June 2024
·
17 Reads
·
2 Citations
Drug Discovery Today
This page lists works of an author who doesn't have a ResearchGate profile or hasn't added the works to their profile yet. It is automatically generated from public (personal) data to further our legitimate goal of comprehensive and accurate scientific recordkeeping. If you are this author and want this page removed, please let us know.
June 2024
·
17 Reads
·
2 Citations
Drug Discovery Today
April 2024
·
25 Reads
·
1 Citation
Journal of Medicinal Chemistry
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 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.
December 2023
·
11 Reads
December 2023
·
65 Reads
·
7 Citations
Cancer Cell International
This work compared the metabolic profile of a parental MDA-MB-231 cisplatin-sensitive triple negative breast cancer (TNBC) cell line with that of a derived cisplatin-resistant line, to characterize inherent metabolic adaptations to resistance, as a means for marker and new TNBC therapies discovery. Supported by cytotoxic, microscopic and biochemical characterization of both lines, Nuclear Magnetic Resonance (NMR) metabolomics was employed to characterize cell polar extracts for the two cell lines, as a function of time (0, 24 and 48 h), and identify statistically relevant differences both between sensitive and resistant cells and their time course behavior. Biochemical results revealed a slight increase in activation of the NF-κB pathway and a marked decrease of the ERK signaling pathway in resistant cells. This was accompanied by lower glycolytic and glutaminolytic activities, possibly linked to glutamine being required to increase stemness capacity and, hence, higher survival to cisplatin. The TCA cycle dynamics seemed to be time-dependent, with an apparent activation at 48 h preferentially supported by anaplerotic aromatic amino acids, leucine and lysine. A distinct behavior of leucine, compared to the other branched-chain-amino-acids, suggested the importance of the recognized relationship between leucine and in mTOR-mediated autophagy to increase resistance. Suggested markers of MDA-MB-231 TNBC cisplatin-resistance included higher phosphocreatine/creatine ratios, hypotaurine/taurine–mediated antioxidant protective mechanisms, a generalized marked depletion in nucleotides/nucleosides, and a distinctive pattern of choline compounds. Although the putative hypotheses generated here require biological demonstration, they pave the way to the use of metabolites as markers of cisplatin-resistance in TNBC and as guidance to develop therapies. Supplementary Information The online version contains supplementary material available at 10.1186/s12935-023-03124-0.
July 2023
·
8 Reads
April 2023
·
114 Reads
·
6 Citations
Pharmaceutics
Triple-negative breast cancer (TNBC) is one of the most aggressive forms of breast cancer and constitutes 10–20% of all breast cancer cases. Even though platinum-based drugs such as cisplatin and carboplatin are effective in TNBC patients, their toxicity and development of cancer drug resistance often hamper their clinical use. Hence, novel drug entities with improved tolerability and selectivity profiles, as well as the ability to surpass resistance, are needed. The current study focuses on Pd(II) and Pt(II) trinuclear chelates with spermidine (Pd3Spd2 and Pt3Spd2) for evaluating their antineoplastic activity having been assessed towards (i) cisplatin-resistant TNBC cells (MDA-MB-231/R), (ii) cisplatin-sensitive TNBC cells (MDA-MB-231) and (iii) non-cancerous human breast cells (MCF-12A, to assess the cancer selectivity/selectivity index). Additionally, the complexes’ ability to overcome acquired resistance (resistance index) was determined. This study revealed that Pd3Spd2 activity greatly exceeds that displayed by its Pt analog. In addition, Pd3Spd2 evidenced a similar antiproliferative activity in both sensitive and resistant TNBC cells (IC50 values 4.65–8.99 µM and 9.24–13.34 µM, respectively), with a resistance index lower than 2.3. Moreover, this Pd compound showed a promising selectivity index ratio: >6.28 for MDA-MB-231 cells and >4.59 for MDA-MB-231/R cells. Altogether, the data presently gathered reveal Pd3Spd2 as a new, promising metal-based anticancer agent, which should be further explored for the treatment of TNBC and its cisplatin-resistant forms.
November 2022
·
58 Reads
·
1 Citation
International Journal of Molecular Sciences
Cisplatin (cDDP)-based chemotherapy is often limited by severe deleterious effects (nephrotoxicity, hepatotoxicity and neurotoxicity). The polynuclear palladium(II) compound Pd2Spermine (Pd2Spm) has emerged as a potential alternative drug, with favorable pharmacokinetic/pharmacodynamic properties. This paper reports on a Nuclear Magnetic Resonance metabolomics study to (i) characterize the response of mice brain and liver to Pd2Spm, compared to cDDP, and (ii) correlate brain-liver metabolic variations. Multivariate and correlation analysis of the spectra of polar and lipophilic brain and liver extracts from an MDA-MB-231 cell-derived mouse model revealed a stronger impact of Pd2Spm on brain metabolome, compared to cDDP. This was expressed by changes in amino acids, inosine, cholate, pantothenate, fatty acids, phospholipids, among other compounds. Liver was less affected than brain, with cDDP inducing more metabolite changes. Results suggest that neither drug induces neuronal damage or inflammation, and that Pd2Spm seems to lead to enhanced brain anti-inflammatory and antioxidant mechanisms, regulation of brain bioactive metabolite pools and adaptability of cell membrane characteristics. The cDDP appears to induce higher extension of liver damage and an enhanced need for liver regeneration processes. This work demonstrates the usefulness of untargeted metabolomics in evaluating drug impact on multiple organs, while confirming Pd2Spm as a promising replacement of cDDP.
October 2022
·
92 Reads
·
2 Citations
Pharmaceuticals
Corema (C.) album belongs to the family Ericaceae and can be found in the Iberian Peninsula, especially on the coastal areas facing the Atlantic coast. C. album berries have been used for centuries in traditional medicine. Recent studies have revealed that not only the berries but also the leaves have relevant antioxidant, antiproliferative, and anti-inflammatory properties, bringing this plant to the forefront of discussion. A systematic review of the literature was carried out to summarize the phenolic compounds and bioactive properties identified in C. album berries and leaves and to search for research gaps on this topic. The search was conducted in three electronic databases (PubMed, SCOPUS, and Web of Science) using PRISMA methodology. The inclusion criteria were the chemical compositions of the berries, leaves, or their extracts and their bioactive properties. The exclusion criteria were agronomic and archaeological research. The number of studies concerning phenolic compounds’ composition and the bioactive properties of C. album berries and leaves is still limited (11 articles). However, the variety of polyphenolic compounds identified make it possible to infer new insights into their putative mechanism of action towards the suppression of NF-kB transcription factor activation, the modulation of inflammatory mediators/enzymes, the induction of apoptosis, the modulation of mitogen activated protein kinase, cell cycle arrest, and the reduction of oxidative stress. These factors can be of major relevance concerning the future use of C. album as nutraceuticals, food supplements, or medicines. Nevertheless, more scientific evidence concerning C. album’s bioactivity is required.
August 2022
·
53 Reads
·
3 Citations
Current Issues in Molecular Biology
Corema (C.) album is a shrub endemic to the Atlantic coast and has been described as yielding beneficial effects for human health. Nevertheless, studies concerning the bioactivity of C. album leaves are scarce. This study aims at investigating the anticancer potential and mode of action, of an hydroethanolic extract of C. album leaves (ECAL) on triple-negative breast cancer. This is a poor survival breast cancer subtype, owing to its high risk of distant reappearance, metastasis rates and the probability of relapse. The ECAL ability to prevent tumor progression through (i) the inhibition of cell proliferation (cell viability); (ii) the induction of apoptosis (morphological changes, TUNEL assay, caspase-3 cleaved) and (iii) the induction of DNA damage (PARP1 and γH2AX) with (iv) the involvement of NF-κB and of ERK1/2 pathways (AlphaScreen assay) was evaluated. ECAL activated the apoptotic pathway (through caspase-3) along with the inhibition of ERK and NF-κB pathways causing DNA damage and cell death. The large polyphenolic content of ECAL was presumed to be accountable for these effects. The extract of C. album leaves can target multiple pathways and, thus, can block more than one possible means of disease progression, evidencing the anticancer therapeutic potential from a plant source.
January 2022
·
177 Reads
·
6 Citations
Pharmaceutics
The new palladium agent Pd2Spermine (Spm) has been reported to exhibit promising cytotoxic properties, while potentially circumventing the known disadvantages associated to cisplatin therapeutics, namely acquired resistance and high toxicity. This work presents a nuclear magnetic resonance (NMR) metabolomics study of brain extracts obtained from healthy mice, to assess the metabolic impacts of the new Pd2Spm complex in comparison to that of cisplatin. The proton NMR spectra of both polar and nonpolar brain extracts were analyzed by multivariate and univariate statistics, unveiling several metabolite variations during the time course of exposition to each drug (1–48 h). The distinct time-course dependence of such changes revealed useful information on the drug-induced dynamics of metabolic disturbances and recovery periods, namely regarding amino acids, nucleotides, fatty acids, and membrane precursors and phospholipids. Putative biochemical explanations were proposed, based on existing pharmacokinetics data and previously reported metabolic responses elicited by the same metal complexes in the liver of the same animals. Generally, results suggest a more effective response of brain metabolism towards the possible detrimental effects of Pd2Spm, with more rapid recovery back to metabolites’ control levels and, thus, indicating that the palladium drug may exert a more beneficial role than cDDP in relation to brain toxicity.
... For example, it can be used to detect alterations in the metabolism of certain amino acids (e.g., arginine, proline, glutathione, and b-alanine) associated with doxorubicin resistance (237). Carneiro et al. showed that an increase in phosphocreatine, taurine, and NF-kB pathway signaling, together with a decrease in ERK pathway signaling, glycolytic and glutaminolytic activity and nucleotide depletion, improved cisplatin resistance in MDA-MB-231 cells (238). Response to NAC is also associated with the metabolic profile. ...
December 2023
Cancer Cell International
... Regarding the cellular biochemical profile as probed by nano-FTIR, the proteins -mainly represented by the Amide I signal -were found to vary significantly between untreated and drug-treated cells (Figs 3 and 4). The data presently gathered evidence a very strong effect of cisplatin on the protein constituents of osteosarcoma cells, which agrees with previous studies by the authors (via micro-Raman) on the effect of cisplatin-like drugs on human triple-negative breast cancer cells 6,38 . Indeed, protein metalation is expected to induce conformational rearrangements, and may also trigger unfolding processes and even aggregation. ...
April 2023
Pharmaceutics
... The health-promoting properties of C. album are frequently attributed to its antioxidant capacity as a free radical scavenger, as well as its ability to enhance non-enzymatic cellular antioxidant defenses [25]. Phenolic compounds, mainly phenolic acids and flavonoids, are believed to be responsible for many of the health benefits associated with C. album [25,26]. Additionally, the antiinflammatory potential of these compounds through the modulation of inflammatory mediators and enzymes has been demonstrated [26]. ...
October 2022
Pharmaceuticals
... On the other hand, extracts of C. album leaves have the ability to prevent triple-negative breast cancer tumour progression through multiple pathways and to regulate reactive oxygen species (ROS). These effects are mainly attributed to the phenolic acids and flavonoids present in C. album fruit, which act as effective chemical reducers and antioxidants in cell cultures [29]. Furthermore, treatment with C. album extracts significantly increases cellular GSH values, the main nonenzymatic antioxidant within cells, offering protection against potential oxidative damage [21,29]. ...
August 2022
Current Issues in Molecular Biology
... Due to the high similarity between Pt(II) and Pd(II), palladium chelates are among the molecules that have drawn increasing interest. In particular, the cellular effects of Pd(II)-spermine and Pt(II)-spermine complexes have been extensively characterized via 1 H NMR metabolomics in osteosarcoma cells, also in comparison to cisplatin and oxaliplatin [37][38][39]41]. In this case, it is the different metal center that modulates the extent of the typical changes in the cell metabolome. ...
January 2022
Pharmaceutics
... 12 −19 In addition, in vivo studies have shown a more favorable biodistribution profile of Pd(II) in healthy BALB/c mice compared to that of Pt(II), while exposure of a MDA-MB-231 cell-derived xenograft (CDX) mouse model to Pd 2 Spm resulted in the reduction of tumor size and cell proliferation rate, as well as lower systemic toxicity, compared to cDDP. 20,21 Pd 2 Spm also appears to be more selective for TNBC cells, having less deleterious effects on noncancerous breast cells, at least viewed under in vitro conditions. 21 Metabolomics has been extensively highlighted as a valuable tool towards the understanding of the interplay between drugs and cellular metabolism in breast cancer. ...
January 2022
... DNA TOPO II inhibitors have proven to be effective in the treatment of breast carcinoma. 54,55,71 Our study on molecular docking has shown that [PdL] complex has a strong binding ability with DNA topoisomerase IIa protein, which may hinder its activity. We have hypothesized that the [PdL] complex could potentially inhibit the TOPO II enzyme, which is responsible for relaxing DNA strands and promoting replication and cell proliferation. ...
October 2021
International Journal of Molecular Sciences
... Intracellular 5-HT1BR is located predominantly in the nuclear region, while 5-HT2BR is distributed rather evenly in the cells. Expression in the nuclear membrane has been shown for different G-proteincoupled receptors (GPCRs) [41,42]. Various nuclear receptors activate G-proteins and stimulate the formation of second messengers (cAMP, IP3, etc.). ...
May 2021
Pharmaceuticals
... 12 −19 In addition, in vivo studies have shown a more favorable biodistribution profile of Pd(II) in healthy BALB/c mice compared to that of Pt(II), while exposure of a MDA-MB-231 cell-derived xenograft (CDX) mouse model to Pd 2 Spm resulted in the reduction of tumor size and cell proliferation rate, as well as lower systemic toxicity, compared to cDDP. 20,21 Pd 2 Spm also appears to be more selective for TNBC cells, having less deleterious effects on noncancerous breast cells, at least viewed under in vitro conditions. 21 Metabolomics has been extensively highlighted as a valuable tool towards the understanding of the interplay between drugs and cellular metabolism in breast cancer. ...
February 2021
Pharmaceuticals
... 23,24 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. 25,26 This corroborated other reports of lower in vivo toxicity of the Pd(II) compound, compared to that of cDDP. 20,21 In an attempt to address cDDP resistance, the biochemical effects of Pd(II) agents on cDDP-sensitive and cDDP-resistant MDA-MB-231 cells have been investigated. ...
February 2021
Metabolites