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Current Opinion in Chemical Biology Apr 2023Metal-based anticancer agents occupy a distinct chemical space due to their particular coordination geometry and reactivity. Despite the initial DNA-targeting paradigm... (Review)
Review
Metal-based anticancer agents occupy a distinct chemical space due to their particular coordination geometry and reactivity. Despite the initial DNA-targeting paradigm for this class of compounds, it is now clear that they can also be tuned to target proteins in cells, depending on the metal and ligand scaffold. Since metallodrug discovery is dominated by phenotypic screenings, tailored proteomics strategies were crucial to identify and validate protein targets of several investigative and clinically advanced metal-based drugs. Here, such experimental approaches are discussed, which showed that metallodrugs based on ruthenium, gold, rhenium and even platinum, can selectively and specifically target proteins with clear-cut down-stream effects. Target identification strategies are expected to support significantly the mechanism-driven clinical translation of metal-based drugs.
Topics: Antineoplastic Agents; Platinum; Ruthenium; Gold; DNA; Coordination Complexes
PubMed: 36599256
DOI: 10.1016/j.cbpa.2022.102257 -
Magyar Onkologia Mar 2020Germinal or somatic mutations of the BRCA genes may serve as therapeutic targets. Deficient functioning of the BRCA genes render the cancer vulnerable to such... (Review)
Review
Germinal or somatic mutations of the BRCA genes may serve as therapeutic targets. Deficient functioning of the BRCA genes render the cancer vulnerable to such therapeutic interventions as chemotherapy with DNA-targeted agents and PARP inhibitors targeting DNA repair capacity. Although BRCA mutations may be detected in a large variety of cancers, the mentioned specific therapies are efficient in the so called BRCA-associated cancers only including ovarian, breast, pancreatic, prostate cancers and the rare uterine sarcomas. While in ovarian and prostate carcinomas both germinal and somatic, in breast and pancreatic cancers exclusively germinal, and in uterine sarcomas mostly somatic mutations specify the tumor as BRCA-dependent; platinum-sensitivity in ovarian cancer may replace BRCA testing by indicating the presence of frequent DNA repair deficiency. Platinum-based chemotherapy is frequently efficient in BRCA-dependent cancers, while PARP inhibitors yet registered for ovarian, breast and pancreatic cancers bring paradigm change in the treatment of ovarian cancer and provide an additional treatment option of the others.
Topics: Genes, BRCA1; Genes, BRCA2; Humans; Mutation; Neoplasms; Platinum; Poly(ADP-ribose) Polymerase Inhibitors
PubMed: 32181758
DOI: No ID Found -
Molecules (Basel, Switzerland) Nov 2020Platinum-based anticancer drugs are a class of widely used agents in clinical cancer treatment. However, their efficacy was greatly limited by their severe side effects... (Review)
Review
Platinum-based anticancer drugs are a class of widely used agents in clinical cancer treatment. However, their efficacy was greatly limited by their severe side effects and the arising drug resistance. The selective activation of inert platinum-based drugs in the tumor site by light irradiation is able to reduce side effects, and the novel mechanism of action of photoactivatable platinum drugs might also conquer the resistance. In this review, the recent advances in the design of photoactivatable platinum-based drugs were summarized. The complexes are classified according to their mode of action, including photoreduction, photo-uncaging, and photodissociation. The rationale of drug design, dark stability, photoactivation process, cytotoxicity, and mechanism of action of typical photoactivatable platinum drugs were reviewed. Finally, the challenges and opportunities for designing more potent photoactivatable platinum drugs were discussed.
Topics: Animals; Antineoplastic Agents; Humans; Light; Organoplatinum Compounds; Photochemical Processes; Platinum; Quantum Dots
PubMed: 33171980
DOI: 10.3390/molecules25215167 -
IUBMB Life Mar 2018Platinum-based chemotherapy agents are widely used in the treatment of various solid malignancies. However, their efficacy is limited by drug resistance. Recent studies... (Review)
Review
Platinum-based chemotherapy agents are widely used in the treatment of various solid malignancies. However, their efficacy is limited by drug resistance. Recent studies suggest that copper efflux transporters, which are encoded by ATP7A and ATP7B, play an important role in platinum drug resistance. Over-expressions of ATP7A and ATP7B are observed in multiple cancers. Moreover, their expressions are associated with cancer prognosis and treatment outcomes of platinum-based chemotherapy. In our review, we highlight the roles of ATP7A/7B in platinum drug resistance and cancer progression. We also discuss the possible mechanisms of platinum drug resistance mediated by ATP7A/7B and provide novel strategies for overcoming resistance. This review may be helpful for understanding the roles of ATP7A and ATP7B in platinum drug resistance. © 2018 IUBMB Life, 70(3):183-191, 2018.
Topics: Biomarkers, Tumor; Copper-Transporting ATPases; Drug Resistance, Neoplasm; Humans; Neoplasms; Platinum
PubMed: 29394468
DOI: 10.1002/iub.1722 -
Chembiochem : a European Journal of... Feb 2021Three chiral tridentate N^N^S coordinating pyridine-carbaldehyde (S)-N4-(α-methylbenzyl)thiosemicarbazones (HTSCmB) were synthesised along with lysine-modified...
Three chiral tridentate N^N^S coordinating pyridine-carbaldehyde (S)-N4-(α-methylbenzyl)thiosemicarbazones (HTSCmB) were synthesised along with lysine-modified derivatives. One of them was selected and covalently conjugated to the cell-penetrating peptide sC18 by solid-phase peptide synthesis. The HTSCmB model ligands, the HTSCLp derivatives and the peptide conjugate rapidly and quantitatively form very stable Pt chlorido complexes [Pt(TSC)Cl] when treated with K PtCl in solution. The Pt(CN) derivatives were obtained from one TSCmB model complex and the peptide conjugate complex through Cl →CN exchange. Ligands and complexes were characterised by NMR, IR spectroscopy, HR-ESI-MS and single-crystal XRD. Intriguingly, no decrease in cell viability was observed when testing the biological activity of the lysine-tagged HdpyTSCLp, its sC18 conjugate HdpyTSCL-sC18 or the PtCl and Pt(CN) conjugate complexes in three different cell lines. Thus, given the facile and effective preparation of such Pt-TSC-peptide conjugates, these systems might pave the way for future use in late-stage labelling with Pt radionuclides and application in nuclear medicine.
Topics: Cell-Penetrating Peptides; Humans; Lysine; Organometallic Compounds; Peptide Fragments; Platinum; Thiosemicarbazones
PubMed: 32909347
DOI: 10.1002/cbic.202000564 -
Medycyna Pracy Jul 2019Platinum nanoparticles (PtNPs) have been widely used not only in industry, but above all in medicine and diagnostics. However, there are disturbing reports related to... (Review)
Review
Platinum nanoparticles (PtNPs) have been widely used not only in industry, but above all in medicine and diagnostics. However, there are disturbing reports related to the toxic effects of nanoplatinum, which is the main reason why the authors of this study have decided to review and analyze literature data related to its toxicity and impact on human health. While PtNPs may be absorbed by the respiratory and digestive tract, and can penetrate through the epidermis, there is no evidence concerning their absorption through the skin. Platinum nanoparticles accumulate mainly in the liver and spleen although they also reach other internal organs, such as lungs, kidneys or heart. Toxicokinetics of platinum nanoparticles depends strongly on the particle size. Only few studies regarding platinum nanoparticles toxicity have been conducted. Animals intratracheally exposed to platinum nanoparticles have demonstrated an increased level of proinflammatory cytokines in bronchoalveolar lavage which confirms inflammatory response in the lungs. Oral administration of PtNPs can cause inflammatory response and induce oxidative stress. Nanoplatinum has been found to induce hepatotoxicity and nephrotoxicity via the intravenous route. It can cause DNA damage and cellular apoptosis without significant cytotoxicity. There are no research studies on its carcinogenicity. Fetal or maternal toxicity has not been observed, but an increased mortality and a decreased growth of the offspring have been demonstrated. Platinum nanoparticles may permeate the skin barrier but there is no evidence for their absorption. Due to the insufficient number of tests that have been carried out to date, it is not possible to clearly determine the occupational exposure limit value; however, caution is recommended to employees exposed to their effects. Med Pr. 2019;70(4):487-95.
Topics: Animals; Humans; Inflammation; Metal Nanoparticles; Occupational Exposure; Oxidative Stress; Particle Size; Platinum
PubMed: 31162484
DOI: 10.13075/mp.5893.00847 -
Biomolecules Dec 2019Along with surgery and radiotherapy, chemotherapeutic agents belong to the therapeutic arsenal in cancer treatment. In addition to their direct cytotoxic effects, these... (Review)
Review
Along with surgery and radiotherapy, chemotherapeutic agents belong to the therapeutic arsenal in cancer treatment. In addition to their direct cytotoxic effects, these agents also impact the host immune system, which might enhance or counteract their antitumor activity. The platinum derivative compounds family, mainly composed of carboplatin, cisplatin and oxaliplatin, belongs to the chemotherapeutical arsenal used in numerous cancer types. Here, we will focus on the effects of these molecules on antitumor immune response. These compounds can induce or not immunogenic cell death (ICD), and some strategies have been found to induce or further enhance it. They also regulate immune cells' fate. Platinum derivatives can lead to their activation. Additionally, they can also dampen immune cells by selective killing or inhibiting their activity, particularly by modulating immune checkpoints' expression.
Topics: Animals; Antineoplastic Agents; Humans; Immune System; Immunologic Factors; Neoplasms; Platinum
PubMed: 31861811
DOI: 10.3390/biom10010013 -
Oncogene Nov 2021Platinum-based chemotherapy, including cisplatin, carboplatin, and oxaliplatin, is prescribed to 10-20% of all cancer patients. Unfortunately, platinum resistance... (Review)
Review
Platinum-based chemotherapy, including cisplatin, carboplatin, and oxaliplatin, is prescribed to 10-20% of all cancer patients. Unfortunately, platinum resistance develops in a significant number of patients and is a determinant of clinical outcome. Extensive research has been conducted to understand and overcome platinum resistance, and mechanisms of resistance can be categorized into several broad biological processes, including (1) regulation of drug entry, exit, accumulation, sequestration, and detoxification, (2) enhanced repair and tolerance of platinum-induced DNA damage, (3) alterations in cell survival pathways, (4) alterations in pleiotropic processes and pathways, and (5) changes in the tumor microenvironment. As a resource to the cancer research community, we provide a comprehensive overview accompanied by a manually curated database of the >900 genes/proteins that have been associated with platinum resistance over the last 30 years of literature. The database is annotated with possible pathways through which the curated genes are related to platinum resistance, types of evidence, and hyperlinks to literature sources. The searchable, downloadable database is available online at http://ptrc-ddr.cptac-data-view.org .
Topics: Data Curation; Databases, Genetic; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Gene Regulatory Networks; Humans; Neoplasms; Platinum; Tumor Microenvironment
PubMed: 34645978
DOI: 10.1038/s41388-021-02055-2 -
Journal of Clinical Oncology : Official... Jan 2023Journal Journal of Clinical OncologyThe systemic treatment for metastatic urothelial carcinoma has evolved over the past decade; however, changes in the first-line... (Review)
Review
Journal Journal of Clinical OncologyThe systemic treatment for metastatic urothelial carcinoma has evolved over the past decade; however, changes in the first-line setting have remained elusive and dependent on platinum-based chemotherapy regimens. Hoimes et al now present an update on the results of cohort A of the EV-103 phase Ib/II trial combining enfortumab vedotin and pembrolizumab in the first-line setting for patients with cisplatin-ineligible metastatic urothelial carcinoma. The efficacy results in this small, phase I cohort demonstrate an impressive response rate with the majority of patients deriving benefit in tumor control. In conjunction with the results from cohort K of EV-103, recently reported at the 2022 ESMO Congress, there is much anticipation regarding this combination as a future standard of care. However, despite this combination not including a traditional cytotoxic chemotherapeutic, it is still associated with potentially life-altering treatment-related toxicity, most notably rash and peripheral neuropathy, along with the risks of immune-related adverse events, which will need to be carefully calibrated for patients.
Topics: Humans; Carcinoma, Transitional Cell; Urinary Bladder Neoplasms; Platinum; Cisplatin
PubMed: 36343307
DOI: 10.1200/JCO.22.01992 -
Cancer Chemotherapy and Pharmacology Nov 2017Platinum chemotherapy, particularly cisplatin, is commonly associated with electrolyte imbalances, including hypomagnesemia, hypokalemia, hypophosphatemia, hypocalcemia... (Review)
Review
Platinum chemotherapy, particularly cisplatin, is commonly associated with electrolyte imbalances, including hypomagnesemia, hypokalemia, hypophosphatemia, hypocalcemia and hyponatremia. The corpus of literature on these dyselectrolytemias is large; the objective of this review is to synthesize the literature and summarize the mechanisms responsible for these particular electrolyte disturbances in the context of platinum-based treatment as well as to present the clinical manifestations and current management strategies for oncologists and primary care physicians, since the latter are increasingly called on to provide care for cancer patients with medical comorbidities. Correct diagnosis and effective treatment are essential to improved patient outcomes.
Topics: Humans; Neoplasms; Platinum; Water-Electrolyte Imbalance
PubMed: 28730291
DOI: 10.1007/s00280-017-3392-8