Co-Treatment With Copper Compounds Dramatically Decreases Toxicities Observed With Cisplatin Cancer Therapy And The Anticancer Efficacy Of Some Copper Chelates Supports The Conclusion That Copper Chelate Therapy May Be Markedly More Effective And Less Toxic Than Cisplatin Therapy

Abstract

Co-Administration of Cu(II) chelates are reported to decrease life threatening Cisplatin [Pt(II) (NH3)2(CL)2]-induced acute degenerative renal, gastrointestinal, thymic, and bone marrow states consistent with serious necrotizing and immune-mediated inflammatory disease. Initially it was found that copper sulfate treatment completely prevented lethality as well as gastric and nephrotoxicity without compromising Pt(II) (NH3)2(CL) 2 antineoplastic activity, which led to suggestions that prior Cu(II)-treatment be used clinically to prevent serious side effects of Pt(II) (NH3)2(CL)2-treatment. In the course of these studies it was discovered that Cu(II)-treatments alone inhibited neoplastic growth and increased survival of rat and mouse models of cancer. Subsequently it was discovered that a stable non-toxic and non-polar lipophilic chelate, Copper(II)2(3,5-diisopropylsalicylate)4, caused redifferentiation of cultured neuroblastoma and mouse muscle-implanted mammary adenocarcinoma without neoplastic cell killing. Another stable non-toxic and non-polar lipophilic chelate, Copper(II)2(3,5-ditertiarybutylsalicylate)4, was found to prevent Bax-initiated and caspases-3-activation mediated apoptosis. These remarkable observations are concluded to be due to enzyme-mimetic or modulating reactivities of Cu(II) chelates and/or facilitation of Cu(II or I)-dependent enzyme syntheses required to overcome inflammatory-neoplastic disease states. Further, approaches to treating neoplastic diseases by removal of Cu from tissues with ammonium tetrathiomolybdate in an anticopper approach to therapy are not well founded based upon existing scientific literature.

Transcriptional up-regulation of SOD1 by CEBPD: A potential target for cisplatin resistant human urothelial carcinoma cells

“…Interestingly, specific copper chelators that inhibit SOD1 activity are well tolerated and have already been used in clinical trials in cancer patients due to their anti-angiogenic activity [63,64]. Furthermore, it has been shown that Cu/Zn chelators dramatically reduce cisplatin toxicity in animal models [65]. Our data suggest that SOD1 can contribute to cisplatin resistance in bladder carcinoma cells.…”

Mononuclear copper (II) salicylate complexes with 1,2-dimethylimidazole and 2-methylimidazole: Synthesis, spectroscopic and crystal structure characterization and their superoxide scavenging activities

“…Collectively these spectral and magnetic results along with analytical data indicate that Cu (II) ion in complex 2 is coordinated to three 2-methylimidazole ligands and one doubly deprotonated salicylate ion (sal 2À ), which is chelated to Cu (II) ion through one of its carboxylate oxygen atoms and the deprotonated hydroxyl oxygen atom to form Cu(2-MeIm) 3 (sal) complex which has distorted square pyramidal CuN 3 O + O chromophore (Scheme 1).…”

“…Salicylic acid (a) and its derivatives have been used for many years as anti-inflammatory, antipyretic and analgesic drugs. Binary and ternary Cu (II) complexes of salicylic acid and its derivatives with basic ligands have been found to exhibit several pharmacological effects suggesting treatment of many pathological disease states [3][4][5][6][7][8][9][10]. These disease states include many inflammations, seizures, gastric and intestinal ulcers, diabetes, neoplasias carcinogenesis, convulsion, mutagenesis, ischemia-reperfusion injury, and radiation injury.…”

Salicylate •Phenanthroline copper (II) complex induces apoptosis in triple-negative breast cancer cells

“…Specifically, these compounds inhibit the growth of tumor cells, and Sorenson et al ., showed that copper salicylic acid had anti-tumor potential in animal models. Treatment led to reduced tumor growth and metastasis, induced tumor cell differentiation, and increased host survival [22, 23]. Other studies have found that copper salicylic acid chelated with phenanthroline increased its toxicity in tumor cells [24].…”