Cisplatin (cDDP) resistance is a matter of concern
in triple-negative breast cancer therapeutics. We measured the
metabolic response of cDDP-sensitive (S) and -resistant (R) MDAMB-231 cells to Pd2Sper Show more
Cisplatin (cDDP) resistance is a matter of concern
in triple-negative breast cancer therapeutics. We measured the
metabolic response of cDDP-sensitive (S) and -resistant (R) MDAMB-231 cells to Pd2Spermine(Spm) (a possible alternative to
cDDP) compared to cDDP to investigate (i) intrinsic response/
resistance mechanisms and (ii) the potential cytotoxic role of
Pd2Spm. Cell extracts were analyzed by untargeted nuclear
magnetic resonance metabolomics, and cell media were analyzed
for particular metabolites. CDDP-exposed S cells experienced
enhanced antioxidant protection and small deviations in the
tricarboxylic acid cycle (TCA), pyrimidine metabolism, and lipid
oxidation (proposed cytotoxicity signature). R cells responded
more strongly to cDDP, suggesting a resistance signature of
activated TCA cycle, altered AMP/ADP/ATP and adenine/uracil fingerprints, and phospholipid biosynthesis (without significant
antioxidant protection). Pd2Spm impacted more markedly on R/S cell metabolisms, inducing similarities to cDDP/S cells (probably
reflecting high cytotoxicity) and strong additional effects indicative of amino acid depletion, membrane degradation, energy/
nucleotide adaptations, and a possible beneficial intracellular γ-aminobutyrate/glutathione-mediated antioxidant mechanism.
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Pd(II)-compounds are presently regarded as promising anticancer drugs, as an alternative to
Pt(II)-based drugs (e.g., cisplatin), which typically trigger severe side-effects and acquired resistance.
D Show more
Pd(II)-compounds are presently regarded as promising anticancer drugs, as an alternative to
Pt(II)-based drugs (e.g., cisplatin), which typically trigger severe side-effects and acquired resistance.
Dinuclear Pd(II) complexes with biogenic polyamines such as spermine (Pd2 Spm) have exhibited
particularly beneficial cytotoxic properties, hence unveiling the importance of understanding their
impact on organism metabolism. The present study reports the first nuclear magnetic resonance
(NMR)-based metabolomics study to assess the in vivo impact of Pd2 Spm on the metabolism of
healthy mice, to identify metabolic markers with possible relation to biotoxicity/side-effects and
their dynamics. The changes in the metabolic profiles of both aqueous and lipophilic extracts of mice
kidney, liver, and breast tissues were evaluated, as a function of drug-exposure time, using cisplatin
as a reference drug. A putative interpretation was advanced for the metabolic deviations specifically
triggered by Pd2 Spm, this compound generally inducing faster metabolic response and recovery to
control levels for all organs tested, compared to cisplatin (except for kidney lipid metabolism). These
results constitute encouraging preliminary metabolic data suggestive of potential lower negative
effects of Pd2 Spm administration.
Academic Editor: Ian D Wilson Show less
Conformational isomerization of native calf thymus DNA under the influence of spermine, spermidine and putrescine was monitored by UV absorption and immunospecific anti-Z-DNA antibodies. Immunological Show more
Conformational isomerization of native calf thymus DNA under the influence of spermine, spermidine and putrescine was monitored by UV absorption and immunospecific anti-Z-DNA antibodies. Immunological data indicated increased binding of anti-Z-DNA antibodies to polyamine-perturbed conformations of native DNA and double stranded poly(dG-dC). In the absence of polyamines, anti-Z-DNA antibodies did not bind to either polymers. Analysis of UV absorption studies indicates a left handed conformation of nDNA in the presence of polyamines. Moreover, we observed total aggregation of DNA in the presence of spermine on prolongued incubation. These perturbations in conformation were dependent on polyamine concentration. The results clearly suggest that certain regions of nDNA are sensitive to elevated levels of polyamines and are capable of undergoing B-->Z transition. Show less