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Metal-Based Complexes in Cancer

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (31 October 2022) | Viewed by 23332

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Dr. Claudia Riccardi

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Department of Chemical Sciences, University of Naples Federico II, 80126 Naples, Italy
Interests: ruthenium complexes; platinum complexes; benzodifuran compounds; oligonucleotides; G-quadruplex; aptamers; thrombin binding aptamers; nanosystems; nanomaterials
Special Issues, Collections and Topics in MDPI journals

Dr. Marialuisa Piccolo

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Department of Pharmacy, School of Medicine, University of Naples Federico II, 80131 Naples, Italy
Interests: preclinical investigation of anticancer compounds: antiproliferative and antimetastatic potential; evaluation of inflammatory pathways on cancer onset; xenobiotics effects on human cells
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Metal-based drugs have attracted growing interest in biomedicine due to their potential value for both therapeutic and diagnostic applications in different diseases, especially in cancer.

Metal-based complexes are endowed with an impressive chemical diversity and versatility, depending on the metal of choice, its oxidation state, the number and type of coordinating ligands, and specific magnetic and/or optical properties.

This Special Issue of the International Journal of Molecular Sciences will include both regular articles and reviews focused on the most recent advances in metal-based complexes used in cancer therapy and diagnostics.

Contributions dealing with the design, synthesis, and characterization of novel metal-based compounds with biological activities, their mechanism of action, and innovative metal-based drug delivery systems are particularly welcome.

Topics of interest for this Special Issue include, but are not limited to, the following:

chemistry of metal-based anticancer drugs;
synthesis/improvement of metal-based complexes;
identification of the mechanism of action/biological targets;
interactions of metal-based complexes with proteins and/or nucleic acids;
uptake, toxicity, and resistance of metal-based anticancer agents;
metal-based complexes in targeted drug delivery systems;
metal-based drugs in cancer combinatorial therapy.

Dr. Claudia Riccardi
Dr. Marialuisa Piccolo
Guest Editors

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

metal-based drugs
metal-based drug delivery systems
metal–protein interactions
metal–nucleic acid interactions
mechanism of action
anticancer activity

Published Papers (11 papers)

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Editorial

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3 pages, 207 KiB

Open AccessEditorial

Metal-Based Complexes in Cancer

by Claudia Riccardi and Marialuisa Piccolo

Int. J. Mol. Sci. 2023, 24(8), 7289; https://doi.org/10.3390/ijms24087289 - 14 Apr 2023

Cited by 7 | Viewed by 1332

Abstract

Metal-based drugs have attracted growing interest in biomedicine [...] Full article

(This article belongs to the Special Issue Metal-Based Complexes in Cancer)

Research

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12 pages, 1934 KiB

Open AccessArticle

by Toni Martinez-Bernabe, Jordi Oliver, Jorge Sastre-Serra and Daniel Gabriel Pons

Int. J. Mol. Sci. 2023, 24(4), 3821; https://doi.org/10.3390/ijms24043821 - 14 Feb 2023

Cited by 5 | Viewed by 1851

Abstract

Oxaliplatin is successfully used to eradicate micro-metastasis and improve survival, whereas the benefit of adjuvant chemotherapy in the early stages of colorectal cancer remains controversial. Inflammation plays a crucial role in colorectal cancer tumorigenesis. Inflammatory mechanisms are mediated by different immune cells through different cytokines, chemokines, and other proinflammatory molecules that trigger cell progression, an increase of cancer stem cell population, hyperplasia, and metastasis. This study focuses on the analysis of the oxaliplatin effect on tumourspheres formation efficiency, cell viability, cancer stem cells and stemness marker mRNA expression, as well as inflammation-related signature profile expression and its prognosis in primary- and metastatic-derived colorectal tumourspheres derived from colorectal cell lines isolated from the same patient 1 year apart. The results indicate that primary-derived colorectal tumourspheres respond to oxaliplatin, adapting to the adverse conditions through the modulation of CSCs and the stemness properties of tumourspheres. However, metastatic-derived colorectal tumourspheres response led to the release of cytokines and chemokines, promoting an inflammatory process. In addition, the expression of inflammatory markers showing greater difference between primary and metastatic tumours after oxaliplatin treatment correlates with poor prognosis in KM survival studies and is associated with a metastatic phenotype. Our data demonstrated that oxaliplatin triggers an inflammation-related signature profile expression in primary-derived colorectal tumourspheres, related with poor prognosis and a metastatic phenotype, which allow the tumour cells to adapt to the adverse condition. These data highlight the need for of drug testing and personalized medicine in the early stages of colorectal cancer. Full article

(This article belongs to the Special Issue Metal-Based Complexes in Cancer)

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17 pages, 2099 KiB

Open AccessArticle

Synthesis, Characterization and Photoactivation Studies on the Novel Pt(IV)-Based [Pt(OCOCH₃)₃(phterpy)] Complex

by Giovanni Canil, Juan Gurruchaga-Pereda, Simona Braccini, Lorella Marchetti, Tiziana Funaioli, Fabio Marchetti, Alessandro Pratesi, Luca Salassa and Chiara Gabbiani

Int. J. Mol. Sci. 2023, 24(2), 1106; https://doi.org/10.3390/ijms24021106 - 6 Jan 2023

Cited by 3 | Viewed by 1586

Abstract

Photoactivatable Pt(IV) prodrugs represent nowadays an intriguing class of potential metal-based drugs, endowed with more chemical inertness in their oxidized form and better selectivity for the target with respect to the clinically established Pt(II) compounds. In fact, they have the possibility to be reduced by light irradiation directly at the site of interest. For this reason, we synthesized a new Pt(IV) complex, [Pt(OCOCH₃)₃(4′-phenyl-2,2′:6′,2′′-terpyridine)][CF₃SO₃] (1), that is well soluble in aqueous medium and totally unreactive towards selected model biomolecules until its reduction. The highlight of this work is the rapid and efficient photoreduction of 1 with visible light (460 nm), which leads to its reactive Pt(II) analogue. This behavior was made possible by taking advantage of an efficient catalytic system based on flavin and NADH, which is naturally present in the cellular environment. As a comparison, the reduction of 1 was also studied with simple UV irradiation, but both UV-Vis spectrophotometry and ¹H-NMR spectrometry showed that the flavin-catalyzed reduction with visible light was faster. Lastly, the reactivity against two representative biological targets, i.e., human serum albumin and one monofilament oligonucleotide fragment, was evaluated by high-resolution mass spectrometry. The results clearly pointed out that the prodrug 1 did not interact with these targets until its photoreduction to the Pt(II) analogue. Full article

(This article belongs to the Special Issue Metal-Based Complexes in Cancer)

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14 pages, 3623 KiB

Open AccessArticle

Anticancer Activity, Reduction Mechanism and G-Quadruplex DNA Binding of a Redox-Activated Platinum(IV)–Salphen Complex

by Vincenzo Vigna, Stefano Scoditti, Angelo Spinello, Gloria Mazzone and Emilia Sicilia

Int. J. Mol. Sci. 2022, 23(24), 15579; https://doi.org/10.3390/ijms232415579 - 8 Dec 2022

Cited by 5 | Viewed by 1642

Abstract

Aiming at reducing the unselective cytotoxicity of Pt(II) chemotherapeutics, a great deal of effort has been concentrated into the design of metal-containing drugs with different anticancer mechanisms of action. Inert Pt(IV) prodrugs have been proposed to be a valid alternative as they are activated by reduction directly into the cell releasing active Pt(II) species. On the other hand, a promising strategy for designing metallodrugs is to explore new potential biological targets rather than canonical B-DNA. G-quadruplex nucleic acid, obtained by self-assembly of guanine-rich nucleic acid sequences, has recently been considered an attractive target for anticancer drug design. Therefore, compounds capable of binding and stabilizing this type of DNA structure would be greatly beneficial in anticancer therapy. Here, computational analysis reports the mechanism of action of a recently synthesized Pt(IV)–salphen complex conjugating the inertness of Pt(IV) prodrugs with the ability to bind G-quadruplexes of the corresponding Pt(II) complex. The reduction mechanism of the Pt(IV) complex with a biological reducing agent was investigated in depth by means of DFT, whereas classical MD simulations were carried out to shed light into the binding mechanism of the released Pt(II) complex. The results show that the Pt(IV) prodrug may be reduced by both inner- and outer-sphere mechanisms, and the active Pt(II) complex, as a function of its protonation state, stabilizes the G-quadruplex DNA prevalently, either establishing π-stacking interactions with the terminal G-tetrad or through electrostatic interactions along with H-bonds formation. Full article

(This article belongs to the Special Issue Metal-Based Complexes in Cancer)

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24 pages, 6039 KiB

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Simultaneous Probing of Metabolism and Oxygenation of Tumors In Vivo Using FLIM of NAD(P)H and PLIM of a New Polymeric Ir(III) Oxygen Sensor

by Yulia P. Parshina, Anastasia D. Komarova, Leonid N. Bochkarev, Tatyana A. Kovylina, Anton A. Plekhanov, Larisa G. Klapshina, Aleksey N. Konev, Artem M. Mozherov, Ilya D. Shchechkin, Marina A. Sirotkina, Vladislav I. Shcheslavskiy and Marina V. Shirmanova

Int. J. Mol. Sci. 2022, 23(18), 10263; https://doi.org/10.3390/ijms231810263 - 6 Sep 2022

Cited by 10 | Viewed by 1824

Abstract

Tumor cells are well adapted to grow in conditions of variable oxygen supply and hypoxia by switching between different metabolic pathways. However, the regulatory effect of oxygen on metabolism and its contribution to the metabolic heterogeneity of tumors have not been fully explored. In this study, we develop a methodology for the simultaneous analysis of cellular metabolic status, using the fluorescence lifetime imaging microscopy (FLIM) of metabolic cofactor NAD(P)H, and oxygen level, using the phosphorescence lifetime imaging (PLIM) of a new polymeric Ir(III)-based sensor (PIr3) in tumors in vivo. The sensor, derived from a polynorbornene and cyclometalated iridium(III) complex, exhibits the oxygen-dependent quenching of phosphorescence with a 40% longer lifetime in degassed compared to aerated solutions. In vitro, hypoxia resulted in a correlative increase in PIr3 phosphorescence lifetime and free (glycolytic) NAD(P)H fraction in cells. In vivo, mouse tumors demonstrated a high degree of cellular-level heterogeneity of both metabolic and oxygen states, and a lower dependence of metabolism on oxygen than cells in vitro. The small tumors were hypoxic, while the advanced tumors contained areas of normoxia and hypoxia, which was consistent with the pimonidazole assay and angiographic imaging. Dual FLIM/PLIM metabolic/oxygen imaging will be valuable in preclinical investigations into the effects of hypoxia on metabolic aspects of tumor progression and treatment response. Full article

(This article belongs to the Special Issue Metal-Based Complexes in Cancer)

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15 pages, 2461 KiB

Open AccessArticle

Synthesis and Biological Evaluation of Thiazole-Based Derivatives with Potential against Breast Cancer and Antimicrobial Agents

by Ekaterina Pivovarova, Alina Climova, Marcin Świątkowski, Marek Staszewski, Krzysztof Walczyński, Marek Dzięgielewski, Marta Bauer, Wojciech Kamysz, Anna Krześlak, Paweł Jóźwiak and Agnieszka Czylkowska

Int. J. Mol. Sci. 2022, 23(17), 9844; https://doi.org/10.3390/ijms23179844 - 30 Aug 2022

Cited by 4 | Viewed by 2496

Abstract

Investigating novel, biologically-active coordination compounds that may be useful in the design of breast anticancer, antifungal, and antimicrobial agents is still the main challenge for chemists. In order to get closer to solving this problem, three new copper coordination compounds containing thiazole-based derivatives were synthesized. The structures of the synthesized compounds and their physicochemical characterization were evaluated based on elemental analysis, ¹H and ^l3C nuclear magnetic resonance (NMR), flame atomic absorption spectroscopy (F-AAS), single-crystal X-ray diffraction, thermogravimetric analysis (TGA), and Fourier-transform infrared spectroscopy (FTIR). The pharmacokinetics were studied using SwissADME. The results obtained from the computational studies supported the results obtained from the MTT analysis, and the antimicrobial activity was expressed as the minimum inhibitory concentration (MIC). Full article

(This article belongs to the Special Issue Metal-Based Complexes in Cancer)

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19 pages, 4086 KiB

Open AccessArticle

New Derivatives of 5-((1-Methyl-Pyrrol-2-yl) Methyl)-4-(Naphthalen-1-yl)-1,2,4-Triazoline-3-Thione and Its Coordination Compounds with Anticancer Activity

by Agnieszka Czylkowska, Suneel Lanka, Małgorzata Szczesio, Kamila Czarnecka, Paweł Szymański, Monika Pitucha, Aneta Drabińska, Bruno Cury Camargo and Jacek Szczytko

Int. J. Mol. Sci. 2022, 23(16), 9162; https://doi.org/10.3390/ijms23169162 - 15 Aug 2022

Cited by 3 | Viewed by 2082

Abstract

A new ligand 5-((1-methyl-pyrrol-2-yl) methyl)-4-(naphthalen-1-yl)-1,2,4-triazoline-3-thione (C15) and its metal complexes with formulae: Mn(C15)Cl₂MeOH (1), Fe(C15)Cl₂MeOH (2), Ni(C15)Cl₂MeOH (3), Cu(C15)₂Cl₂ (4) and Zn(C15)₄Cl₂ (5) have been synthesized. The C15 ligand and complexes were characterized by NMR, elemental analysis, FT-IR, EPR, magnetic and TGA studies. The anticancer activities of the organic ligand (C15) and complexes (1–5) were evaluated against human colon adenocarcinoma (HT29) and human lung (A549) cancer cell lines. The complex (1) exhibited potential activity at concentration of 794.37 μM (A549) and 654.31 μM (HT29) in both cancer cells. The complex (3) showed significant activity against the HT29 cancer cell line with an IC₅₀ value of 1064.05 μM. This article highlights some of the metals that have become important in the development of new coordination complexes and the treatment of cancer. Additionally, for C15, the toxicity was predicted by ADMET analysis and molecular docking. Full article

(This article belongs to the Special Issue Metal-Based Complexes in Cancer)

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21 pages, 3419 KiB

Open AccessArticle

The Pt(S-pr-thiosal)2 and BCL1 Leukemia Lymphoma: Antitumor Activity In Vitro and In Vivo

by Zana Besser Silconi, Vesna Rosic, Sasa Benazic, Gordana Radosavljevic, Marina Mijajlovic, Jelena Pantic, Zoran R. Ratkovic, Gordana Radic, Aleksandar Arsenijevic, Marija Milovanovic, Nebojsa Arsenijevic and Jelena Milovanovic

Int. J. Mol. Sci. 2022, 23(15), 8161; https://doi.org/10.3390/ijms23158161 - 24 Jul 2022

Cited by 1 | Viewed by 2176

Abstract

B cell malignancies are, despite the development of targeted therapy in a certain percentage of the patients still a chronic disease with relapses, requiring multiple lines of therapy. Regimens that include platinum-based drugs provide high response rates in different B cell lymphomas, high-risk chronic lymphocytic leukemia (CLL), and devastating complication of CLL, Richter’s syndrome. The aim of this study was to explore the potential antitumor activity of previously synthetized platinum(IV) complex with alkyl derivatives of thyosalicilc acid, PtCl2(S-pr-thiosal)2, toward murine BCL1 cells and to delineate possible mechanisms of action. The PtCl2(S-pr-thiosal)2 reduced the viability of BCL1 cells in vitro but also reduced the growth of metastases in the leukemia lymphoma model in BALB/c mice. PtCl2(S-pr-thiosal)2 induced apoptosis, inhibited proliferation of BCL1 cells, and induced cell cycle disturbance. Treatment of BCL1 cells with PtCl2(S-pr-thiosal)2 inhibited expression of cyclin D3 and cyclin E and enhanced expression of cyclin-dependent kinase inhibitors p16, p21, and p27 resulting in cell cycle arrest in the G1 phase, reduced the percentage of BCL1 cells in the S phase, and decreased expression of Ki-67. PtCl2(S-pr-thiosal)2 treatment reduced expression of phosphorylated STAT3 and downstream-regulated molecules associated with cancer stemness and proliferation, NANOG, cyclin D3, and c-Myc, and expression of phosphorylated NFκB in vitro and in vivo. In conclusion, PtCl2(S-pr-thiosal)2 reduces STAT3 and NFκB phosphorylation resulting in inhibition of BCL1 cell proliferation and the triggering of apoptotic cell death. Full article

(This article belongs to the Special Issue Metal-Based Complexes in Cancer)

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19 pages, 1872 KiB

Open AccessArticle

Novel Nickel(II), Palladium(II), and Platinum(II) Complexes with O,S Bidendate Cinnamic Acid Ester Derivatives: An In Vitro Cytotoxic Comparison to Ruthenium(II) and Osmium(II) Analogues

by Jana Hildebrandt, Norman Häfner, Helmar Görls, Marie-Christin Barth, Matthias Dürst, Ingo B. Runnebaum and Wolfgang Weigand

Int. J. Mol. Sci. 2022, 23(12), 6669; https://doi.org/10.3390/ijms23126669 - 15 Jun 2022

Cited by 7 | Viewed by 2107

Abstract

(1) Background: Since the discovery of cisplatin’s cytotoxic properties, platinum(II) compounds have attracted much interest in the field of anticancer drug development. Over the last few years, classical structure–activity relationships (SAR) have been broken by some promising new compounds based on platinum or other metals. We focus on the synthesis and characterization of 17 different complexes with β-hydroxydithiocinnamic acid esters as O,S bidendate ligands for nickel(II), palladium(II), and platinum(II) complexes. (2) Methods: The bidendate compounds were synthesized and characterized using classical methods including NMR spectroscopy, MS spectrometry, elemental analysis, and X-ray crystallography, and their cytotoxic potential was assessed using in vitro cell culture assays. Data were compared with other recently reported platinum(II), ruthenium(II), and osmium(II) complexes based on the same main ligand system. (3) Results: SAR analyses regarding the metal ion (M), and the alkyl-chain position (P) and length (L), revealed the following order of the effect strength for in vitro activity: M > P > L. The highest activities have Pd complexes and ortho-substituted compounds. Specific palladium(II) complexes show lower IC₅₀ values compared to cisplatin, are able to elude cisplatin resistance mechanisms, and show a higher cancer cell specificity. (4) Conclusion: A promising new palladium(II) candidate (Pd3) should be evaluated in further studies using in vivo model systems, and the identified SARs may help to target platinum-resistant tumors. Full article

(This article belongs to the Special Issue Metal-Based Complexes in Cancer)

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29 pages, 3639 KiB

Open AccessArticle

Highly Cytotoxic Osmium(II) Compounds and Their Ruthenium(II) Analogues Targeting Ovarian Carcinoma Cell Lines and Evading Cisplatin Resistance Mechanisms

by Jana Hildebrandt, Norman Häfner, Daniel Kritsch, Helmar Görls, Matthias Dürst, Ingo B. Runnebaum and Wolfgang Weigand

Int. J. Mol. Sci. 2022, 23(9), 4976; https://doi.org/10.3390/ijms23094976 - 29 Apr 2022

Cited by 16 | Viewed by 2369

Abstract

(1) Background: Ruthenium and osmium complexes attract increasing interest as next generation anticancer drugs. Focusing on structure-activity-relationships of this class of compounds, we report on 17 different ruthenium(II) complexes and four promising osmium(II) analogues with cinnamic acid derivatives as O,S bidentate ligands. The aim of this study was to determine the anticancer activity and the ability to evade platin resistance mechanisms for these compounds. (2) Methods: Structural characterizations and stability determinations have been carried out with standard techniques, including NMR spectroscopy and X-ray crystallography. All complexes and single ligands have been tested for cytotoxic activity on two ovarian cancer cell lines (A2780, SKOV3) and their cisplatin-resistant isogenic cell cultures, a lung carcinoma cell line (A549) as well as selected compounds on three non-cancerous cell cultures in vitro. FACS analyses and histone γH2AX staining were carried out for cell cycle distribution and cell death or DNA damage analyses, respectively. (3) Results: IC50 values show promising results, specifically a high cancer selective cytotoxicity and evasion of resistance mechanisms for Ru(II) and Os(II) compounds. Histone γH2AX foci and FACS experiments validated the high cytotoxicity but revealed diminished DNA damage-inducing activity and an absence of cell cycle disturbance thus pointing to another mode of action. (4) Conclusion: Ru(II) and Os(II) compounds with O,S-bidentate ligands show high cytotoxicity without strong effects on DNA damage and cell cycle, and this seems to be the basis to circumvent resistance mechanisms and for the high cancer cell specificity. Full article

(This article belongs to the Special Issue Metal-Based Complexes in Cancer)

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Review

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42 pages, 3338 KiB

Open AccessReview

Revisiting the Anti-Cancer Toxicity of Clinically Approved Platinating Derivatives

by Benjamin N. Forgie, Rewati Prakash and Carlos M. Telleria

Int. J. Mol. Sci. 2022, 23(23), 15410; https://doi.org/10.3390/ijms232315410 - 6 Dec 2022

Cited by 23 | Viewed by 2859

Abstract

Cisplatin (CDDP), carboplatin (CP), and oxaliplatin (OXP) are three platinating agents clinically approved worldwide for use against a variety of cancers. They are canonically known as DNA damage inducers; however, that is only one of their mechanisms of cytotoxicity. CDDP mediates its effects through DNA damage-induced transcription inhibition and apoptotic signalling. In addition, CDDP targets the endoplasmic reticulum (ER) to induce ER stress, the mitochondria via mitochondrial DNA damage leading to ROS production, and the plasma membrane and cytoskeletal components. CP acts in a similar fashion to CDDP by inducing DNA damage, mitochondrial damage, and ER stress. Additionally, CP is also able to upregulate micro-RNA activity, enhancing intrinsic apoptosis. OXP, on the other hand, at first induces damage to all the same targets as CDDP and CP, yet it is also capable of inducing immunogenic cell death via ER stress and can decrease ribosome biogenesis through its nucleolar effects. In this comprehensive review, we provide detailed mechanisms of action for the three platinating agents, going beyond their nuclear effects to include their cytoplasmic impact within cancer cells. In addition, we cover their current clinical use and limitations, including side effects and mechanisms of resistance. Full article

(This article belongs to the Special Issue Metal-Based Complexes in Cancer)

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