Novel Insights into Mice Multi-Organ Metabolism upon Exposure to a Potential Anticancer Pd(II)-Agent

Carneiro, Tatiana J.; Araújo, Rita; Vojtek, Martin; Gonçalves-Monteiro, Salomé; Diniz, Carmen; Carvalho, Ana L. M. Batista de; Marques, M. P. M.; Gil, Ana M.

doi:10.3390/metabo11020114

Cited by 10 publications

(7 citation statements)

References 67 publications

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“…A recent pharmacokinetic study in mice also showed that while Pd 2 Spm has a very similar serum terminal half-life to cisplatin, it presents a lower accumulation in major organs as compared to cisplatin [ 15 ]. Therefore, Pd 2 Spm is expected to show a superior tolerability as well as lower nephrotoxicity/hepatotoxicity than cisplatin, owing to both lower tissue accumulation and decreased metabolic reactivity with kidney and liver biomolecules responsible for the associated toxicity (which was recently reported by our group) [ 15 , 19 ]. Based on these previous findings, the present study has sought to investigate, for the first time, the in vivo efficacy (to reduce tumor growth) and tolerability (changes in body weight, behavior, histopathological features and biochemical and hematological parameters) of a 5-day Pd 2 Spm treatment compared to cisplatin’s treatment in mice bearing TNBC MDA-MB-231 breast tumors.…”

Section: Introductionmentioning

confidence: 95%

Pd2Spermine Complex Shows Cancer Selectivity and Efficacy to Inhibit Growth of Triple-Negative Breast Tumors in Mice

et al. 2022

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Pd2Spm is a dinuclear palladium(II)-spermine chelate with promising anticancer properties against triple-negative breast cancer (TNBC), a breast carcinoma subset with poor prognosis and limited treatment options. The present study evaluated the in vitro and in vivo anticancer effects of Pd2Spm compared to the reference metal-based drug cisplatin. Triple-negative breast cancer MDA-MB-231 cells, non-cancerous MCF-12A breast cells and chorioallantoic membrane (CAM) assay were used for antiproliferative, antimigratory and antiangiogenic studies. For an in vivo efficacy study, female CBA nude mice with subcutaneously implanted MDA-MB-231 breast tumors were treated with Pd2Spm (5 mg/kg/day) or cisplatin (2 mg/kg/day) administered intraperitoneally during 5 consecutive days. Promising selective antiproliferative activity of Pd2Spm was observed in MDA-MB-231 cells (IC50 values of 7.3–8.3 µM), with at least 10-fold lower activity in MCF-12A cells (IC50 values of 89.5–228.9 µM). Pd2Spm inhibited the migration of MDA-MB-231 cells, suppressed angiogenesis in CAM and decreased VEGF secretion from MDA-MB-231 cells with similar potency as cisplatin. Pd2Spm-treated mice showed a significant reduction in tumor growth progression, and tumors evidenced a reduction in the Ki-67 proliferation index and number of mitotic figures, as well as increased DNA damage, similar to cisplatin-treated animals. Encouragingly, systemic toxicity (hematotoxicity and weight loss) observed in cisplatin-treated animals was not observed in Pd2Spm-treated mice. The present study reports, for the first time, promising cancer selectivity, in vivo antitumor activity towards TNBC and a low systemic toxicity of Pd2Spm. Thus, this agent may be viewed as a promising Pd(II) drug candidate for the treatment of this type of low-prognosis neoplasia.

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Section: Introductionmentioning

confidence: 95%

Pd2Spermine Complex Shows Cancer Selectivity and Efficacy to Inhibit Growth of Triple-Negative Breast Tumors in Mice

et al. 2022

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“…Promising antiproliferative activities via apoptosis induction in preclinical BC cellular models, including cisplatin-resistant cells, have also emerged during the trialling of binuclear Pd(II) complexes, conceived using biogenic polyamines (e.g., spermine) and named Pd2Spm. In addition to showing additional antiangiogenic and antimetastatic activities in vivo, Pd2Spm derivatives seem to share profitable pharmacokinetic and toxicological profiles; thus, additional investigations towards prospective clinical applications are warranted [ 203 , 204 ]. These findings still confirm attractive bioactivities for many Pd(II) derivatives working against BC tumour models, including TNBC phenotypes [ 191 ].…”

Section: Palladiummentioning

confidence: 99%

Bioactivity and Development of Small Non-Platinum Metal-Based Chemotherapeutics

et al. 2022

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Countless expectations converge in the multidisciplinary endeavour for the search and development of effective and safe drugs in fighting cancer. Although they still embody a minority of the pharmacological agents currently in clinical use, metal-based complexes have great yet unexplored potential, which probably hides forthcoming anticancer drugs. Following the historical success of cisplatin and congeners, but also taking advantage of conventional chemotherapy limitations that emerged with applications in the clinic, the design and development of non-platinum metal-based chemotherapeutics, either as drugs or prodrugs, represents a rapidly evolving field wherein candidate compounds can be fine-tuned to access interactions with druggable biological targets. Moving in this direction, over the last few decades platinum family metals, e.g., ruthenium and palladium, have been largely proposed. Indeed, transition metals and molecular platforms where they originate are endowed with unique chemical and biological features based on, but not limited to, redox activity and coordination geometries, as well as ligand selection (including their inherent reactivity and bioactivity). Herein, current applications and progress in metal-based chemoth are reviewed. Converging on the recent literature, new attractive chemotherapeutics based on transition metals other than platinum—and their bioactivity and mechanisms of action—are examined and discussed. A special focus is committed to anticancer agents based on ruthenium, palladium, rhodium, and iridium, but also to gold derivatives, for which more experimental data are nowadays available. Next to platinum-based agents, ruthenium-based candidate drugs were the first to reach the stage of clinical evaluation in humans, opening new scenarios for the development of alternative chemotherapeutic options to treat cancer.

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“…Metabolomics has been extensively highlighted as a valuable tool towards the understanding of the interplay between drugs and cellular metabolism in breast cancer . Indeed, metabolomics of CDX mice with TNBC showed that, compared to cDDP, Pd 2 Spm induced (i) pronounced metabolic disturbances in tumor metabolism (energy, membrane, nucleotides, and one-carbon metabolisms), possibly reflecting a different mechanism of action of the Pd(II) complex, and (ii) an enhanced neuroprotective response of brain, along with lower impact on liver. , Furthermore, Pd 2 Spm administration induced initial metabolic deviations in healthy BALB/c mice, which, however, returned to control levels faster (within 48 h) than with cDDP, namely, in kidney, liver, breast tissue and brain. , This corroborated other reports of lower in vivo toxicity of the Pd(II) compound, compared to that of cDDP. , …”

Section: Introductionmentioning

confidence: 99%

Pd₂Spermine as an Alternative Therapeutics for Cisplatin-Resistant Triple-Negative Breast Cancer

Carneiro,

Batista de Carvalho,

Vojtek

et al. 2024

J. Med. Chem.

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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) MDA-MB-231 cells to Pd 2 Spermine(Spm) (a possible alternative to cDDP) compared to cDDP to investigate (i) intrinsic response/ resistance mechanisms and (ii) the potential cytotoxic role of Pd 2 Spm. 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). Pd 2 Spm 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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Novel Insights into Mice Multi-Organ Metabolism upon Exposure to a Potential Anticancer Pd(II)-Agent

Cited by 10 publications

References 67 publications

Pd2Spermine Complex Shows Cancer Selectivity and Efficacy to Inhibit Growth of Triple-Negative Breast Tumors in Mice

Pd2Spermine Complex Shows Cancer Selectivity and Efficacy to Inhibit Growth of Triple-Negative Breast Tumors in Mice

Bioactivity and Development of Small Non-Platinum Metal-Based Chemotherapeutics

Pd₂Spermine as an Alternative Therapeutics for Cisplatin-Resistant Triple-Negative Breast Cancer

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Novel Insights into Mice Multi-Organ Metabolism upon Exposure to a Potential Anticancer Pd(II)-Agent

Cited by 10 publications

References 67 publications

Pd2Spermine Complex Shows Cancer Selectivity and Efficacy to Inhibit Growth of Triple-Negative Breast Tumors in Mice

Pd2Spermine Complex Shows Cancer Selectivity and Efficacy to Inhibit Growth of Triple-Negative Breast Tumors in Mice

Bioactivity and Development of Small Non-Platinum Metal-Based Chemotherapeutics

Pd2Spermine as an Alternative Therapeutics for Cisplatin-Resistant Triple-Negative Breast Cancer

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Product

Resources

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Pd₂Spermine as an Alternative Therapeutics for Cisplatin-Resistant Triple-Negative Breast Cancer