Bis(4,7‐dimethyl and 5‐dinitro‐1,10‐phenanthroline) sulfato‐oxovanadium(IV)‐mediated in vivo male germ cell apoptosis

Abstract

Oxovanadium(IV) [VO] complexes of 1,10-phenanthroline are a new class of potent apoptosis-inducing cytotoxic agents against human testicular cancer cells in vitro. The present study investigated the in vivo ability of four(bis)-chelated 1,10-phenanthroline [phen] complexes of sulfato-oxovanadium(IV)-VO(phen)(2), VO(Cl-phen)(2), VO(Me(2)-phen)(2) and VO(NO(2)-phen)(2)-with and without substitutions, to induce testicular germ cell apoptosis. Male germ cell loss in mice was measured by determining the epididymal sperm count, testicular weight and histological evaluation of the testes. Repetitive intratesticular injection (7.5 mg kg(-1) testis(-1)) of bis-chelated 1,10-phenanthroline complexes of oxovanadium(IV) with 4,7-dimethyl [VO(Me(2)-phen)(2)] and 5-dinitro [VO(NO(2)-phen)(2)] substitution led to decreased sperm counts and reduced testicular weights. Histopathological examination of testicular sections from VO(Me(2)-phen)(2)- and VO(NO(2)-phen)(2)-treated mice revealed a marked inhibition of spermatogenesis and preferential loss of maturing, as well as elongated spermatids. In situ evaluation of seminiferous tubule cross-sections by terminal deoxynucleotidyl transferase-mediated FITC-deoxyuridine triphosphate nick end-labeling (TUNEL) and laser scanning confocal microscopy showed characteristic apoptotic germ cells delineating the periphery of the seminiferous tubules. The ability of bis-chelated 4,7-dimethyl- and 5-dinitro-substituted 1,10-phenanthroline complexes of oxovanadium(IV) to induce germ cell apoptosis in vivo may have potential utility in the treatment of human testicular germ cell tumors.

Molecular Symmetry: A Structural Property Frequently Present in New Cytotoxic and Proapoptotic Drugs

“…These compounds were shown to have a pseudo-first-order rate constant that is one order of magnitude higher than that of cisplatin in the reaction with glutathione. In the search for other active antitumor complexes, various metals have been reported and the most interesting of these are ruthenium [60], cobalt [61], gold [62], iron [63], copper [64] and vanadium [65]. The structure-activity relationships for such systems have not yet been clearly established.…”

“…Certain vanadium complexes [65,138] have anticancer activity against human cancer cells in vitro (testicular, multiple myeloma, glioblastoma, ovarian, prostate, breast, leukemia). Some of these compounds, particularly when one of the ligands is a phenanthroline derivative [138,139], are new potent apoptosis inducers associated with a loss of mitochondrial transmembrane potential, the generation of reactive oxygen species and depletion of glutathione.…”