Copper(II) and manganese(III) complexes of N'-[(2-hydroxy phenyl) carbonothioyl] pyridine-2-carbohydrazide: novel therapeutic agents for cancer.
c-Src is a non-receptor tyrosine kinase which plays a significant role in the growth mediated signaling pathway impacting cellular proliferation, differentiation, mobility, survival and transformation. Myristoylation of pp60(c-src) leads to its membrane association and activation, a process catalyzed by N-myristoyltransferase (NMT). We have shown earlier increased NMT activity in the early stages of colon cancer. A novel sulfur nitrogen donor ligand and its Cu(II) and Mn(III) complexes have been prepared and characterized using various physicochemical analyses. These Cu(II) and Mn(III) complexes showed cytotoxicity against the colon cancer cell line HT29. The IC(50) for Cu(II) and Mn(III) complexes were 12.2 and 16.1 microM, respectively. HT29 cells treated with Cu(II) and Mn(III) complexes induced apoptosis and inhibited endogenous NMT activity. Furthermore, they induced higher levels of hsc70 and inhibited the expression of c-Src. Inhibition of endogenous NMT activity by metal complexes was demonstrated for the first time. This study also suggested that NMT activity is crucial for cell survival and demonstrated that cessation in activity results in apoptosis. These metal complexes may prove to be novel therapeutic agents for cancer targeting NMT.
Shrivastav
Anuraag
A
Department of Pathology, College of Medicine, University of Saskatchewan and Health Research Division, Saskatchewan Cancer Agency, Saskatoon, Saskatchewan, Canada SK S7N 4H4.
Singh
Nand K
NK
Tripathi
Pratibha
P
George
Theresa
T
Dimmock
Jonathan R
JR
Sharma
Rajendra K
RK
D000217:Acyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000230:Adenocarcinoma / Q000188:drug therapy* / Q000201:enzymology; D000970:Antineoplastic Agents / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D003300:Copper / Q000737:chemistry* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D019073:HT29 Cells; D006801:Humans; D006834:Hydrazines / Q000737:chemistry* / Q000378:metabolism; D008024:Ligands; D008345:Manganese / Q000737:chemistry* / Q000378:metabolism; D009942:Organometallic Compounds / Q000737:chemistry / Q000494:pharmacology*; D013438:Sulfhydryl Compounds / Q000737:chemistry* / Q000378:metabolism
D000970:Antineoplastic Agents; D006834:Hydrazines; D008024:Ligands; C516322:N'-((2-hydroxyphenyl)carbonothioyl)pyridine-2-carbohydrazide; D009942:Organometallic Compounds; D013438:Sulfhydryl Compounds; D008345:Manganese; D003300:Copper; D000217:Acyltransferases; C050480:glycylpeptide N-tetradecanoyltransferase