 95% and proliferation by up to 85% was observed in cells treated with DSF-Cu. We also showed increased ubiquitinated protein levels, as well as apoptosis-related PARP cleavage and morphological changes [181]. Not surprisingly, DSF alone had no obvious effects in cul- tured cells, which do not contain high levels of copper, but enhanced response was observed in breast cancer cells cultured in copper-enriched medium. Importantly, DSF had no effects on normal breast MCF-10A cells, suggesting a lack of toxicity and a strategy that takes advantage of the increased copper levels observed in human tumor tissues as an anti-tumor mechanism [181]. Our lab has also shown that disulfiram effectively inhibits the proteasome in vivo. We reported signi- ficant tumor growth inhibition (74%) in female athymic nude mice bearing MDA-MB-231 xenografts treated with 50 mg/kg DSF daily for 30 days. A significant decrease in chymotrypsin-like activity (87%) and associated accumulation of Bax, p27 and ubiquitinated proteins were apparent and increases in caspase-3 activity and PARP cleavage associated with apoptosis induction were also observed ...

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... a phase I study investigating the toxicity profile and safety of DSF in combination with copper gluconate (Figure 3) in refractory malignancies with liver metastases (NCT00742911; Hunts- man Cancer Institute) is currently recruiting patients. Another phase I/II clinical trial evaluating the effects of DSF in stage IV metastatic melanoma patients has been completed, but results are not yet available (NCT00256230; UC-Irvine). One study is recruiting patients to examine the effects of DSF on PSA levels in recurrent prostate cancer patients (NCT01118741; Johns Hopkins University). Two additional trials are investigating the efficacy of DSF in combination treatments. One is currently re-cruiting multiple myeloma patients with one previous treatment and will assess response rate and du- ration following treatment with DSF and arsenic trioxide (NCT00571116; UC-Irvine). Though results are unavailable, another study, determining the effects of addition of DSF to current chemotherapeutic treatments in patients with non-small cell lung cancer, has been completed (NCT00312819; Hadassah Medical Organization). Overall, these results suggest a potential novel approach for the treatment of human malignancies that utilizes the ability of DSF to chelate cellular ...

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... discovery that metals like copper and zinc are altered in tumors led to extensive research regarding the roles of these metals in the development and progression of human cancers as well as their potential as anti-cancer therapeutics. High serum and tissue levels of copper have been reported in several tumor types including colon [150], lung [151], prostate [150,152], breast [153,154] and brain [155]. Studies have shown a role for copper as a co-factor in angiogenesis through its ability to induce VEGF mRNA transcription as well as protein expression [156,157]. These studies led to the investigation of copper chelators for anti-angiogenic therapy in cancer treatment regimens [158,159]. Zinc, like copper, plays a key role in cellular processes, including defense against free radicals and proli- feration [43][44] as well as being structurally important to several proteins and enzymes [160,161]. Zinc has also been implicated in apoptosis, but this role appears complex and cell-type specific [162][163][164][165]. Additionally, studies have shown an association between altered Zn levels and systemic abnormalities such as cancer [166], though this, like its role in apoptosis, appears cell-type specific and a firm rela- tionship between zinc levels and tumor development has not yet been established [164,167,168]. Copper and zinc are not only essential to criti- cal biological processes such as tumorigenesis, but they have also been investigated as possible anticancer targets and as metal centers in anti- cancer drugs, especially following the discovery that some metal-based compounds, such as ci- splatin (Figure 3), possess potent anti-cancer properties. Since its discovery, over 90% of te- sticular cancer cases have been cured by cispla- tin, and it has also been important in the treat- ment of several other types of cancer, including bladder, cervical, head and neck, lymphoma, melanoma and ovarian [169]. Cisplatin causes apoptosis via its interaction with DNA and for- mation of adducts which interfere with replica- tion and transcription [170]. After thorough investigation, a (Pt)-GG intrastrand cross-link has been found to be responsible for the cytoto- xicity of cisplatin [171]. Unfortunately, the toxi- cities and drug resistance, both intrinsic and acquired, associated with cisplatin have hinde- red its widespread clinical use [172,173]. The success and limitations of cisplatin have spur- red the search for new, less-toxic metal-based complexes, employing Cu, Zn, Ga, Au, Sn and many other metals, as well as second generation platinum drugs like carboplatin (Figure 3). In these putative drugs, keeping in mind important properties that may affect the activities of these compounds is important. For example, activity is not solely governed by the presence of the metal itself, but can also be influenced by the oxidation state, number and type of ligand bound, and the co- ordination geometry of the complex. Other important properties that can play a role in the activity of metal complexes include kinetic lability, redox behavior, and electric charge/radius ratio. The functio- nal importance of metals, such as copper and zinc, to normal cellular homeostasis coupled with the success of metal-containing chemotherapeutics has resulted in studies investigating chelation of these vital metals with metal-chelators. One example of metal-chelating compounds is dithiocarbamates, which include several drugs that have been previously approved for use in the treatment of various diseases, including bacterial and fungal infections, AIDS, and alcoholism [174][175][176]. Taking advantage of the approval of drugs used to treat different conditions which have also been shown to function as metal chelators is an exciting concept in the field of cancer drug development and design. Previously approved drugs, such as disulfiram (DSF, Figure 3), that may form metal complexes with copper and zinc, have been explored as potential proteasome inhibitors that may serve as novel anticancer ...

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... discovery that metals like copper and zinc are altered in tumors led to extensive research regarding the roles of these metals in the development and progression of human cancers as well as their potential as anti-cancer therapeutics. High serum and tissue levels of copper have been reported in several tumor types including colon [150], lung [151], prostate [150,152], breast [153,154] and brain [155]. Studies have shown a role for copper as a co-factor in angiogenesis through its ability to induce VEGF mRNA transcription as well as protein expression [156,157]. These studies led to the investigation of copper chelators for anti-angiogenic therapy in cancer treatment regimens [158,159]. Zinc, like copper, plays a key role in cellular processes, including defense against free radicals and proli- feration [43][44] as well as being structurally important to several proteins and enzymes [160,161]. Zinc has also been implicated in apoptosis, but this role appears complex and cell-type specific [162][163][164][165]. Additionally, studies have shown an association between altered Zn levels and systemic abnormalities such as cancer [166], though this, like its role in apoptosis, appears cell-type specific and a firm rela- tionship between zinc levels and tumor development has not yet been established [164,167,168]. Copper and zinc are not only essential to criti- cal biological processes such as tumorigenesis, but they have also been investigated as possible anticancer targets and as metal centers in anti- cancer drugs, especially following the discovery that some metal-based compounds, such as ci- splatin (Figure 3), possess potent anti-cancer properties. Since its discovery, over 90% of te- sticular cancer cases have been cured by cispla- tin, and it has also been important in the treat- ment of several other types of cancer, including bladder, cervical, head and neck, lymphoma, melanoma and ovarian [169]. Cisplatin causes apoptosis via its interaction with DNA and for- mation of adducts which interfere with replica- tion and transcription [170]. After thorough investigation, a (Pt)-GG intrastrand cross-link has been found to be responsible for the cytoto- xicity of cisplatin [171]. Unfortunately, the toxi- cities and drug resistance, both intrinsic and acquired, associated with cisplatin have hinde- red its widespread clinical use [172,173]. The success and limitations of cisplatin have spur- red the search for new, less-toxic metal-based complexes, employing Cu, Zn, Ga, Au, Sn and many other metals, as well as second generation platinum drugs like carboplatin (Figure 3). In these putative drugs, keeping in mind important properties that may affect the activities of these compounds is important. For example, activity is not solely governed by the presence of the metal itself, but can also be influenced by the oxidation state, number and type of ligand bound, and the co- ordination geometry of the complex. Other important properties that can play a role in the activity of metal complexes include kinetic lability, redox behavior, and electric charge/radius ratio. The functio- nal importance of metals, such as copper and zinc, to normal cellular homeostasis coupled with the success of metal-containing chemotherapeutics has resulted in studies investigating chelation of these vital metals with metal-chelators. One example of metal-chelating compounds is dithiocarbamates, which include several drugs that have been previously approved for use in the treatment of various diseases, including bacterial and fungal infections, AIDS, and alcoholism [174][175][176]. Taking advantage of the approval of drugs used to treat different conditions which have also been shown to function as metal chelators is an exciting concept in the field of cancer drug development and design. Previously approved drugs, such as disulfiram (DSF, Figure 3), that may form metal complexes with copper and zinc, have been explored as potential proteasome inhibitors that may serve as novel anticancer ...

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... discovery that metals like copper and zinc are altered in tumors led to extensive research regarding the roles of these metals in the development and progression of human cancers as well as their potential as anti-cancer therapeutics. High serum and tissue levels of copper have been reported in several tumor types including colon [150], lung [151], prostate [150,152], breast [153,154] and brain [155]. Studies have shown a role for copper as a co-factor in angiogenesis through its ability to induce VEGF mRNA transcription as well as protein expression [156,157]. These studies led to the investigation of copper chelators for anti-angiogenic therapy in cancer treatment regimens [158,159]. Zinc, like copper, plays a key role in cellular processes, including defense against free radicals and proli- feration [43][44] as well as being structurally important to several proteins and enzymes [160,161]. Zinc has also been implicated in apoptosis, but this role appears complex and cell-type specific [162][163][164][165]. Additionally, studies have shown an association between altered Zn levels and systemic abnormalities such as cancer [166], though this, like its role in apoptosis, appears cell-type specific and a firm rela- tionship between zinc levels and tumor development has not yet been established [164,167,168]. Copper and zinc are not only essential to criti- cal biological processes such as tumorigenesis, but they have also been investigated as possible anticancer targets and as metal centers in anti- cancer drugs, especially following the discovery that some metal-based compounds, such as ci- splatin (Figure 3), possess potent anti-cancer properties. Since its discovery, over 90% of te- sticular cancer cases have been cured by cispla- tin, and it has also been important in the treat- ment of several other types of cancer, including bladder, cervical, head and neck, lymphoma, melanoma and ovarian [169]. Cisplatin causes apoptosis via its interaction with DNA and for- mation of adducts which interfere with replica- tion and transcription [170]. After thorough investigation, a (Pt)-GG intrastrand cross-link has been found to be responsible for the cytoto- xicity of cisplatin [171]. Unfortunately, the toxi- cities and drug resistance, both intrinsic and acquired, associated with cisplatin have hinde- red its widespread clinical use [172,173]. The success and limitations of cisplatin have spur- red the search for new, less-toxic metal-based complexes, employing Cu, Zn, Ga, Au, Sn and many other metals, as well as second generation platinum drugs like carboplatin (Figure 3). In these putative drugs, keeping in mind important properties that may affect the activities of these compounds is important. For example, activity is not solely governed by the presence of the metal itself, but can also be influenced by the oxidation state, number and type of ligand bound, and the co- ordination geometry of the complex. Other important properties that can play a role in the activity of metal complexes include kinetic lability, redox behavior, and electric charge/radius ratio. The functio- nal importance of metals, such as copper and zinc, to normal cellular homeostasis coupled with the success of metal-containing chemotherapeutics has resulted in studies investigating chelation of these vital metals with metal-chelators. One example of metal-chelating compounds is dithiocarbamates, which include several drugs that have been previously approved for use in the treatment of various diseases, including bacterial and fungal infections, AIDS, and alcoholism [174][175][176]. Taking advantage of the approval of drugs used to treat different conditions which have also been shown to function as metal chelators is an exciting concept in the field of cancer drug development and design. Previously approved drugs, such as disulfiram (DSF, Figure 3), that may form metal complexes with copper and zinc, have been explored as potential proteasome inhibitors that may serve as novel anticancer ...

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... the success achieved in preclinical studies, several clinical trials evaluating the effectiveness of bortezomib for the treatment of multiple myeloma in patients have been completed. In a dose-defining phase I trial investigating bortezomib as a single agent, bortezomib induced a dose-dependent inhibi- tion of 20S proteasome activity from 36%, 60%, 65%, to 74%, after 1 hour treatment of bortezomib at 0.40, 1.04, 1.20, and 1.38 mg/m 2 doses, respectively [128]. The results of this study of 27 patients with relapsed multiple myeloma confirmed preclinical findings that bortezomib could inhibit proteasome activity in a dose-and time-dependent manner. The highest dose of bortezomib tested, 1.04 mg/m 2 , was well tolerated and of the nine patients that completed at least one full cycle and were assessable for response, one had a complete response and eight showed improvement in paraprotein levels and marrow plasmacytosis [128]. In another phase I clinical trial bortezomib was used in combination with doxorubicin ( Figure 2). For- ty-two patients with advanced hematologic malignancies were enrolled to obtain preliminary response data and to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs). The maximum tolerated dose was 1.30 mg/m 2 and the most common adverse effects were fatigue (88%), thrombocytopenia (69%), lymphopenia (64%), nausea (64%), constipation (60%), peripheral neuro- pathy (55%), and anemia (52%) [98]. In another clinical trial evaluating 22 multiple myeloma patients with a combination of bortezomib and doxorubicin, eight patients had a complete response (CR, 36%) or near-CR, and another eight had partial responses (PRs, 36%) [98]. Other phase I clinical trials have also investigated the effects of bortezomib either alone or in combina- tion on solid tumors. Bortezomib as a single agent showed anti-tumor activity in patients with advan- ced androgen-independent prostate cancer [129], and an overall response rate of 47% was observed in recurrent ovarian or primary peritoneal cancer after treatment with bortezomib in combination with carboplatin ( Figure 3) [130]. No significant responses were observed in patients with aggressive meta- static breast cancer or neuroendocrine tumors treated with bortezomib alone [38,131,132]. Similarly, in a study of patients with hormone refractory prostate cancer and castrate-resistant metastatic pro- state cancer [133], no significant responses were seen after treatment with bortezomib in combination with either docetaxel [134] or prednisone (Figure 2) ...