Molecular Mechanisms of Cancer Drug Resistance

A special issue of Biomedicines (ISSN 2227-9059).

Deadline for manuscript submissions: closed (31 January 2024) | Viewed by 7377

Special Issue Editors

Department of Medicine and Surgery, University of Milano-Bicocca, Via Cadore 48, 20900 Monza, Italy
Interests: breast cancer; colon cancer; drug-resistant; metronomic chemotherapy
Department of Clinical and Experimental Medicine School of Medicine, University of Pisa, Via Roma 55, 56126 Pisa, Italy
Interests: cancer cell biology; mechanisms of cancer cell death; cancer stem cells; drug resistance; tumor microenvironment; microbiome and cancer; pharmacology; pharmacokinetics of antineoplastic drugs
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Special Issue Information

Dear Colleagues,

Drug resistance, existing before treatment (intrinsic) or generated after therapy (acquired), is responsible for most cancer relapses and associated deaths. Drug resistance arises not only with classical chemotherapy but also, more recently, with tumor-target and immunotarget therapies.

The heterogeneity among patients, tumors, and cancer microenvironments and the adaptability of cancer cells in evading therapies make it more challenging to address drug resistance. Although our knowledge in understanding drug resistance over the past decade has definitively grown, gaps remain in identifying the biological, pharmacodynamic, and pharmacokinetic causes behind drug resistance and designing cancer therapies and schedules to overcome it.

This Special Issue aims to respond to this clinical need, with studies leading to the discovery of significant biomarkers for the development of a new combination of anticancer treatments that prevent or overcome potential resistance. Furthermore, emphasizing the pharmacological action of anticancer drugs may help to challenge complexity by better predicting optimal strategies.

Dr. Maria Grazia Cerrito
Prof. Dr. Guido Bocci
Guest Editors

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Keywords

  • drug resistance
  • intracellular signaling mechanisms
  • cancer stem cells
  • tumor microenvironment
  • extracellular vesicles
  • liquid biopsies
  • drug repurposing
  • immunotherapy
  • pharmacology

Published Papers (4 papers)

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Research

20 pages, 31289 KiB  
Article
Unlocking the Molecular Secrets of Antifolate Drug Resistance: A Multi-Omics Investigation of the NCI-60 Cell Line Panel
by Blake R. Rushing
Biomedicines 2023, 11(9), 2532; https://doi.org/10.3390/biomedicines11092532 - 14 Sep 2023
Viewed by 897
Abstract
Drug resistance continues to be a significant problem in cancer therapy, leading to relapse and associated mortality. Although substantial progress has been made in understanding drug resistance, significant knowledge gaps remain concerning the molecular underpinnings that drive drug resistance and which processes are [...] Read more.
Drug resistance continues to be a significant problem in cancer therapy, leading to relapse and associated mortality. Although substantial progress has been made in understanding drug resistance, significant knowledge gaps remain concerning the molecular underpinnings that drive drug resistance and which processes are unique to certain drug classes. The NCI-60 cell line panel program has evaluated the activity of numerous anticancer agents against many common cancer cell line models and represents a highly valuable resource to study intrinsic drug resistance. Furthermore, great efforts have been undertaken to collect high-quality omics datasets to characterize these cell lines. The current study takes these two sources of data—drug response and omics profiles—and uses a multi-omics investigation to uncover molecular networks that differentiate cancer cells that are sensitive or resistant to antifolates, which is a commonly used class of anticancer drugs. Results from a combination of univariate and multivariate analyses showed numerous metabolic processes that differentiate sensitive and resistant cells, including differences in glycolysis and gluconeogenesis, arginine and proline metabolism, beta-alanine metabolism, purine metabolism, and pyrimidine metabolism. Further analysis using multivariate and integrated pathway analysis indicated purine metabolism as the major metabolic process separating cancer cells sensitive or resistant to antifolates. Additional pathways differentiating sensitive and resistant cells included autophagy-related processes (e.g., phagosome, lysosome, autophagy, mitophagy) and adhesion/cytoskeleton-related pathways (e.g., focal adhesion, regulation of actin cytoskeleton, tight junction). Volcano plot analysis and the receiver operating characteristic (ROC) curves of top selected variables differentiating Q1 and Q4 revealed the importance of genes involved in the regulation of the cytoskeleton and extracellular matrix (ECM). These results provide novel insights toward mechanisms of intrinsic antifolate resistance as it relates to interactions between nucleotide metabolism, autophagy, and the cytoskeleton. These processes should be evaluated in future studies to potentially derive novel therapeutic strategies and personalized treatment approaches to improve antifolate response. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Cancer Drug Resistance)
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11 pages, 2606 KiB  
Article
Photobiomodulation Improves Anti-Tumor Efficacy of Photodynamic Therapy against Resistant MCF-7 Cancer Cells
by Eric Chekwube Aniogo, Blassan P. George and Heidi Abrahamse
Biomedicines 2023, 11(6), 1547; https://doi.org/10.3390/biomedicines11061547 - 26 May 2023
Cited by 2 | Viewed by 2154
Abstract
Cancer resistance is a primary concern in cancer treatment, and developing an effective modality or strategy to improve therapeutic outcomes is imperative. Photodynamic therapy (PDT) is a treatment modality that targets the tumor with a photoactive molecule and light for the specific destruction [...] Read more.
Cancer resistance is a primary concern in cancer treatment, and developing an effective modality or strategy to improve therapeutic outcomes is imperative. Photodynamic therapy (PDT) is a treatment modality that targets the tumor with a photoactive molecule and light for the specific destruction of cancer cells. Photobiomodulation (PBM) is a light exposure of cells to energize their biomolecules to respond to therapy. In the present study, we used PBM to mediate and improve the anti-tumor efficacy of zinc phthalocyanine tetrasulfonic acid (ZnPcS4)-PDT on resistant MCF-7 breast cancer cells and explore molecular changes associated with cell death. Different laser irradiation models were used for PBM and PDT combination. The combined treatment demonstrated an additive effect on the viability and Annexin-V/PI-staining cell death assessed through MTT assay and mitochondrial release of cytochrome c. Rhodamine (Rh123) showed increased affinity to mitochondrial disruption of the strategic treatment with PBM and PDT. Results from the autophagy assay indicate an interplay between the mitochondrial and autophagic proteins. These findings were indicative that PBM might improve the anti-tumor of PDT by inducing autophagy in resistant MCF-7 breast cancer cells that evade apoptosis. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Cancer Drug Resistance)
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14 pages, 2240 KiB  
Article
Reactive Oxygen Species Regulation of Chemoresistance and Metastatic Capacity of Melanoma: Role of the Cancer Stem Cell Marker CD271
by Francesca Beretti, Martina Gatti, Manuela Zavatti, Sara Bassoli, Giovanni Pellacani and Tullia Maraldi
Biomedicines 2023, 11(4), 1229; https://doi.org/10.3390/biomedicines11041229 - 20 Apr 2023
Cited by 1 | Viewed by 1512
Abstract
BRAF mutations are present in 30–50% of cases of cutaneous melanoma, and treatment with selective BRAF and MEK inhibitors has been introduced. However, the development of resistance to these drugs often occurs. Chemo-resistant melanoma cells show increased expression of CD271, a stem cell [...] Read more.
BRAF mutations are present in 30–50% of cases of cutaneous melanoma, and treatment with selective BRAF and MEK inhibitors has been introduced. However, the development of resistance to these drugs often occurs. Chemo-resistant melanoma cells show increased expression of CD271, a stem cell marker that features increased migration. Concordantly, resistance to the selective inhibitor of oncogenic BRAFV600E/K, vemurafenib, is mediated by the increased expression of CD271. It has recently been shown that the BRAF pathway leads to an overexpression of the NADPH oxidase Nox4, which produces reactive oxygen species (ROS). Here, we examined in vitro how Nox-derived ROS in BRAF-mutated melanoma cells regulates their drug sensitivity and metastatic potential. We demonstrated that DPI, a Nox inhibitor, reduced the resistance of a melanoma cell line (SK-MEL-28) and a primary culture derived from a BRAFV600E-mutated biopsy to vemurafenib. DPI treatment affected the expression of CD271 and the ERK and Akt signaling pathways, leading to a drop in epithelial–mesenchymal transition (EMT), which undoubtedly promotes an invasive phenotype in melanoma. More importantly, the scratch test demonstrated the efficacy of the Nox inhibitor (DPI) in blocking migration, supporting its use to counteract drug resistance and thus cell invasion and metastasis in BRAF-mutated melanoma. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Cancer Drug Resistance)
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22 pages, 8387 KiB  
Article
Repurposing Benztropine, Natamycin, and Nitazoxanide Using Drug Combination and Characterization of Gastric Cancer Cell Lines
by Eduarda Ribeiro, Diana Araújo, Mariana Pereira, Bruna Lopes, Patrícia Sousa, Ana Catarina Sousa, André Coelho, Alexandra Rêma, Rui Alvites, Fátima Faria, Cláudia Oliveira, Beatriz Porto, Ana Colette Maurício, Irina Amorim and Nuno Vale
Biomedicines 2023, 11(3), 799; https://doi.org/10.3390/biomedicines11030799 - 06 Mar 2023
Cited by 3 | Viewed by 2010
Abstract
Gastric cancer (GC) ranked as the fifth most incident cancer in 2020 and the third leading cause of cancer mortality. Surgical prevention and radio/chemotherapy are the main approaches used in GC treatment, and there is an urgent need to explore and discover innovative [...] Read more.
Gastric cancer (GC) ranked as the fifth most incident cancer in 2020 and the third leading cause of cancer mortality. Surgical prevention and radio/chemotherapy are the main approaches used in GC treatment, and there is an urgent need to explore and discover innovative and effective drugs to better treat this disease. A new strategy arises with the use of repurposed drugs. Drug repurposing coupled with drug combination schemes has been gaining interest in the scientific community. The main objective of this project was to evaluate the therapeutic effects of alternative drugs in GC. For that, three GC cell lines (AGS, MKN28, and MKN45) were used and characterized. Cell viability assays were performed with the reference drug 5-fluororacil (5-FU) and three repurposed drugs: natamycin, nitazoxanide, and benztropine. Nitazoxanide displayed the best results, being active in all GC cells. Further, 5-FU and nitazoxanide in combination were tested in MKN28 GC cells, and the results obtained showed that nitazoxanide alone was the most promising drug for GC therapy. This work demonstrated that the repurposing of drugs as single agents has the ability to decrease GC cell viability in a concentration-dependent manner. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Cancer Drug Resistance)
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