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Cancers
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Cancer Chemotherapy: Combination with Inhibitors (2nd Edition)
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Cancer Chemotherapy: Combination with Inhibitors (2nd Edition)

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

Deadline for manuscript submissions: 31 December 2024 | Viewed by 4318

Special Issue Editors

Dr. Gabriella D’Orazi

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Guest Editor
1. Department of Neuroscience and Imaging, University G. D’Annunzio, 66013 Chieti, Italy
2. Department of Research, Unit of Cellular Network and Therapeutic Innovation, Regina Elena National Cancer Institute, 00144 Rome, Italy
Interests: tumor biology; molecular oncology; onco-suppressor p53; autophagy; hypoxia; oxidative stress; tumor microenvironment; glioblastoma; personalized medicine
Special Issues, Collections and Topics in MDPI journals
Dr. Mara Cirone

E-Mail Website
Guest Editor
Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy
Interests: herpesviruses; viral oncology; autophagy and unfolded protein response
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

We are excited to invite you to contribute to this Special Issue, which is the second edition of "Cancer Chemotherapy: Combination with Inhibitors" (https://www.mdpi.com/journal/cancers/special_issues/Chemotherapy_Inhibitors).

Cancer is among the leading causes of mortality worldwide. Despite advances in cancer treatments, the development of drug resistance often occurs, enabling cancer cells to avoid senescence or apoptosis, and inducing disease recurrence and progression. Several different molecular pathways have been implicated in the development of resistance, including those regulating stress responses, such as autophagy, unfolded protein response (UPR), DNA damage response (DDR), antioxidant response, and heat shock response (HSR). Unfortunately, following the inhibition of one of the oncogenic pathways, cancer cells may hyperactivate others in order to survive. Therefore, to combat drug resistance, combination therapies targeting several molecular pathways and their induced protective processes seem to be more promising than a single targeted therapy, especially if they also result in anti-cancer immune activation.

This Special Issue aims to collect research articles, reviews and communications focused on (but not limited to) experimental studies in the research area of chemoresistance and combination therapies with inhibitors to overcome or prevent potential drug resistance.

We look forward to receiving your contributions.

Dr. Gabriella D'Orazi
Dr. Mara Cirone
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

  • solid cancer
  • chemoresistance
  • chemotherapy
  • unfolded protein response (UPR)
  • heat shock response (HSR)
  • antioxidant response
  • NRF2
  • autophagy
  • combination therapy
  • DDR

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Published Papers (3 papers)

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Research

25 pages, 9863 KiB  
Article
Targeting PARP-1 and DNA Damage Response Defects in Colorectal Cancer Chemotherapy with Established and Novel PARP Inhibitors
by Philipp Demuth, Lea Thibol, Anna Lemsch, Felix Potlitz, Lukas Schulig, Christoph Grathwol, Georg Manolikakes, Dennis Schade, Vassilis Roukos, Andreas Link and Jörg Fahrer
Cancers 2024, 16(20), 3441; https://doi.org/10.3390/cancers16203441 - 10 Oct 2024
Viewed by 1078
Abstract
The DNA repair protein PARP-1 emerged as a valuable target in the treatment of tumor entities with deficiencies of BRCA1/2, such as breast cancer. More recently, the application of PARP inhibitors (PARPi) such as olaparib has been expanded to other cancer entities [...] Read more.
The DNA repair protein PARP-1 emerged as a valuable target in the treatment of tumor entities with deficiencies of BRCA1/2, such as breast cancer. More recently, the application of PARP inhibitors (PARPi) such as olaparib has been expanded to other cancer entities including colorectal cancer (CRC). We previously demonstrated that PARP-1 is overexpressed in human CRC and promotes CRC progression in a mouse model. However, acquired resistance to PARPi and cytotoxicity-mediated adverse effects limit their clinical applicability. Here, we detailed the role of PARP-1 as a therapeutic target in CRC and studied the efficacy of novel PARPi compounds in wildtype (WT) and DNA repair-deficient CRC cell lines together with the chemotherapeutics irinotecan (IT), 5-fluorouracil (5-FU), and oxaliplatin (OXA). Based on the ComPlat molecule archive, we identified novel PARPi candidates by molecular docking experiments in silico, which were then confirmed by in vitro PARP activity measurements. Two promising candidates (X17613 and X17618) also showed potent PARP-1 inhibition in a CRC cell-based assay. In contrast to olaparib, the PARPi candidates caused no PARP-1 trapping and, consistently, were not or only weakly cytotoxic in WT CRC cells and their BRCA2- or ATR-deficient counterparts. Importantly, both PARPi candidates did not affect the viability of nonmalignant human colonic epithelial cells. While both olaparib and veliparib increased the sensitivity of WT CRC cells towards IT, no synergism was observed for X17613 and X17618. Finally, we provided evidence that all PARPi (olaparib > veliparib > X17613 > X17618) synergize with chemotherapeutic drugs (IT > OXA) in a BRCA2-dependent manner in CRC cells, whereas ATR deficiency had only a minor impact. Collectively, our study identified novel lead structures with potent PARP-1 inhibitory activity in CRC cells but low cytotoxicity due to the lack of PARP-1 trapping, which synergized with IT in homologous recombination deficiency. Full article
(This article belongs to the Special Issue Cancer Chemotherapy: Combination with Inhibitors (2nd Edition))
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12 pages, 1910 KiB  
Article
HSP110 Inhibition in Primary Effusion Lymphoma Cells: One Molecule, Many Pro-Survival Targets
by Roberta Gonnella, Roberta Zarrella, Michele Di Crosta, Rossella Benedetti, Andrea Arena, Roberta Santarelli, Maria Saveria Gilardini Montani, Gabriella D’Orazi and Mara Cirone
Cancers 2023, 15(23), 5651; https://doi.org/10.3390/cancers15235651 - 29 Nov 2023
Cited by 1 | Viewed by 1091
Abstract
Heat shock proteins (HSPs) are highly expressed in cancer cells and represent a promising target in anti-cancer therapy. In this study, we investigated for the first time the expression of high-molecular-weight HSP110, belonging to the HSP70 family of proteins, in Primary Effusion Lymphoma [...] Read more.
Heat shock proteins (HSPs) are highly expressed in cancer cells and represent a promising target in anti-cancer therapy. In this study, we investigated for the first time the expression of high-molecular-weight HSP110, belonging to the HSP70 family of proteins, in Primary Effusion Lymphoma (PEL) and explored its role in their survival. This is a rare lymphoma associated with KSHV, for which an effective therapy remains to be discovered. The results obtained from this study suggest that targeting HSP110 could be a very promising strategy against PEL, as its silencing induced lysosomal membrane permeabilization, the cleavage of BID, caspase 8 activation, downregulated c-Myc, and strongly impaired the HR and NHEJ DNA repair pathways, leading to apoptotic cell death. Since chemical inhibitors of this HSP are not commercially available yet, this study encourages a more intense search in this direction in order to discover a new potential treatment that is effective against this and likely other B cell lymphomas that are known to overexpress HSP110. Full article
(This article belongs to the Special Issue Cancer Chemotherapy: Combination with Inhibitors (2nd Edition))
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16 pages, 3291 KiB  
Article
Novel Therapeutic Strategies Exploiting the Unique Properties of Neuroendocrine Neoplasms
by Maryam Safari, Luigi Scotto, Thomas Litman, Lubov A. Petrukhin, Hu Zhu, Min Shen, Robert W. Robey, Matthew D. Hall, Tito Fojo and Susan E. Bates
Cancers 2023, 15(20), 4960; https://doi.org/10.3390/cancers15204960 - 12 Oct 2023
Cited by 1 | Viewed by 1537
Abstract
Background: Over the last few decades of treatment, the outcomes for at least some subsets of neuroendocrine neoplasms (NENs) have improved. However, the identification of new vulnerabilities for this heterogeneous group of cancers remains a priority. Methods: Using two libraries of compounds selected [...] Read more.
Background: Over the last few decades of treatment, the outcomes for at least some subsets of neuroendocrine neoplasms (NENs) have improved. However, the identification of new vulnerabilities for this heterogeneous group of cancers remains a priority. Methods: Using two libraries of compounds selected for potential repurposing, we identified the inhibitors of nicotinamide phosphoribosyltransferase (NAMPT) and histone deacetylases (HDAC) as the agents with the highest activity. We validated the hits in an expanded set of neuroendocrine cell lines and examined the mechanisms of action. Results: In Kelly, NH-6, and NCI-H82, which are two neuroblastoma and one small cell lung cancer cell lines, respectively, metabolic studies suggested that cell death following NAMPT inhibition is the result of a reduction in basal oxidative phosphorylation and energy production. NAMPT is the rate-limiting enzyme in the production of NAD+, and in the three cell lines, NAMPT inhibition led to a marked reduction in the ATP and NAD+ levels and the catalytic activity of the citric acid cycle. Moreover, comparative analysis of the mRNA expression in drug-sensitive and -insensitive cell lines found less dependency of the latter on oxidative phosphorylation for their energy requirement. Further, the analysis of HDAC and NAMPT inhibitors administered in combination found marked activity using low sub-lethal concentrations of both agents, suggesting a synergistic effect. Conclusion: These data suggest NAMPT inhibitors alone or in combination with HDAC inhibitors could be particularly effective in the treatment of neuroendocrine neoplasms. Full article
(This article belongs to the Special Issue Cancer Chemotherapy: Combination with Inhibitors (2nd Edition))
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