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

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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 January 2026) | Viewed by 30020

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Dr. Adrian-Bogdan Țigu

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Department of Translational Medicine, MEDFUTURE—Institute of Medical Research and Life Sciences, "Iuliu Hațieganu" University of Medicine and Pharmacy, 400337 Cluj-Napoca, Romania
Interests: signaling pathways; biochemistry; cell-culture; cell death mechanism; cancer research; hematology
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Dear Colleagues,

Cancer initiation and progression are driven by a complex interplay of genetic errors, environmental factors, and dysregulated molecular pathways. Among these pathways, the mechanism of cell death plays a critical role in regulating tumor growth and survival. Alterations in cell death pathways enable cancer cells to evade apoptosis, proliferate uncontrollably, and resist therapy. Therefore, targeting these pathways represents a promising therapeutic strategy for combating cancer.

This Special Issue aims to showcase cutting-edge research focused on elucidating the molecular mechanisms underlying cell death dysregulation in cancer and identifying novel therapeutic compounds capable of restoring its normal function. The featured studies will highlight both newly discovered molecules and repurposed drugs, offering insights into innovative strategies for overcoming treatment resistance and improving patient outcomes in both solid tumors and hematological malignancies.

The research presented in this collection will delve into the intricate molecular events driving cell death dysregulation in cancer, including disruptions in signaling cascades, DNA repair mechanisms, and the aberrant expression of regulatory proteins. Furthermore, the impact of environmental factors such as carcinogen exposure and chronic inflammation on these processes will be explored. By unraveling the complex mechanisms governing cell death in cancer, researchers aim to identify vulnerabilities that can be exploited for therapeutic intervention.

Through comprehensive exploration of the cell death machinery, this Special Issue seeks to accelerate the development of effective anti-cancer therapies with broad applicability across diverse cancer types. By highlighting promising compounds and therapeutic approaches, the collection aims to provide valuable insights into the future of cancer treatment and pave the way for improved outcomes for patients worldwide.

Dr. Adrian-Bogdan Țigu
Guest Editor

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Keywords

cell death
drug repositioning
translational research
oncology
cancer therapy
apoptosis

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Mechanisms of Cell Death in Cancer Cells: A New Therapeutic Opportunity in Biomedicines (11 articles)

Published Papers (9 papers)

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Research

Jump to: Review, Other

34 pages, 21239 KB

Open AccessArticle

Antipsychotic Drug Cariprazine Induces Distinct Cell Death Mechanisms in HeLa and HCT116 Cells as a Potential Inhibitor of Qi-Site of Cytochrome bc1 Reductase

by Marina Mitrovic, Bojana Simovic Markovic, Gvozden Rosic, Marija Ristic, Nemanja Jovicic, Vladimir Jurisic, Jovan Milosavljevic, Sanja Matic, Biljana Ljujic and Dragica Selakovic

Biomedicines 2026, 14(2), 315; https://doi.org/10.3390/biomedicines14020315 - 30 Jan 2026

Cited by 1 | Viewed by 1227

Abstract

Background/Objectives: Cariprazine (CAR), an atypical antipsychotic drug, exhibits potent anticancer activity; however, its mechanism of action remains unclear. Methods: We conducted a comparison of CAR-induced cell death mechanism in HeLa and HCT116 cancer cells and explored its potential role as a Qi-site inhibitor of cytochrome bc1 reductase (complex III). Results: CAR induced a dose-dependent cytotoxic effect and triggered apoptosis in both cell lines; however, the mitochondrial responses were distinctively different. HeLa cells exhibited significant mitochondrial membrane depolarization, significant cytochrome c release, a strong increase in the Bax/Bcl-2 ratio, elevated caspase-3 activation, and notable S phase arrest along with autophagy induction, indicating that mitochondria-driven apoptosis occurred rapidly. In contrast, HCT116 cells showed moderate mitochondrial dysfunction, moderate cytochrome c release, enhanced suppression of Akt signaling, and significant G0/G1 phase arrest, which are consistent with a slower and mixed apoptotic response. The findings from molecular docking studies predicted that CAR had stable binding at the Qi site and showed interactions at the Qi site that were comparable to those of antimycin A, thereby suggesting its possible inhibitory effect on complex III. Conclusions: The results from our study indicate the engagement of CAR-activated apoptotic pathways that are specific to different types of cancer cells, and hence suggest that CAR may act as a new anticancer drug by potentially directing its action towards the mitochondrial Qi-sites of complex III. Full article

(This article belongs to the Special Issue Mechanisms of Cell Death in Cancer Cells: A New Therapeutic Opportunity—2nd Edition)

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15 pages, 736 KB

Open AccessArticle

Shear Wave Elastography for Distinguishing Cervical Lymph Node Malignancy: A Prospective, Observational Study

by Dragos A. Termure, Manuela Lenghel, Mindra E. Badea, Horatiu A. Rotar, Ciprian Tomuleasa, Bobe Petrushev, Emil Botan, Madalina Moldovan-Lazar and Alexandru F. Badea

Biomedicines 2025, 13(8), 2001; https://doi.org/10.3390/biomedicines13082001 - 18 Aug 2025

Cited by 1 | Viewed by 2559

Abstract

Background/Objectives: Differentiating between benign and malignant cervical lymph nodes (LNs) is a critical challenge in the clinical setting. We assessed the ability of shear wave elastography (SWE) to distinguish between lymphomas and solid tumor metastases presenting as cervical adenopathy. Methods: We performed a single-center, prospective, observational study in adults with clinically suspicious cervical lymph nodes. The ultrasound examination included conventional ultrasound and SWE with quantitative assessment (tissue stiffness in kPa). Pathology examination was the definitive confirmation method. Simple univariate binary logistic regression and multiple univariate binary logistic regression were used. Results: The maximum shear wave velocity (SWV) in patients with benign pathologies was 35 kPa, lower than the minimal values for lymphoma (40 kPa) and metastases (50 kPa). Furthermore, squamous cell carcinoma and distant metastases were more prevalent among men. Independent from other factors used in the statistical model, we found a positive association between sex and the presence of metastatic lymph nodes. Finally, each 1 kPa from SWE measurement was associated with a 3% increase in the risk for LNs to present metastatic adenopathy. Conclusions: This study highlights the potential of SWE for the preoperative assessment of nodal status in patients with various malignancies affecting the head and neck region, thyroid, and other areas. Full article

(This article belongs to the Special Issue Mechanisms of Cell Death in Cancer Cells: A New Therapeutic Opportunity—2nd Edition)

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20 pages, 7679 KB

Open AccessArticle

Parecoxib and 5-Fluorouracil Synergistically Inhibit EMT and Subsequent Metastasis in Colorectal Cancer by Targeting PI3K/Akt/NF-κB Signaling

by Wan-Ling Chang, Jyun-Yu Peng, Chain-Lang Hong, Pei-Ching Li, Fung-Jou Lu and Ching-Hsein Chen

Biomedicines 2024, 12(7), 1526; https://doi.org/10.3390/biomedicines12071526 - 9 Jul 2024

Cited by 5 | Viewed by 2704

Abstract

Colorectal cancer is one of the most common causes of cancer mortality worldwide, and innovative drugs for the treatment of colorectal cancer are continually being developed. 5-Fluorouracil (5-FU) is a common clinical chemotherapeutic drug. Acquired resistance to 5-FU is a clinical challenge in colorectal cancer treatment. Parecoxib is a selective COX-2-specific inhibitor that was demonstrated to inhibit metastasis in colorectal cancers in our previous study. This study aimed to investigate the synergistic antimetastatic activities of parecoxib to 5-FU in human colorectal cancer cells and determine the underlying mechanisms. Parecoxib and 5-FU synergistically suppressed metastasis in colorectal cancer cells. Treatment with the parecoxib/5-FU combination induced an increase in E-cadherin and decrease in β-catenin expression. The parecoxib/5-FU combination inhibited MMP-9 activity, and the NF-κB pathway was suppressed as well. Mechanistic analysis denoted that the parecoxib/5-FU combination hindered the essential molecules of the PI3K/Akt route to obstruct metastatic colorectal cancer. Furthermore, the parecoxib/5-FU combination could inhibit reactive oxygen species. Our work showed the antimetastatic capacity of the parecoxib/5-FU combination for treating colorectal cancers via the targeting of the PI3K/Akt/NF-κB pathway. Full article

(This article belongs to the Special Issue Mechanisms of Cell Death in Cancer Cells: A New Therapeutic Opportunity—2nd Edition)

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Review

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22 pages, 2004 KB

Open AccessReview

Exercise, Cellular Senescence, and Cancer: Novel Perspectives on Functional Aging Through Block Strength Training in Older Adults—A Narrative Review

by Rodrigo L. Castillo, Emilio Jofré-Saldía, Daniela Cáceres-Vergara, Georgina M. Renard and Esteban G. Figueroa

Biomedicines 2026, 14(4), 875; https://doi.org/10.3390/biomedicines14040875 - 11 Apr 2026

Viewed by 1557

Abstract

Population aging has markedly increased the burden of cancer in older adults, in whom frailty, sarcopenia, and reduced physiological reserve limit tolerance to treatment and worsen clinical outcomes. Aging is accompanied by progressive functional decline and by biological processes such as cellular senescence, characterized by irreversible cell cycle arrest, chronic low-grade inflammation, and impaired immune surveillance. The accumulation of senescent cells and the persistence of a senescence-associated secretory phenotype contribute to tissue dysfunction and generate a microenvironment that favors tumor initiation and progression. Physical exercise has been associated with attenuation of inflammation, improvements in metabolic and immune function, and with lower levels of senescence-related biomarkers. Although aerobic exercise has been extensively studied in this setting, resistance training holds relevance for older adults due to its capacity to counteract sarcopenia, preserve muscle strength and power, and sustain functional independence. Structured and periodized approaches to resistance exercise may further enhance these benefits by delivering targeted stimuli aligned with age-related physiological deficits. Block strength training (BST), a periodized model that concentrates training adaptations into sequential phases of maximal strength, power, and muscular endurance, has demonstrated consistent improvements in functional performance and reductions in frailty risk in community-dwelling older adults. BST improves physical function. It may also influence biological processes related to aging and cancer; however, mechanistic evidence specific to BST remains to be established. We hypothesized that the exercise in block as a targeted, a structured and physiologically grounded resistance training intervention highlights the potential of BST to promote functional aging and healthy. In the case of cancer biology, and the environment near to tumour, the relationship between aging mechanisms in older adults and controlled exercise effects are currently in advance, but mechanistic trials are still lacking. Finally, we propose a novel training method, structured and personalized, that could impact different clinical outcomes in older patients with cancer. Full article

(This article belongs to the Special Issue Mechanisms of Cell Death in Cancer Cells: A New Therapeutic Opportunity—2nd Edition)

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20 pages, 712 KB

Open AccessReview

Salmonella-Induced Cell Death in Cancer Immunotherapy: What Lies Beneath?

by Amy Mónaco, Sofía Chilibroste, María Clara Plata, Jose Alejandro Chabalgoity and María Moreno

Biomedicines 2026, 14(1), 12; https://doi.org/10.3390/biomedicines14010012 - 20 Dec 2025

Viewed by 1138

Abstract

Bacteria-based cancer immunotherapies are regaining attention due to recent advances in understanding the mechanisms underlying their efficacy, making them promising tools for cancer treatment. Among these, Salmonella stands out as one of the most extensively studied microorganisms in this field. Its ability to directly induce tumor cell death while stimulating the immune system offers unique therapeutic advantages, as cell death within an inflammatory environment may enhance the release of tumor antigens and promote effective antitumor immune responses. Although multiple studies have addressed Salmonella-induced cell death, the nomenclature and classification of death modalities are often inconsistent—either because earlier reports predate the formalization of certain death pathways, or due to overlapping criteria between different types of cell death. This review aims to comprehensively analyze the available evidence on Salmonella-induced apoptosis, pyroptosis and autophagy, as well as other less characterized death modalities. Given that most mechanistics evidence on Salmonella-induced cell death has been generated in myeloid cells, we primarily focus on the myeloid compartment while integrating available observations from tumor cells and other immune populations when relevant, organizing the existing data under current definitions and concepts, and highlighting the challenges of manipulating these pathways to optimize bacterial-based immunotherapies. Full article

(This article belongs to the Special Issue Mechanisms of Cell Death in Cancer Cells: A New Therapeutic Opportunity—2nd Edition)

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29 pages, 2861 KB

Open AccessReview

Advances in Cell and Immune Therapies for Melanoma

by Tanase Timis, Sanda Buruiana, Delia Dima, Madalina Nistor, Ximena Maria Muresan, Diana Cenariu, Adrian-Bogdan Tigu and Ciprian Tomuleasa

Biomedicines 2025, 13(1), 98; https://doi.org/10.3390/biomedicines13010098 - 3 Jan 2025

Cited by 15 | Viewed by 5905

Abstract

The incidence rate of cutaneous melanoma is on the rise worldwide, due to increased exposure to UV radiation, aging populations, and exposure to teratogen agents. However, diagnosis is more precise, and the increased number of new cases is related to the improved diagnosis tools. Despite better early diagnosis and better therapies, melanoma has remained a significant public health challenge because of its aggressive behavior and high potential for metastasis. In 2020, cutaneous melanoma constituted approximately 1.3% of all cancer deaths that occurred within the European Union, thereby highlighting the necessity for effective prevention, timely diagnosis, and sustainable treatment measures, especially as a growing number of cases occur among younger patients. Melanoma is regarded as one of the most inflamed cancers due to its high immune cell presence and strong response to immunotherapy, fueling the need for development of immune-driven innovative treatments. Approved therapies, including immune checkpoint inhibitors (e.g., anti-PD-1 and anti-CTLA-4), have notably improved survival rates in melanoma. However, the limitations of the PD-1/PD-L1 and CTLA-4 axes inhibitors, such as low response rates, treatment resistance, and toxicity, have driven the need for continued research and advancements in treatment strategies. Current clinical trials are exploring various combinations of immune checkpoint inhibitors with costimulatory receptor agonists, chemotherapy, targeted therapies, and other immunotherapies, with the goal of improving outcomes and reducing side effects for melanoma patients. Emerging approaches, including adoptive cell therapy with tumor-infiltrating lymphocytes (TILs) and oncolytic virotherapy, are showing promise. While CAR-T cell therapy has been less successful in melanoma compared to blood cancers, ongoing research is addressing challenges like the tumor microenvironment and antigen specificity. This review provides an overview of the requirement for advances in these medications, to mark a significant step forward in melanoma management, set to bring a fresh breath of hope for patients. Full article

(This article belongs to the Special Issue Mechanisms of Cell Death in Cancer Cells: A New Therapeutic Opportunity—2nd Edition)

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16 pages, 2831 KB

Open AccessReview

Review of T Helper 2-Type Inflammatory Diseases Following Immune Checkpoint Inhibitor Treatment

by Yoshihito Mima, Tsutomu Ohtsuka, Ippei Ebato, Yukihiro Nakata, Akihiro Tsujita, Yoshimasa Nakazato and Yuta Norimatsu

Biomedicines 2024, 12(8), 1886; https://doi.org/10.3390/biomedicines12081886 - 19 Aug 2024

Cited by 2 | Viewed by 3241

Abstract

Immune checkpoints are mechanisms that allow cancer cells to evade immune surveillance and avoid destruction by the body’s immune system. Tumor cells exploit immune checkpoint proteins to inhibit T cell activation, thus enhancing their resistance to immune attacks. Immune checkpoint inhibitors, like nivolumab, work by reactivating these suppressed T cells to target cancer cells. However, this reactivation can disrupt immune balance and cause immune-related adverse events. This report presents a rare case of prurigo nodularis that developed six months after administering nivolumab for lung adenocarcinoma. While immune-related adverse events are commonly linked to T helper-1- or T helper-17-type inflammations, T helper-2-type inflammatory reactions, as observed in our case, are unusual. The PD-1–PD-L1 pathway is typically associated with T helper-1 and 17 responses, whereas the PD-1–PD-L2 pathway is linked to T helper-2 responses. Inhibition of PD-1 can enhance PD-L1 functions, potentially shifting the immune response towards T helper-1 and 17 types, but it may also influence T helper-2-type inflammation. This study reviews T helper-2-type inflammatory diseases emerging from immune checkpoint inhibitor treatment, highlighting the novelty of our findings. Full article

(This article belongs to the Special Issue Mechanisms of Cell Death in Cancer Cells: A New Therapeutic Opportunity—2nd Edition)

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17 pages, 1657 KB

Open AccessReview

Advanced and Metastatic Non-Melanoma Skin Cancer: Epidemiology, Risk Factors, Clinical Features, and Treatment Options

by Zoe Gabrielle Attal, Walid Shalata, Arina Soklakova, Lena Tourkey, Sondos Shalata, Omar Abu Saleh, Fahed Abu Salamah, Ibrahim Alatawneh and Alexander Yakobson

Biomedicines 2024, 12(7), 1448; https://doi.org/10.3390/biomedicines12071448 - 28 Jun 2024

Cited by 30 | Viewed by 8093

Abstract

Non-melanoma skin cancers (NMSC) form the majority of skin cancers, with basal cell carcinoma (BCC) being the most common and cutaneous squamous cell carcinoma (cSCC) being second. Prolonged ultraviolet (UV) exposure, aging, male gender, and immunosuppression represent most of the causes of this category of diseases. BCCs and cSCCs both include different types of skin cancers, such as nodular or morpheaform BCC or flat cSCC. Locally advanced and metastatic NMSCs cannot be treated surgically; thus, systemic therapy (TKI and Immunotherapy) is needed. Interestingly, NMSCs are frequently linked to abnormal Hedgehog (HH) signaling which most systemic immunotherapies for these cancers are based upon. Of note, the first line therapies of BCC, sonidegib and vismodegib, are HH inhibitors. Programmed death receptor 1 antibody (PD-1) inhibitors such as cemiplimab, pembrolizumab, and nivolumab have been approved for the treatment of cSCC. Thus, this paper reviews the epidemiology, risk factors, clinical features, and treatment options for both BCC and cSCC. Full article

(This article belongs to the Special Issue Mechanisms of Cell Death in Cancer Cells: A New Therapeutic Opportunity—2nd Edition)

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Other

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12 pages, 247 KB

Open AccessCase Report

Clinical and Biological Characteristics of Four Patients with Aggressive Systemic Mastocytosis Treated with Midostaurin

by Delia Soare, Dan Soare, Camelia Dobrea, Eugen Radu and Horia Bumbea

Biomedicines 2025, 13(7), 1655; https://doi.org/10.3390/biomedicines13071655 - 7 Jul 2025

Viewed by 1541

Abstract

Systemic mastocytosis (SM) is a rare and heterogeneous disorder characterized by clonal proliferation and accumulation of neoplastic mast cells in one or more organs, most commonly the bone marrow, liver, spleen, and skin. Among its clinical variants, aggressive SM (ASM) presents organ damage and debilitating symptoms due to extensive mast cell infiltration. The management of ASM remains challenging, primarily because treatment must address both symptom control and disease progression. Background/Objectives: Recent therapeutic approaches have focused on tyrosine kinase inhibitors (TKIs) that target the oncogenic KIT driver mutation, predominantly the D816V mutation, which is implicated in mast cell proliferation. We report a case series of four patients diagnosed with ASM to highlight the real-world experience in the management of ASM. All patients had confirmed KIT D816V mutations and presented with signs of advanced organ dysfunction, such as marked hepatosplenomegaly, cytopenia, and significant bone marrow infiltration. First-line therapies, including cytoreductive agents or other TKIs were used. Responses varied in these patients, and ultimately, they were initiated on or transitioned to midostaurin, a multikinase TKI. Results: All four patients, after the initiation of midostaurin, presented clinical and biological improvement—at least a clinical improvement response according to the International Working Group-Myeloproliferative Neoplasms Research and Treatment & European Competence Network on Mastocytosis (IWG-MRT-ECNM) criteria. These findings highlight the benefits of KIT inhibition in managing ASM, especially for patients with inadequate responses to traditional therapies. The impact of midostaurin on organ function, mast cell burden, and symptom control emphasizes the importance of the timely integration of TKIs into therapeutic protocols. However, optimal treatment duration, long-term safety, and the development of acquired resistance remain critical questions that warrant further studies. Larger prospective trials are needed to better delineate the prognostic factors associated with sustained response, refine patient selection, and explore combination strategies that may enhance therapeutic efficacy. Conclusions: The patients presented in this case series benefited from midostaurin therapy, showing either a clinical improvement or partial response according to the IWG-MRT-ECNM criteria. Our case series illustrates that KIT inhibitors can offer meaningful clinical benefit in ASM, reinforcing their position as an emerging cornerstone option in ASM management. Full article

(This article belongs to the Special Issue Mechanisms of Cell Death in Cancer Cells: A New Therapeutic Opportunity—2nd Edition)

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