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Novel Insights into Cancer Drug Resistance: From Molecular Basis to Emerging Therapeutic Strategies

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 November 2022) | Viewed by 14558

Special Issue Editor

Dr. Fabrizio Fontana

E-Mail Website
Guest Editor
Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Via Balzaretti 9, 20133 Milano, Italy
Interests: prostate cancer; melanoma; ovarian cancer; cancer biology; mechanisms of cancer cell death; cancer metastasis; cancer metabolism; cancer drug resistance; cancer stem cells; tumor microenvironment; extracellular vesicles
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Drug resistance still represents the main reason for therapy failure in cancer patients. Indeed, despite being initially susceptible to standard strategies, tumor cells frequently become irresponsive to current treatments via different mechanisms able to impair drug efficacy, including reduced drug adsorption, increased DNA repair and cell death suppression, gene mutation and amplification, and epigenetic changes. Other key processes frequently involved in reduction in drug sensitivity are based on cancer stem cell selection and survival, as well as on the complex interaction network occurring in the tumor microenvironment. More recently, the crucial role of gut microbiome in cancer recurrence has also been highlighted.

Based on these premises, several efforts have been directed toward the identification of new biomarkers able to predict therapeutic outcomes: circulating cancer cells, as well as circulating tumor DNA, cancer cell secretome, and tumor-derived extracellular vesicles and miRNAs can be easily isolated from patient body fluids. On the other hand, novel therapeutic approaches, involving both synthetic and natural compounds, are being developed to overcome drug resistance.

The aim of this Special Issue is to publish original articles and reviews in the field of basic and translational cancer research that specifically addresses the above topics, leading to the discovery of new molecular pathways and biomarkers associated with chemoresistance, as well as to the definition of novel drug combinations that could prevent tumor relapse.

Dr. Fabrizio Fontana
Guest Editor

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 short 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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

  • cancer drug resistance
  • cancer stem cells
  • tumor microenvironment
  • gut microbiome
  • cancer secretome
  • extracellular vesicles
  • -omics
  • biomarkers
  • combination therapies

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Related Special Issues

Published Papers (5 papers)

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Research

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18 pages, 1834 KiB  
Article
Ruthenium Complex HB324 Induces Apoptosis via Mitochondrial Pathway with an Upregulation of Harakiri and Overcomes Cisplatin Resistance in Neuroblastoma Cells In Vitro
by Nicola L. Wilke, Hilke Burmeister, Corazon Frias, Ingo Ott and Aram Prokop
Int. J. Mol. Sci. 2023, 24(2), 952; https://doi.org/10.3390/ijms24020952 - 4 Jan 2023
Cited by 12 | Viewed by 2093
Abstract
Ruthenium(II) complexes with N-heterocyclic carbene (NHC) ligands have recently attracted attention as novel chemotherapeutic agents. The complex HB324 was intensively studied as an apoptosis-inducing compound in resistant cell lines. HB324 induced apoptosis via mitochondrial pathways. Of particular interest is the upregulation of the [...] Read more.
Ruthenium(II) complexes with N-heterocyclic carbene (NHC) ligands have recently attracted attention as novel chemotherapeutic agents. The complex HB324 was intensively studied as an apoptosis-inducing compound in resistant cell lines. HB324 induced apoptosis via mitochondrial pathways. Of particular interest is the upregulation of the Harakiri resistance protein, which inhibits the anti-apoptotic and death repressor proteins Bcl-2 (B-cell lymphoma 2) and BCL-xL (B-cell lymphoma-extra large). Moreover, HB324 showed synergistic activity with various established anticancer drugs and overcame resistance in several cell lines, such as neuroblastoma cells. In conclusion, HB324 showed promising potential as a novel anticancer agent in vitro, suggesting further investigations on this and other preclinical ruthenium drug candidates. Full article
(This article belongs to the Special Issue Novel Insights into Cancer Drug Resistance: From Molecular Basis to Emerging Therapeutic Strategies)
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17 pages, 6723 KiB  
Article
TSLP as a Potential Therapy in the Treatment of CRLF2 B Cell Acute Lymphoblastic Leukemia
by Hossam R. Alkashgari, Caleb Ruiz-Jimenez, Cornelia Stoian, Jacqueline S. Coats, Ineavely Baez, Evgeny Chirshev, Shannalee R. Martinez, Sinisa Dovat, Olivia L. Francis-Boyle, Carlos A. Casiano and Kimberly J. Payne
Int. J. Mol. Sci. 2023, 24(1), 474; https://doi.org/10.3390/ijms24010474 - 28 Dec 2022
Cited by 5 | Viewed by 2861
Abstract
Cytokine receptor-like factor 2 B-cell acute lymphoblastic leukemia (CRLF2 B-ALL) is a high-risk subtype characterized by CRLF2 overexpression with poor survival rates in children and adults. CRLF2 and interleukin-7 receptor alpha (IL-7Rα) form a receptor for the cytokine thymic stromal lymphopoietin (TSLP), which [...] Read more.
Cytokine receptor-like factor 2 B-cell acute lymphoblastic leukemia (CRLF2 B-ALL) is a high-risk subtype characterized by CRLF2 overexpression with poor survival rates in children and adults. CRLF2 and interleukin-7 receptor alpha (IL-7Rα) form a receptor for the cytokine thymic stromal lymphopoietin (TSLP), which induces JAK/STAT and PI3K/AKT/mTOR pathway signals. Previous studies from our group showed that low TSLP doses increased STAT5, AKT, and S6 phosphorylation and contributed to CRLF2 B-ALL cell survival. Here we investigated the role of TSLP in the survival and proliferation of CRLF2 B-ALL cells in vitro and in vivo. We hypothesized that high doses of TSLP increase CRLF2 signals and contribute to increased proliferation of CRLF2 B-ALL cells in vitro and in vivo. Interestingly, we observed the opposite effect. Specifically, high doses of TSLP induced apoptosis in human CRLF2 B-ALL cell lines in vitro, prevented engraftment of CRLF2 B-ALL cells, and prolonged the survival of +TSLP patient-derived-xenograft mice. Mechanistically, we showed that high doses of TSLP induced loss of its receptor and loss of CRLF2 signals in vitro. These results suggest that high doses of TSLP could be further investigated as a potential therapy for the treatment of CRLF2 B-ALL. Full article
(This article belongs to the Special Issue Novel Insights into Cancer Drug Resistance: From Molecular Basis to Emerging Therapeutic Strategies)
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20 pages, 3926 KiB  
Article
From Nature to Synthetic Compounds: Novel 1(N),2,3 Trisubstituted-5-oxopyrrolidines Targeting Multiple Myeloma Cells
by Roberta Listro, Alessio Malacrida, Francesca Alessandra Ambrosio, Giacomo Rossino, Marcello Di Giacomo, Valeria Cavalloro, Martina Garbagnoli, Pasquale Linciano, Daniela Rossi, Guido Cavaletti, Giosuè Costa, Stefano Alcaro, Mariarosaria Miloso and Simona Collina
Int. J. Mol. Sci. 2022, 23(21), 13061; https://doi.org/10.3390/ijms232113061 - 27 Oct 2022
Cited by 5 | Viewed by 2078
Abstract
The insurgence of drug resistance in treating Multiple Myeloma (MM) still represents a major hamper in finding effective treatments, although over the past decades new classes of drugs, such as proteasome inhibitors and immunomodulatory drugs, have been discovered. Recently, our research team, within [...] Read more.
The insurgence of drug resistance in treating Multiple Myeloma (MM) still represents a major hamper in finding effective treatments, although over the past decades new classes of drugs, such as proteasome inhibitors and immunomodulatory drugs, have been discovered. Recently, our research team, within a Nature-Aided Drug Discovery project, isolated from Hibiscus Sabdariffa L. calyces the secondary metabolite called Hib-ester which possesses antiproliferative properties against human multiple myeloma RPMI 8226 cells, reduces migration and cell invasion and inhibits proteasome without neurotoxic effects. In the present study, we explored the chemical spaces of the hit compound Hib-ester. We explored the structure-activity relationships (SAR), and we optimized the scaffold through sequentially modifying Hib-ester subunits. Compound screening was performed based on cytotoxicity against the RPMI 8226 cells to assess the potential efficacy toward human MM. The ability of the most effective molecules to inhibit the proteasome was evaluated and the binding mode of the most promising compounds in the proteasome chymotrypsin binding pocket was deciphered through molecular modeling simulations. Compounds 13 and 14 are more potent than Hib-ester, demonstrating that our strategy was suitable for the identification of a novel chemotype for developing possible drug candidates and hopefully widening the drug armamentarium against MM. Full article
(This article belongs to the Special Issue Novel Insights into Cancer Drug Resistance: From Molecular Basis to Emerging Therapeutic Strategies)
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Review

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25 pages, 1731 KiB  
Review
The Critical Impact of Sphingolipid Metabolism in Breast Cancer Progression and Drug Response
by Paola Antonia Corsetto, Stefania Zava, Angela Maria Rizzo and Irma Colombo
Int. J. Mol. Sci. 2023, 24(3), 2107; https://doi.org/10.3390/ijms24032107 - 20 Jan 2023
Cited by 9 | Viewed by 2854
Abstract
Breast cancer is the second leading cause of cancer-related death in women in the world, and its management includes a combination of surgery, radiation therapy, chemotherapy, and immunotherapy, whose effectiveness depends largely, but not exclusively, on the molecular subtype (Luminal A, Luminal B, [...] Read more.
Breast cancer is the second leading cause of cancer-related death in women in the world, and its management includes a combination of surgery, radiation therapy, chemotherapy, and immunotherapy, whose effectiveness depends largely, but not exclusively, on the molecular subtype (Luminal A, Luminal B, HER2+ and Triple Negative). All breast cancer subtypes are accompanied by peculiar and substantial changes in sphingolipid metabolism. Alterations in sphingolipid metabolite levels, such as ceramides, dihydroceramide, sphingosine, sphingosine-1-phosphate, and sphingomyelin, as well as in their biosynthetic and catabolic enzymatic pathways, have emerged as molecular mechanisms by which breast cancer cells grow, respond to or escape therapeutic interventions and could take on diagnostic and prognostic value. In this review, we summarize the current landscape around two main themes: 1. sphingolipid metabolites, enzymes and transport proteins that have been found dysregulated in human breast cancer cells and/or tissues; 2. sphingolipid-driven mechanisms that allow breast cancer cells to respond to or evade therapies. Having a complete picture of the impact of the sphingolipid metabolism in the development and progression of breast cancer may provide an effective means to improve and personalize treatments and reduce associated drug resistance. Full article
(This article belongs to the Special Issue Novel Insights into Cancer Drug Resistance: From Molecular Basis to Emerging Therapeutic Strategies)
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15 pages, 617 KiB  
Review
Role of Non-Coding RNAs in Colorectal Cancer: Focus on Long Non-Coding RNAs
by Matteo Lulli, Cristina Napoli, Ida Landini, Enrico Mini and Andrea Lapucci
Int. J. Mol. Sci. 2022, 23(21), 13431; https://doi.org/10.3390/ijms232113431 - 3 Nov 2022
Cited by 16 | Viewed by 3697
Abstract
Colorectal cancer is one of the most common causes of cancer-related deaths worldwide. Despite the advances in the knowledge of pathogenetic molecular mechanisms and the implementation of more effective drug treatments in recent years, the overall survival rate of patients remains unsatisfactory. The [...] Read more.
Colorectal cancer is one of the most common causes of cancer-related deaths worldwide. Despite the advances in the knowledge of pathogenetic molecular mechanisms and the implementation of more effective drug treatments in recent years, the overall survival rate of patients remains unsatisfactory. The high death rate is mainly due to metastasis of cancer in about half of the cancer patients and the emergence of drug-resistant populations of cancer cells. Improved understanding of cancer molecular biology has highlighted the role of non-coding RNAs (ncRNAs) in colorectal cancer development and evolution. ncRNAs regulate gene expression through various mechanisms, including epigenetic modifications and interactions of long non-coding RNAs (lncRNAs) with both microRNAs (miRNAs) and proteins, and through the action of lncRNAs as miRNA precursors or pseudogenes. LncRNAs can also be detected in the blood and circulating ncRNAs have become a new source of non-invasive cancer biomarkers for the diagnosis and prognosis of colorectal cancer, as well as for predicting the response to drug therapy. In this review, we focus on the role of lncRNAs in colorectal cancer development, progression, and chemoresistance, and as possible therapeutic targets. Full article
(This article belongs to the Special Issue Novel Insights into Cancer Drug Resistance: From Molecular Basis to Emerging Therapeutic Strategies)
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