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New Diagnostic and Therapeutic Tools Against Multidrug Resistant Tumors (STRATAGEM Special Issue, EU-COST CA17104)

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A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (31 January 2022) | Viewed by 55693

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Special Issue Editors

Prof. Dr. Chiara Riganti

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Department of Oncology, University of Torino, via Santena 5/bis, 10126 Torino, Italy
Interests: multidrug resistance; immune-resistance; immune-evasion; cancer metabolism
Special Issues, Collections and Topics in MDPI journals

Dr. M. Helena Vasconcelos

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Guest Editor

1. FFUP – Faculdade de Farmácia da Universidade do Porto, 4050-313 Porto, Potugal
2. i3S—Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal
Interests: cancer drug resistance; cancer multidrug resistance; intercellular transfer of drug resistance mediated by Extracellular Vesicles (EVs); new approaches to overcome drug resistance; drug-efflux pumps; escape from apoptosis; autophagy; metabolic alterations associated with drug resistance; tumour-microenvironment interactions; cancer stem cells; microRNAs; biomarkers of minimal residual disease and of drug resistance
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Prof. Dr. Catherine Passirani

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Guest Editor

1. Department of Pharmacy, University of Angers, 16 Boulevard Daviers, 49045 Angers, France
2. Micro et Nanomédecines Translationnelles, MINT, UNIV Angers, INSERM 1066, CNRS 6021, Angers, France
Interests: nanomedicine; lipid nanocapsules; ferrocifene; self-assemblies; active targeting; multidrug resistance; structure-property relationship
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Resistance towards chemotherapy, targeted therapies, and immunotherapy occurs in up to 70% of tumors, at diagnosis or during treatment. It is often a feature of a complex tumor phenotype characterized by simultaneous resistance toward different agents. This multidrug resistance (MDR), is a challenge that needs multi-disciplinary approaches to better understand its underlying mechanisms and identify predictive markers and new therapeutic targets. An in-depth knowledge of the biological processes that determine the onset of MDR will lead to the design and formulation of anti-cancer agents effective against tumors that are refractory to conventional agents, reversing their resistance to treatment.

In April 2018, the European COST (Cooperation in Science and Technology) Action STRATAGEM “New Diagnostic and Therapeutic Tools against Multidrug-Resistant Tumors” was funded by the European Union. It was launched as the first multidisciplinary open consortium studying simultaneously the diagnostic, therapeutic, and toxicological challenges related to MDR tumors. Multiple tools must be used to overcome MDR, including high-throughput bioinformatic analyses, “OMICS” technologies, biochemical and pharmacological assays, rational design and synthesis of new synthetic or natural bioactive compounds, formulations using nanocarriers to improve drug solubilization, selectivity, and anti-cancer action.

The latest works from members of the STRATAGEM COST Action will be collected in this Special Issue of Cancers that is open to research articles and timely reviews on all aspects of drug resistance in tumors. Please note that this Special Issue is open only to members of STRATAGEM.

Prof. Dr. Chiara Riganti
Prof. Dr. M. Helena Vasconcelos
Prof. Dr. Catherine Passirani
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

multidrug resistance
ABC transporters
resistance to chemotherapy
resistance to immunotherapy
resistance to targeted therapies
intercellular transfer of drug resistance traits mediated by extracellular vesicles (EVs)
tumor–microenvironment interactions
cancer stem cells
microRNAs
molecular targets
precision therapeutic strategies
personalized medicine
pharmacological strategies against resistant tumors
nanomedicine
active targeting
structure–activity relationship
drug repurposing
biomarkers of drug resistance

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Published Papers (10 papers)

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Editorial

Jump to: Research, Review

5 pages, 219 KiB

Open AccessEditorial

Special Issue: “New Diagnostic and Therapeutic Tools against Multidrug-Resistant Tumors (STRATAGEM Special Issue, EU-COST CA17104)”

by M. Helena Vasconcelos, Catherine Passirani and Chiara Riganti

Cancers 2022, 14(22), 5491; https://doi.org/10.3390/cancers14225491 - 8 Nov 2022

Viewed by 1031

Abstract

Cancer drug resistance, either intrinsic or acquired, often causes treatment failure and increased mortality [...] Full article

(This article belongs to the Special Issue New Diagnostic and Therapeutic Tools Against Multidrug Resistant Tumors (STRATAGEM Special Issue, EU-COST CA17104))

Research

Jump to: Editorial, Review

17 pages, 4212 KiB

Open AccessArticle

New Therapeutic Strategy for Overcoming Multidrug Resistance in Cancer Cells with Pyrazolo[3,4-d]pyrimidine Tyrosine Kinase Inhibitors

by Ana Podolski-Renić, Jelena Dinić, Tijana Stanković, Ivanka Tsakovska, Ilza Pajeva, Tiziano Tuccinardi, Lorenzo Botta, Silvia Schenone and Milica Pešić

Cancers 2021, 13(21), 5308; https://doi.org/10.3390/cancers13215308 - 22 Oct 2021

Cited by 7 | Viewed by 2248

Abstract

Tyrosine kinase inhibitors (TKIs) often interact with the multidrug resistant (MDR) phenotype of cancer cells. In some cases, TKIs increase the susceptibility of MDR cancer cells to chemotherapy. As the overexpression of membrane transporter P-glycoprotein (P-gp) is the most common alteration in MDR cancer cells, we investigated the effects of TKI pyrazolo[3,4-d]pyrimidines on P-gp inhibition in two cellular models comprising sensitive and corresponding MDR cancer cells (human non-small cell lung carcinoma and colorectal adenocarcinoma). Tested TKIs showed collateral sensitivity by inducing stronger inhibition of MDR cancer cell line viability. Moreover, TKIs directly interacted with P-gp and inhibited its ATPase activity. Their potential P-gp binding site was proposed by molecular docking simulations. TKIs reversed resistance to doxorubicin and paclitaxel in a concentration-dependent manner. The expression studies excluded the indirect effect of TKIs on P-gp through regulation of its expression. A kinetics study showed that TKIs decreased P-gp activity and this effect was sustained for seven days in both MDR models. Therefore, pyrazolo[3,4-d]pyrimidines with potential for reversing P-gp-mediated MDR even in prolonged treatments can be considered a new therapeutic strategy for overcoming cancer MDR. Full article

(This article belongs to the Special Issue New Diagnostic and Therapeutic Tools Against Multidrug Resistant Tumors (STRATAGEM Special Issue, EU-COST CA17104))

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26 pages, 1133 KiB

Open AccessArticle

Cyano- and Ketone-Containing Selenoesters as Multi-Target Compounds against Resistant Cancers

by Nikoletta Szemerédi, Simona Dobiasová, Noemi Salardón-Jiménez, Annamária Kincses, Márta Nové, Giyaullah Habibullah, Clotilde Sevilla-Hernández, Miguel Benito-Lama, Francisco-Javier Alonso-Martínez, Jitka Viktorová, Gabriella Spengler and Enrique Domínguez-Álvarez

Cancers 2021, 13(18), 4563; https://doi.org/10.3390/cancers13184563 - 11 Sep 2021

Cited by 13 | Viewed by 2786

Abstract

Fifteen selenocompounds, comprising of eight ketone-containing selenoesters (K1–K8, also known as oxoselenoesters) and seven cyano-containing selenoesters (N1–N7, known also as cyanoselenoesters), have been designed, synthesized, and evaluated as novel anticancer agents. These compounds are derivatives of previously reported active selenoesters and were prepared following a three-step one-pot synthetic route. The following evaluations were performed in their biological assessment: cytotoxicity determination, selectivity towards cancer cells in respect to non-cancer cells, checkerboard combination assay, ABCB1 inhibition and inhibition of ABCB1 ATPase activity, apoptosis induction, and wound healing assay. As key results, all the compounds showed cytotoxicity against cancer cells at low micromolar concentrations, with cyanoselenoesters being strongly selective. All of the oxoselenoesters, except K4, were potent ABCB1 inhibitors, and two of them, namely K5 and K6, enhanced the activity of doxorubicin in a synergistic manner. The majority of these ketone derivatives modulated the ATPase activity, showed wound healing activity, and induced apoptosis, with K3 being the most potent, with a potency close to that of the reference compound. To summarize, these novel derivatives have promising multi-target activity, and are worthy to be studied more in-depth in future works to gain a greater understanding of their potential applications against cancer. Full article

(This article belongs to the Special Issue New Diagnostic and Therapeutic Tools Against Multidrug Resistant Tumors (STRATAGEM Special Issue, EU-COST CA17104))

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21 pages, 3170 KiB

Open AccessArticle

Organoruthenium Complexes with Benzo-Fused Pyrithiones Overcome Platinum Resistance in Ovarian Cancer Cells

by Jerneja Kladnik, James P. C. Coverdale, Jakob Kljun, Hilke Burmeister, Petra Lippman, Francesca G. Ellis, Alan M. Jones, Ingo Ott, Isolda Romero-Canelón and Iztok Turel

Cancers 2021, 13(10), 2493; https://doi.org/10.3390/cancers13102493 - 20 May 2021

Cited by 22 | Viewed by 4239

Abstract

Drug resistance to existing anticancer agents is a growing clinical concern, with many first line treatments showing poor efficacy in treatment plans of some cancers. Resistance to platinum agents, such as cisplatin, is particularly prevalent in the treatment of ovarian cancer, one of the most common cancers amongst women in the developing world. Therefore, there is an urgent need to develop next generation of anticancer agents which can overcome resistance to existing therapies. We report a new series of organoruthenium(II) complexes bearing structurally modified pyrithione ligands with extended aromatic scaffold, which overcome platinum and adriamycin resistance in human ovarian cancer cells. The mechanism of action of such complexes appears to be unique from that of cisplatin, involving G₁ cell cycle arrest without generation of cellular ROS, as is typically associated with similar ruthenium complexes. The complexes inhibit the enzyme thioredoxin reductase (TrxR) in a model system and reduce cell motility towards wound healing. Importantly, this work highlights further development in our understanding of the multi-targeting mechanism of action exhibited by transition metal complexes. Full article

(This article belongs to the Special Issue New Diagnostic and Therapeutic Tools Against Multidrug Resistant Tumors (STRATAGEM Special Issue, EU-COST CA17104))

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17 pages, 3899 KiB

Open AccessArticle

pH-Responsive Lipid Nanocapsules: A Promising Strategy for Improved Resistant Melanoma Cell Internalization

by Vincent Pautu, Elise Lepeltier, Adélie Mellinger, Jérémie Riou, Antoine Debuigne, Christine Jérôme, Nicolas Clere and Catherine Passirani

Cancers 2021, 13(9), 2028; https://doi.org/10.3390/cancers13092028 - 22 Apr 2021

Cited by 12 | Viewed by 2978

Abstract

Despite significant advances in melanoma therapy, low response rates and multidrug resistance (MDR) have been described, reducing the anticancer efficacy of the administered molecules. Among the causes to explain these resistances, the decreased intratumoral pH is known to potentiate MDR and to reduce the sensitivity to anticancer molecules. Nanomedicines have been widely exploited as the carriers of MDR reversing molecules. Lipid nanocapsules (LNC) are nanoparticles that have already demonstrated their ability to improve cancer treatment. Here, LNC were modified with novel copolymers that combine N-vinylpyrrolidone (NVP) to impart stealth properties and vinyl imidazole (Vim), providing pH-responsive ability to address classical chemoresistance by improving tumor cell entry. These copolymers could be post-inserted at the LNC surface, leading to the property of going from neutral charge under physiological pH to positive charge under acidic conditions. LNC modified with polymer P5 (C18H37-P(NVP21-co-Vim15)) showed in vitro pH-responsive properties characterized by an enhanced cellular uptake under acidic conditions. Moreover, P5 surface modification led to an increased biological effect by protecting the nanocarrier from opsonization by complement activation. These data suggest that pH-sensitive LNC responds to what is expected from a promising nanocarrier to target metastatic melanoma. Full article

(This article belongs to the Special Issue New Diagnostic and Therapeutic Tools Against Multidrug Resistant Tumors (STRATAGEM Special Issue, EU-COST CA17104))

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19 pages, 2874 KiB

Open AccessArticle

Molecular Profiling of Docetaxel-Resistant Prostate Cancer Cells Identifies Multiple Mechanisms of Therapeutic Resistance

by Thiago S. Lima, Diego Iglesias-Gato, Luciano D. O. Souza, Jan Stenvang, Diego S. Lima, Martin A. Røder, Klaus Brasso and José M. A. Moreira

Cancers 2021, 13(6), 1290; https://doi.org/10.3390/cancers13061290 - 14 Mar 2021

Cited by 21 | Viewed by 3639

Abstract

Docetaxel—a taxane-based chemotherapeutic agent—was the first treatment to demonstrate significant improvements in overall survival in men with metastatic castration-resistant prostate cancer (mCRPC). However, the response to docetaxel is generally short-lived, and relapse eventually occurs due to the development of resistance. To explore the mechanisms of acquired docetaxel resistance in prostate cancer (PCa) and set these in the context of androgen deprivation therapy, we established docetaxel-resistant PCa cell lines, derived from the androgen-dependent LNCaP cell line, and from the LNCaP lineage-derived androgen-independent C4-2B sub-line. We generated two docetaxel-resistant LNCaPR and C4-2BR sub-lines, with IC50 values 77- and 50-fold higher than those of the LNCaP and C4-2B parental cells, respectively. We performed gene expression analysis of the matched sub-lines and found several alterations that may confer docetaxel resistance. In addition to increased expression of ABCB1, an ATP-binding cassette (ABC) transporter, and a well-known gene associated with development of docetaxel resistance, we identified genes associated with androgen signaling, cell survival, and overexpression of ncRNAs. In conclusion, we identified multiple mechanisms that may be associated with the development of taxane drug resistance in PCa. Actioning these mechanisms could provide a potential approach to re-sensitization of docetaxel-resistant PCa cells to docetaxel treatment and thereby further add to the life-prolonging effects of this drug in men with mCRPC. Full article

(This article belongs to the Special Issue New Diagnostic and Therapeutic Tools Against Multidrug Resistant Tumors (STRATAGEM Special Issue, EU-COST CA17104))

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Review

Jump to: Editorial, Research

30 pages, 2122 KiB

Open AccessReview

3D Cell Culture Models as Recapitulators of the Tumor Microenvironment for the Screening of Anti-Cancer Drugs

by Mélanie A. G. Barbosa, Cristina P. R. Xavier, Rúben F. Pereira, Vilma Petrikaitė and M. Helena Vasconcelos

Cancers 2022, 14(1), 190; https://doi.org/10.3390/cancers14010190 - 31 Dec 2021

Cited by 90 | Viewed by 8356

Abstract

Today, innovative three-dimensional (3D) cell culture models have been proposed as viable and biomimetic alternatives for initial drug screening, allowing the improvement of the efficiency of drug development. These models are gaining popularity, given their ability to reproduce key aspects of the tumor microenvironment, concerning the 3D tumor architecture as well as the interactions of tumor cells with the extracellular matrix and surrounding non-tumor cells. The development of accurate 3D models may become beneficial to decrease the use of laboratory animals in scientific research, in accordance with the European Union’s regulation on the 3R rule (Replacement, Reduction, Refinement). This review focuses on the impact of 3D cell culture models on cancer research, discussing their advantages, limitations, and compatibility with high-throughput screenings and automated systems. An insight is also given on the adequacy of the available readouts for the interpretation of the data obtained from the 3D cell culture models. Importantly, we also emphasize the need for the incorporation of additional and complementary microenvironment elements on the design of 3D cell culture models, towards improved predictive value of drug efficacy. Full article

(This article belongs to the Special Issue New Diagnostic and Therapeutic Tools Against Multidrug Resistant Tumors (STRATAGEM Special Issue, EU-COST CA17104))

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36 pages, 1858 KiB

Open AccessFeature PaperReview

Resistance to Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia—From Molecular Mechanisms to Clinical Relevance

by Raquel Alves, Ana Cristina Gonçalves, Sergio Rutella, António M. Almeida, Javier De Las Rivas, Ioannis P. Trougakos and Ana Bela Sarmento Ribeiro

Cancers 2021, 13(19), 4820; https://doi.org/10.3390/cancers13194820 - 26 Sep 2021

Cited by 83 | Viewed by 11559

Abstract

Resistance to targeted therapies is a complex and multifactorial process that culminates in the selection of a cancer clone with the ability to evade treatment. Chronic myeloid leukemia (CML) was the first malignancy recognized to be associated with a genetic alteration, the t(9;22)(q34;q11). This translocation originates the BCR-ABL1 fusion gene, encoding the cytoplasmic chimeric BCR-ABL1 protein that displays an abnormally high tyrosine kinase activity. Although the vast majority of patients with CML respond to Imatinib, a tyrosine kinase inhibitor (TKI), resistance might occur either de novo or during treatment. In CML, the TKI resistance mechanisms are usually subdivided into BCR-ABL1-dependent and independent mechanisms. Furthermore, patients’ compliance/adherence to therapy is critical to CML management. Techniques with enhanced sensitivity like NGS and dPCR, the use of artificial intelligence (AI) techniques, and the development of mathematical modeling and computational prediction methods could reveal the underlying mechanisms of drug resistance and facilitate the design of more effective treatment strategies for improving drug efficacy in CML patients. Here we review the molecular mechanisms and other factors involved in resistance to TKIs in CML and the new methodologies to access these mechanisms, and the therapeutic approaches to circumvent TKI resistance. Full article

(This article belongs to the Special Issue New Diagnostic and Therapeutic Tools Against Multidrug Resistant Tumors (STRATAGEM Special Issue, EU-COST CA17104))

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26 pages, 1144 KiB

Open AccessEditor’s ChoiceReview

Apoptosis Deregulation and the Development of Cancer Multi-Drug Resistance

by Christiana M. Neophytou, Ioannis P. Trougakos, Nuray Erin and Panagiotis Papageorgis

Cancers 2021, 13(17), 4363; https://doi.org/10.3390/cancers13174363 - 28 Aug 2021

Cited by 150 | Viewed by 12917

Abstract

The ability of tumor cells to evade apoptosis is established as one of the hallmarks of cancer. The deregulation of apoptotic pathways conveys a survival advantage enabling cancer cells to develop multi-drug resistance (MDR), a complex tumor phenotype referring to concurrent resistance toward agents with different function and/or structure. Proteins implicated in the intrinsic pathway of apoptosis, including the Bcl-2 superfamily and Inhibitors of Apoptosis (IAP) family members, as well as their regulator, tumor suppressor p53, have been implicated in the development of MDR in many cancer types. The PI₃K/AKT pathway is pivotal in promoting survival and proliferation and is often overactive in MDR tumors. In addition, the tumor microenvironment, particularly factors secreted by cancer-associated fibroblasts, can inhibit apoptosis in cancer cells and reduce the effectiveness of different anti-cancer drugs. In this review, we describe the main alterations that occur in apoptosis-and related pathways to promote MDR. We also summarize the main therapeutic approaches against resistant tumors, including agents targeting Bcl-2 family members, small molecule inhibitors against IAPs or AKT and agents of natural origin that may be used as monotherapy or in combination with conventional therapeutics. Finally, we highlight the potential of therapeutic exploitation of epigenetic modifications to reverse the MDR phenotype. Full article

(This article belongs to the Special Issue New Diagnostic and Therapeutic Tools Against Multidrug Resistant Tumors (STRATAGEM Special Issue, EU-COST CA17104))

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23 pages, 6845 KiB

Open AccessReview

Ferrocifen Loaded Lipid Nanocapsules: A Promising Anticancer Medication against Multidrug Resistant Tumors

by Pierre Idlas, Elise Lepeltier, Gérard Jaouen and Catherine Passirani

Cancers 2021, 13(10), 2291; https://doi.org/10.3390/cancers13102291 - 11 May 2021

Cited by 20 | Viewed by 3871

Abstract

Resistance of cancer cells to current chemotherapeutic drugs has obliged the scientific community to seek innovative compounds. Ferrocifens, lipophilic organometallic compounds composed of a tamoxifen scaffold covalently bound to a ferrocene moiety, have shown very interesting antiproliferative, cytotoxic and immunologic effects. The formation of ferrocenyl quinone methide plays a crucial role in the multifaceted activity of ferrocifens. Lipid nanocapsules (LNCs), meanwhile, are nanoparticles obtained by a free organic solvent process. LNCs consist of an oily core surrounded by amphiphilic surfactants and are perfectly adapted to encapsulate these hydrophobic compounds. The different in vitro and in vivo experiments performed with this ferrocifen-loaded nanocarrier have revealed promising results in several multidrug-resistant cancer cell lines such as glioblastoma, breast cancer and metastatic melanoma, alone or in combination with other therapies. This review provides an exhaustive summary of the use of ferrocifen-loaded LNCs as a promising nanomedicine, outlining the ferrocifen mechanisms of action on cancer cells, the nanocarrier formulation process and the in vivo results obtained over the last two decades. Full article

(This article belongs to the Special Issue New Diagnostic and Therapeutic Tools Against Multidrug Resistant Tumors (STRATAGEM Special Issue, EU-COST CA17104))

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