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Cancers
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Cancer Chemotherapy Resistance
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Cancer Chemotherapy Resistance

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Therapy".

Deadline for manuscript submissions: closed (1 July 2024) | Viewed by 12750

Special Issue Editor

Dr. Anamaria Brozovic

E-Mail Website
Guest Editor
Ruđer Bošković Institute, Division of Molecular Biology, Bijenička cesta 54, 10000 Zagreb, Croatia
Interests: toxicology; basic oncology; cancer drug resistance; novel anti-cancer compounds
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Chemotherapy remains one of the most successful therapeutic approaches to cancer treatment. It uses anti-cancer drugs with different modes of action to destroy cancer cells. The major problems of chemotherapy are the development of cancer drug resistance and side effects. Tumours may be intrinsically drug-resistant or develop resistance to chemotherapy during this treatment, and acquired resistance is especially a particular problem. Tumours become resistant to used drugs but may also become cross-resistant to other drugs with different mechanisms of action. Even though different anti-cancer drugs have been in clinical use for more than forty years and represent one of the major topics of investigation in cancer research, the problem of drug resistance remains unsolved. To date, there are many molecular mechanisms that are thought to be involved in drug resistance, such as decreased drug uptake, increased drug inactivation, alterations in drug targets, the processing of drug-induced damages, and cell death escape.

This Special Issue will focus on the characterisation of novel molecular mechanisms, the signalling pathways involved in regulating tumour response to chemotherapy, and novel targets which can combat drug resistance. Our main aim is to predict responses to chemotherapy and modulate these responses with targeted therapies with the goal of selecting the best treatment for individual patients.

Dr. Anamaria Brozovic
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 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

  • chemotherapy
  • drug resistance
  • molecular mechanisms
  • cancer
  • signalling pathways

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Published Papers (5 papers)

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Research

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26 pages, 3965 KiB  
Article
Multidrug-Resistant Profiles in Non-Small Cell Lung Carcinoma Patient-Derived Cells: Implications for Personalized Approaches with Tyrosine Kinase Inhibitors
by Jelena Dinić, Miodrag Dragoj, Sofija Jovanović Stojanov, Ana Stepanović, Ema Lupšić, Milica Pajović, Thomas Mohr, Sofija Glumac, Dragana Marić, Maja Ercegovac, Ana Podolski-Renić and Milica Pešić
Cancers 2024, 16(11), 1984; https://doi.org/10.3390/cancers16111984 - 23 May 2024
Cited by 2 | Viewed by 1229
Abstract
The impact of tyrosine kinase inhibitors (TKIs) on multidrug resistance (MDR) in non-small cell lung carcinoma (NSCLC) is a critical aspect of cancer therapy. While TKIs effectively target specific signaling pathways of cancer cells, they can also act as substrates for ABC transporters, [...] Read more.
The impact of tyrosine kinase inhibitors (TKIs) on multidrug resistance (MDR) in non-small cell lung carcinoma (NSCLC) is a critical aspect of cancer therapy. While TKIs effectively target specific signaling pathways of cancer cells, they can also act as substrates for ABC transporters, potentially triggering MDR. The aim of our study was to evaluate the response of 17 patient-derived NSCLC cultures to 10 commonly prescribed TKIs and to correlate these responses with patient mutational profiles. Using an ex vivo immunofluorescence assay, we analyzed the expression of the MDR markers ABCB1, ABCC1, and ABCG2, and correlated these data with the genetic profiles of patients for a functional diagnostic approach. NSCLC cultures responded differently to TKIs, with erlotinib showing good efficacy regardless of mutation burden or EGFR status. However, the modulation of MDR mechanisms by erlotinib, such as increased ABCG2 expression, highlights the challenges associated with erlotinib treatment. Other TKIs showed limited efficacy, highlighting the variability of response in NSCLC. Genetic alterations in signaling pathways associated with drug resistance and sensitivity, including TP53 mutations, likely contributed to the variable responses to TKIs. The relationships between ABC transporter expression, gene alterations, and response to TKIs did not show consistent patterns. Our results suggest that in addition to mutational status, performing functional sensitivity screening is critical for identifying appropriate treatment strategies with TKIs. These results underscore the importance of considering drug sensitivity, off-target effects, MDR risks, and patient-specific genetic profiles when optimizing NSCLC treatment and highlight the potential for personalized approaches, especially in early stages. Full article
(This article belongs to the Special Issue Cancer Chemotherapy Resistance)
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21 pages, 17790 KiB  
Article
Niclosamide Revitalizes Sorafenib through Insulin-like Growth Factor 1 Receptor (IGF-1R)/Stemness and Metabolic Changes in Hepatocellular Carcinoma
by Syue-Wei Peng, Mai-Huong T. Ngo, Yung-Che Kuo, Ming-Hao Teng, Chin-Lin Guo, Hung-Cheng Lai, Te-Sheng Chang and Yen-Hua Huang
Cancers 2023, 15(3), 931; https://doi.org/10.3390/cancers15030931 - 1 Feb 2023
Cited by 7 | Viewed by 2878
Abstract
Sorafenib is the first approved systemic targeting agent for advanced HCC; however, when used alone, drug resistance can result in considerably reduced efficacy. Here, we demonstrate that niclosamide, an antihelminthic agent approved by the US Food and Drug Administration, can be repurposed to [...] Read more.
Sorafenib is the first approved systemic targeting agent for advanced HCC; however, when used alone, drug resistance can result in considerably reduced efficacy. Here, we demonstrate that niclosamide, an antihelminthic agent approved by the US Food and Drug Administration, can be repurposed to increase sorafenib sensitivity in sorafenib-resistant HCC cells. We generated sorafenib-resistant HCC cell lines (HepG2215_R and Hep3B_R) with elevated IGF-1R levels and strong properties in terms of stemness and epithelial–mesenchymal transition. Niclosamide was found to increase sorafenib sensitivity effectively in both cell lines and their organoids. The underlying mechanism involves the modulation of cancer stemness, IGF-1R/p-IGF1R/OCT4, and metabolic changes. The combination of sorafenib and niclosamide, but not linsitinib, effectively suppressed the IGF-1R/OCT4 expressions, yielded a synergistic combination index (CI), and attenuated stemness-related properties such as secondary tumor sphere formation and cell migration in sorafenib-resistant HCC cells. Notably, niclosamide significantly suppressed the sorafenib-induced IGF-1R phosphorylation prompted by IGF-1 treatment. Niclosamide effectively downregulated the sorafenib-induced gene expression associated with glycolysis (GLUT1, HK2, LDHA, and PEPCK), stemness (OCT4), and drug resistance (ABCG2) and enhanced the ability of sorafenib to reduce the mitochondrial membrane potential in vitro. The synergistic effect of a combination of niclosamide and sorafenib in vivo was further demonstrated by the decreased tumor size and tumor volume resulting from apoptosis regulation. Our results suggest that niclosamide can enhance sorafenib sensitivity in sorafenib-resistant HCC cells through IGF-1R/stemness regulation and metabolic changes. Our findings highlight a practical clinical strategy for enhancing sorafenib sensitivity in HCC. Full article
(This article belongs to the Special Issue Cancer Chemotherapy Resistance)
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13 pages, 2715 KiB  
Article
E3 Ubiquitin Ligase TRIP12 Controls Exit from Mitosis via Positive Regulation of MCL-1 in Response to Taxol
by Kripa S. Keyan, Rania Alanany, Amira Kohil and Omar M. Khan
Cancers 2023, 15(2), 505; https://doi.org/10.3390/cancers15020505 - 13 Jan 2023
Cited by 2 | Viewed by 2351
Abstract
Chemotherapy resistance is a major hurdle in cancer treatment. Taxol-based chemotherapy is widely used in the treatment of cancers including breast, ovarian, and pancreatic cancer. Loss of function of the tumor suppressor F-box WD-40 domain containing 7 (FBW7) mutations leads to [...] Read more.
Chemotherapy resistance is a major hurdle in cancer treatment. Taxol-based chemotherapy is widely used in the treatment of cancers including breast, ovarian, and pancreatic cancer. Loss of function of the tumor suppressor F-box WD-40 domain containing 7 (FBW7) mutations leads to the accumulation of its substrate MCL-1 which is associated with Taxol resistance in human cancers. We recently showed that E3 ubiquitin ligase TRIP12 is a negative regulator of FBW7 protein. In this study, we find that Taxol-induced mitotic block in cancer cells is partly controlled by TRIP12 via its positive regulation of MCL-1 protein. Genetic inhibition of TRIP12 accelerates MCL-1 protein degradation in mitosis. Notably, introducing double-point mutations in lysines 404/412 of FBW7 to arginine which makes it resistant to proteasomal degradation, leads to the sharp reduction of MCL-1 protein levels and sensitizes cancer cells to Taxol-induced cell death. Finally, TRIP12 deletion leads to enhanced mitotic arrest and cell death in an FBW7 and MCL-1 dependent manner in multiple cell lines including colorectal and ovarian cancer but not in breast cancer. Thus, the TRIP12/FBW7/MCL-1 axis may provide a therapeutic target to overcome Taxol-associated chemotherapy resistance in cancer. Full article
(This article belongs to the Special Issue Cancer Chemotherapy Resistance)
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Review

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24 pages, 1835 KiB  
Review
Cell Membrane Sialome: Sialic Acids as Therapeutic Targets and Regulators of Drug Resistance in Human Cancer Management
by Patrycja Jastrząb, Karolina Narejko, Halina Car and Przemyslaw Wielgat
Cancers 2023, 15(20), 5103; https://doi.org/10.3390/cancers15205103 - 22 Oct 2023
Cited by 4 | Viewed by 3387
Abstract
A cellular sialome is a physiologically active and dynamically changing component of the cell membrane. Sialylation plays a crucial role in tumor progression, and alterations in cellular sialylation patterns have been described as modulators of chemotherapy effectiveness. However, the precise mechanisms through which [...] Read more.
A cellular sialome is a physiologically active and dynamically changing component of the cell membrane. Sialylation plays a crucial role in tumor progression, and alterations in cellular sialylation patterns have been described as modulators of chemotherapy effectiveness. However, the precise mechanisms through which altered sialylation contributes to drug resistance in cancer are not yet fully understood. This review focuses on the intricate interplay between sialylation and cancer treatment. It presents the role of sialic acids in modulating cell–cell interactions, the extracellular matrix (ECM), and the immunosuppressive processes within the context of cancer. The issue of drug resistance is also discussed, and the mechanisms that involve transporters, the tumor microenvironment, and metabolism are analyzed. The review explores drugs and therapeutic approaches that may induce modifications in sialylation processes with a primary focus on their impact on sialyltransferases or sialidases. Despite advancements in cellular glycobiology and glycoengineering, an interdisciplinary effort is required to decipher and comprehend the biological characteristics and consequences of altered sialylation. Additionally, understanding the modulatory role of sialoglycans in drug sensitivity is crucial to applying this knowledge in clinical practice for the benefit of cancer patients. Full article
(This article belongs to the Special Issue Cancer Chemotherapy Resistance)
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15 pages, 1930 KiB  
Review
Exosomes: Emerging Modulators of Pancreatic Cancer Drug Resistance
by Marzia Di Donato, Nicola Medici, Antimo Migliaccio, Gabriella Castoria and Pia Giovannelli
Cancers 2023, 15(19), 4714; https://doi.org/10.3390/cancers15194714 - 25 Sep 2023
Cited by 3 | Viewed by 1670
Abstract
Pancreatic cancer (PaC) is one of the most lethal tumors worldwide, difficult to diagnose, and with inadequate therapeutical chances. The most used therapy is gemcitabine, alone or in combination with nanoparticle albumin-bound paclitaxel (nab-paclitaxel), and the multidrug FOLFIRINOX. Unfortunately, PaC develops resistance early, [...] Read more.
Pancreatic cancer (PaC) is one of the most lethal tumors worldwide, difficult to diagnose, and with inadequate therapeutical chances. The most used therapy is gemcitabine, alone or in combination with nanoparticle albumin-bound paclitaxel (nab-paclitaxel), and the multidrug FOLFIRINOX. Unfortunately, PaC develops resistance early, thus reducing the already poor life expectancy of patients. The mechanisms responsible for drug resistance are not fully elucidated, and exosomes seem to be actively involved in this phenomenon, thanks to their ability to transfer molecules regulating this process from drug-resistant to drug-sensitive PaC cells. These extracellular vesicles are released by both normal and cancer cells and seem to be essential mediators of intercellular communications, especially in cancer, where they are secreted at very high numbers. This review illustrates the role of exosomes in PaC drug resistance. This manuscript first provides an overview of the pharmacological approaches used in PaC and, in the last part, focuses on the mechanisms exploited by the exosomes released by cancer cells to induce drug resistance. Full article
(This article belongs to the Special Issue Cancer Chemotherapy Resistance)
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