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Mechanisms of Cell Death in Cancer Cells: A New Therapeutic Opportunity

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A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Cell Biology and Pathology".

Deadline for manuscript submissions: closed (31 March 2024) | Viewed by 16031

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Dr. Adrian-Bogdan Țigu

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Guest Editor

MedFuture Research Center for Advanced Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400377 Cluj-Napoca, Romania
Interests: signaling pathways; biochemistry; cell-culture; cell death mechanism; cancer research; hematology
Special Issues, Collections and Topics in MDPI journals

Dr. Ciprian Tomuleasa

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Department of Hematology, Institute of Oncology "Ion Chiricuta", University of Medicine and Pharmacy "Iuliu Hatieganu", 400012 Cluj-Napoca, Romania
Interests: cell culture; cancer; cancer biology; cell signaling; cell proliferation; cancer biomarkers; apoptosis
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

We are pleased to announce a new Special Issue in Biomedicines focused on the “Mechanisms of Cell Death in Cancer Cells: A New Therapeutic Opportunity”.

Cancer initiation and progression are sustained by a series of broad alterations in molecular pathways as a result of genetic error, external stimuli, etc. One such pathway with crucial importance to human health is the mechanism of cell death. As such, multiple cancer-associated alterations have often been proven to modulate or even abrogate cell death. Therefore, targeting the molecular pathways which are directly or indirectly involved in the mechanism of cell death represents a potential therapeutic strategy for the development of efficient antitumor molecules. The Special Issue is meant to highlight outstanding research involving novel and previously described and repositioned therapeutic compounds which can target the mechanism of cell death in both solid and hematological malignancies.

Dr. Adrian-Bogdan Țigu
Dr. Ciprian Tomuleasa
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 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. Biomedicines is an international peer-reviewed open access monthly 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 2600 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

cell death
drug repositioning
translational research
oncology
cancer therapy
apoptosis

Related Special Issue

Mechanisms of Cell Death in Cancer Cells: A New Therapeutic Opportunity—2nd Edition in Biomedicines

Published Papers (9 papers)

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Research

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18 pages, 12585 KiB

Open AccessArticle

SLC31A1 Identifying a Novel Biomarker with Potential Prognostic and Immunotherapeutic Potential in Pan-Cancer

by Pei Zhang, Heqi Yang, Kaiguo Zhu, Chen Chang, Wanrui Lv, Ruizhen Li, Xiaoying Li, Tinghong Ye and Dan Cao

Biomedicines 2023, 11(11), 2884; https://doi.org/10.3390/biomedicines11112884 - 25 Oct 2023

Cited by 2 | Viewed by 1192

Abstract

Solute carrier family 31 member 1 (SLC31A1) encodes a protein that functions as a homotrimer for the uptake of dietary copper. As a vital member of the cuproptosis gene family, it plays an essential role in both normal tissues and tumors. In this study, we analyzed SLC31A1 across human cancer types to gain a better understanding of SLC31A1’s role in cancer development. We searched for information using online databases to analyze, systematically and comprehensively, the role of SLC31A1 in tumors. Amongst nine cancer types, the expression of SLC31A1 was significantly different between tumors and normal tissues. According to further analysis, pancreatic cancer had the highest mutation rate of the SLC31A1 gene, and the methylation levels of the gene were significantly reduced in seven tumors. The expression of SLC31A1 is also linked to the infiltration of tumors by immune cells, the expression of immune checkpoint genes, and immunotherapy markers (TMB and MSI), suggesting that SLC31A1 may be of particular relevance in immunotherapy. This thorough analysis of SLC31A1 across different types of cancer gives us a clear and comprehensive insight into its role in causing cancer on a systemic level. Full article

(This article belongs to the Special Issue Mechanisms of Cell Death in Cancer Cells: A New Therapeutic Opportunity)

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19 pages, 44787 KiB

Open AccessArticle

The Role of NCS1 in Immunotherapy and Prognosis of Human Cancer

by Gen-Chun Wang, Xin Gan, Yun-Qian Zeng, Xin Chen, Hao Kang, Shuai-Wen Huang and Wei-Hua Hu

Biomedicines 2023, 11(10), 2765; https://doi.org/10.3390/biomedicines11102765 - 12 Oct 2023

Cited by 1 | Viewed by 1647

Abstract

The Neural Calcium Sensor1 (NCS1) is a crucial protein that binds to Ca2⁺ and is believed to play a role in regulating tumor invasion and cell proliferation. However, the role of NCS1 in immune infiltration and cancer prognosis is still unknown. Our study aimed to explore the expression profile, immune infiltration pattern, prognostic value, biological function, and potential compounds targeting NCS1 using public databases. High expression of NCS1 was detected by immune histochemical staining in LIHC (Liver hepatocellular carcinoma), BRCA (Breast invasive carcinoma), KIRC (Kidney renal clear cell carcinoma), and SKCM (Skin Cutaneous Melanoma). The expression of NCS1 in cancer was determined by TCGA (The Cancer Genome Atlas Program), GTEx (The Genotype-Tissue Expression), the Kaplan–Meier plotter, GEO (Gene Expression Omnibus), GEPIA2.0 (Gene Expression Profiling Interactive Analysis 2.0), HPA (The Human Protein Atlas), UALCAN, TIMER2.0, TISIDB, Metascape, Drugbank, chEMBL, and ICSDB databases. NCS1 has genomic mutations as well as aberrant DNA methylation in multiple cancers compared to normal tissues. Also, NCS1 was significantly different in the immune microenvironment, tumor mutational burden (TMB), microsatellite instability (MSI), and immune infiltrate-associated cells in different cancers, which could be used for the typing of immune and molecular subtypes of cancer and the presence of immune checkpoint resistance in several cancers. Univariate regression analysis, multivariate regression analysis, and gene enrichment analysis to construct prognostic models revealed that NCS1 is involved in immune regulation and can be used as a prognostic biomarker for SKCM, LIHC, BRCA, COAD, and KIRC. These results provide clues from a bioinformatic perspective and highlight the importance of NCS1 in a variety of cancers. Full article

(This article belongs to the Special Issue Mechanisms of Cell Death in Cancer Cells: A New Therapeutic Opportunity)

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17 pages, 5981 KiB

Open AccessArticle

Electric Fields Regulate In Vitro Surface Phosphatidylserine Exposure of Cancer Cells via a Calcium-Dependent Pathway

by Ahmet Kaynak, Kombo F. N’Guessan, Priyankaben H. Patel, Jing-Huei Lee, Andrei B. Kogan, Daria A. Narmoneva and Xiaoyang Qi

Biomedicines 2023, 11(2), 466; https://doi.org/10.3390/biomedicines11020466 - 06 Feb 2023

Viewed by 1968

Abstract

Cancer is the second leading cause of death worldwide after heart disease. The current treatment options to fight cancer are limited, and there is a critical need for better treatment strategies. During the last several decades, several electric field (EF)-based approaches for anti-cancer therapies have been introduced, such as electroporation and tumor-treating fields; still, they are far from optimal due to their invasive nature, limited efficacy and significant side effects. In this study, we developed a non-contact EF stimulation system to investigate the in vitro effects of a novel EF modality on cancer biomarkers in normal (human astrocytes, human pancreatic ductal epithelial -HDPE-cells) and cancer cell lines (glioblastoma U87-GBM, human pancreatic cancer cfPac-1, and MiaPaCa-2). Our results demonstrate that this EF modality can successfully modulate an important cancer cell biomarker-cell surface phosphatidylserine (PS). Our results further suggest that moderate, but not low, amplitude EF induces p38 mitogen-activated protein kinase (MAPK), actin polymerization, and cell cycle arrest in cancer cell lines. Based on our results, we propose a mechanism for EF-mediated PS exposure in cancer cells, where the magnitude of induced EF on the cell surface can differentially regulate intracellular calcium (Ca²⁺) levels, thereby modulating surface PS exposure. Full article

(This article belongs to the Special Issue Mechanisms of Cell Death in Cancer Cells: A New Therapeutic Opportunity)

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14 pages, 21238 KiB

Open AccessArticle

Comparative Study of Cytotoxic and Membranotropic Properties of Betulinic Acid-F16 Conjugate on Breast Adenocarcinoma Cells (MCF-7) and Primary Human Fibroblasts

by Konstantin N. Belosludtsev, Anna I. Ilzorkina, Natalia V. Belosludtseva, Vyacheslav A. Sharapov, Nikita V. Penkov, Dmitriy A. Serov, Maxim N. Karagyaur, Darya A. Nedopekina, Eldar V. Davletshin, Marina E. Solovieva, Anna Yu Spivak, Ulyana Sh. Kuzmina, Yulia V. Vakhitova, Vladimir S. Akatov and Mikhail V. Dubinin

Biomedicines 2022, 10(11), 2903; https://doi.org/10.3390/biomedicines10112903 - 11 Nov 2022

Cited by 5 | Viewed by 1423

Abstract

The present study evaluates the cytotoxicity of a previously synthesized conjugate of betulinic acid (BA) with the penetrating cation F16 on breast adenocarcinoma (MCF-7) and human fibroblast (HF) cell lines, and also shows the mechanism underlying its membranotropic action. It was confirmed that the conjugate exhibits higher cytotoxicity compared to native BA at low doses also blocking the proliferation of both cell lines and causing cell cycle arrest in the G₀/G₁ phase. We show that the conjugate indeed has a high potential for accumulation in mitochondria, being visualized in these organelles, which is most pronounced in cancer cells. The effect of the conjugate was observed to be accompanied by ROS hyperproduction in both cancerous and healthy cells, despite the lower base level of ROS in the latter. Along with this, using artificial liposomes, we determined that the conjugate is able to influence the phase state of lipid membranes, make them more fluid, and induce nonspecific permeabilization contributing to the overall cytotoxicity of the tested agent. We conclude that the studied BA–F16 conjugate does not have significant selective cytotoxicity, at least against the studied breast cancer cell line MCF-7. Full article

(This article belongs to the Special Issue Mechanisms of Cell Death in Cancer Cells: A New Therapeutic Opportunity)

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17 pages, 3039 KiB

Open AccessArticle

The SIRT2 Pathway Is Involved in the Antiproliferative Effect of Flavanones in Human Leukemia Monocytic THP-1 Cells

by Caterina Russo, Alessandro Maugeri, Laura De Luca, Rosaria Gitto, Giovanni Enrico Lombardo, Laura Musumeci, Giovambattista De Sarro, Santa Cirmi and Michele Navarra

Biomedicines 2022, 10(10), 2383; https://doi.org/10.3390/biomedicines10102383 - 24 Sep 2022

Cited by 9 | Viewed by 1673

Abstract

Acute myeloid leukemia (AML) represents the most alarming hematological disease for adults. Several genetic modifications are known to be pivotal in AML; however, SIRT2 over-expression has attracted the scientific community’s attention as an unfavorable prognostic marker. The plant kingdom is a treasure trove of bioactive principles, with flavonoids standing out among the others. On this line, the aim of this study was to investigate the anti-leukemic properties of the main flavanones of Citrus spp., exploring the potential implication of SIRT2. Naringenin (NAR), hesperetin (HSP), naringin (NRG), and neohesperidin (NHP) inhibited SIRT2 activity in the isolated recombinant enzyme, and more, the combination between NAR and HSP. In monocytic leukemic THP-1 cells, only NAR and HSP induced antiproliferative effects, altering the cell cycle. These effects may be ascribed to SIRT2 inhibition since these flavonoids reduced its gene expression and hampered the deacetylation of p53, known sirtuin substrate, and contextually modulated the expression of the downstream cell cycle regulators p21 and cyclin E1. Additionally, these two flavanones proved to interact with the SIRT2 inhibitory site, as shown by docking simulations. Our results suggest that both NAR and HSP may act as anti-leukemic agents, alone and in combination, via targeting the SIRT2/p53/p21/cyclin E1 pathway, thus encouraging deeper investigations. Full article

(This article belongs to the Special Issue Mechanisms of Cell Death in Cancer Cells: A New Therapeutic Opportunity)

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Review

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30 pages, 3461 KiB

Open AccessReview

Genome, Metabolism, or Immunity: Which Is the Primary Decider of Pancreatic Cancer Fate through Non-Apoptotic Cell Death?

by Erfaneh Barar and Jiaqi Shi

Biomedicines 2023, 11(10), 2792; https://doi.org/10.3390/biomedicines11102792 - 14 Oct 2023

Cited by 1 | Viewed by 1420

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a solid tumor characterized by poor prognosis and resistance to treatment. Resistance to apoptosis, a cell death process, and anti-apoptotic mechanisms, are some of the hallmarks of cancer. Exploring non-apoptotic cell death mechanisms provides an opportunity to overcome apoptosis resistance in PDAC. Several recent studies evaluated ferroptosis, necroptosis, and pyroptosis as the non-apoptotic cell death processes in PDAC that play a crucial role in the prognosis and treatment of this disease. Ferroptosis, necroptosis, and pyroptosis play a crucial role in PDAC development via several signaling pathways, gene expression, and immunity regulation. This review summarizes the current understanding of how ferroptosis, necroptosis, and pyroptosis interact with signaling pathways, the genome, the immune system, the metabolism, and other factors in the prognosis and treatment of PDAC. Full article

(This article belongs to the Special Issue Mechanisms of Cell Death in Cancer Cells: A New Therapeutic Opportunity)

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12 pages, 811 KiB

Open AccessReview

Antineoplastic Properties by Proapoptotic Mechanisms Induction of Inula viscosa and Its Sesquiterpene Lactones Tomentosin and Inuviscolide

by Rossana Migheli, Patrizia Virdis, Grazia Galleri, Caterina Arru, Giada Lostia, Donatella Coradduzza, Maria Rosaria Muroni, Giorgio Pintore, Luigi Podda, Claudio Fozza and Maria Rosaria De Miglio

Biomedicines 2022, 10(11), 2739; https://doi.org/10.3390/biomedicines10112739 - 28 Oct 2022

Cited by 4 | Viewed by 1471

Abstract

Cancer is a complex disease including approximately 200 different entities that can potentially affect all body tissues. Among the conventional treatments, radiotherapy and chemotherapy are most often applied to different types of cancers. Despite substantial advances in the development of innovative antineoplastic drugs, cancer remains one of the most significant causes of death, worldwide. The principal pitfall of successful cancer treatment is the intrinsic or acquired resistance to therapeutic agents. The development of more effective or synergistic therapeutic approaches to improve patient outcomes and minimize toxicity has become an urgent issue. Inula viscosa is widely distributed throughout Europe, Africa, and Asia. Used as a medicinal plant in different countries, I. viscosa has been characterized for its complex chemical composition in order to identify the bioactive compounds responsible for its biological activities, including anticancer effects. Sesquiterpene lactones (SLs) are natural, biologically active products that have attracted considerable attention due to their biological activities. SLs are alkylating agents that form covalent adducts with free cysteine residues within enzymes and key proteins favoring cancer cell cytotoxicity. They are effective inducers of apoptosis in several cancer cell types through different molecular mechanisms. This review focuses on recent advances in the cytotoxic effects of I. viscosa and SLs in the treatment of neoplastic diseases, with a special emphasis on their proapoptotic molecular mechanisms. Full article

(This article belongs to the Special Issue Mechanisms of Cell Death in Cancer Cells: A New Therapeutic Opportunity)

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19 pages, 7693 KiB

Open AccessReview

by Marlena Budek, Jarosław Nuszkiewicz, Anna Piórkowska, Jolanta Czuczejko and Karolina Szewczyk-Golec

Biomedicines 2022, 10(10), 2660; https://doi.org/10.3390/biomedicines10102660 - 21 Oct 2022

Cited by 4 | Viewed by 1786

Abstract

Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are rare neoplasms, which, due to their heterogeneous nature, non-specific symptoms, and lack of specific tumor markers pose many diagnostic and clinical challenges. In recent years, the effectiveness of GEP-NEN diagnosis has increased, which is probably associated with the greater availability of diagnostic tests and the cooperation of many experienced specialists in various scientific disciplines. In addition to the possible genetic etiology, the cause of GEP-NET development is not fully understood. Inflammation and obesity are known risks that contribute to the development of many diseases. Chronic inflammation accompanying obesity affects the hormonal balance and cell proliferation and causes the impairment of the immune system function, leading to neoplastic transformation. This review explores the role of inflammation and obesity in GEP-NETs. The exact mechanisms inducing tumor growth are unknown; however, the profile of inflammatory factors released in the GEP-NET tumor microenvironment is responsible for the progression or inhibition of tumor growth. Both the excess of adipose tissue and the impaired function of the immune system affect not only the initiation of cancer but also reduce the comfort and lifetime of patients. Full article

(This article belongs to the Special Issue Mechanisms of Cell Death in Cancer Cells: A New Therapeutic Opportunity)

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Other

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29 pages, 1138 KiB

Open AccessSystematic Review

Primary Arterial Hypertension and Drug-Induced Hypertension in Philadelphia-Negative Classical Myeloproliferative Neoplasms: A Systematic Review

by Mihnea-Alexandru Găman, Vincent Kipkorir, Bahadar S. Srichawla, Arkadeep Dhali, Amelia Maria Găman and Camelia Cristina Diaconu

Biomedicines 2023, 11(2), 388; https://doi.org/10.3390/biomedicines11020388 - 28 Jan 2023

Cited by 4 | Viewed by 1786

Abstract

The impact of primary arterial hypertension (HTN) in myeloproliferative neoplasms (MPNs) remains unclear, with scant literature available, mostly focusing on cardiovascular risk factors as a singular entity or on organ-specific HTN. Furthermore, available studies reporting findings on drug-induced HTN in MPNs report varying and contradictory findings. In consideration of the above, this study set out to systematically review the available literature and shed light on the occurrence of HTN in MPNs, its association with thrombosis, as well as the drugs used in MPN management that could increase blood pressure. The literature search yielded 598 potentially relevant records of which 315 remained after the duplicates (n = 283) were removed. After we screened the titles and the abstracts of these publications, we removed irrelevant papers (n = 228) and evaluated the full texts of 87 papers. Furthermore, 13 records did not meet the inclusion criteria and were excluded from the systematic review. Finally, a total of 74 manuscripts were entered into the qualitative synthesis and included in the present systematic review. Our systematic review highlights that HTN is the most common comorbidity encountered in MPNs, with an impact on both the occurrence of thrombosis and survival. Moreover, drug-induced HTN remains a challenge in the management of MPNs. Further research should investigate the characteristics of patients with MPNs and HTN, as well as clarify the contribution of HTN to the development of thrombotic complications, survival and management in MPNs. In addition, the relationship between clonal hematopoiesis of indeterminate potential, HTN, cardiovascular disease and MPNs requires examination in upcoming assessments. Full article

(This article belongs to the Special Issue Mechanisms of Cell Death in Cancer Cells: A New Therapeutic Opportunity)

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