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

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

Deadline for manuscript submissions: 30 June 2025 | Viewed by 7508

Special Issue Editor

Dr. Adrian-Bogdan Țigu

E-Mail Website
Guest Editor
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
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

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

Manuscript Submission Information

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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

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Related Special Issue

Published Papers (4 papers)

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Research

Jump to: Review

20 pages, 7679 KiB  
Article
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 1 | Viewed by 1373
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 [...] Read more.
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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Figure 1

Figure 1
<p>Effect of parecoxib and 5-FU on cell viability, as assessed by MTT assay. After incubation, cell viability was assessed by MTT analysis. Significant differences in the untreated group (UN) are shown as follows: <span class="html-italic">p</span> &lt; 0.05 (*), <span class="html-italic">p</span> &lt; 0.01 (**), and <span class="html-italic">p</span> &lt; 0.001 (***).</p> Full article ">Figure 2
<p>Effect of parecoxib and 5-FU on cell migration and invasion by transwell and matrix gel assays in DLD-1 cells. (<b>A</b>,<b>B</b>) Migration assay. (<b>D</b>,<b>E</b>) Invasion assay. (<b>A</b>,<b>D</b>) Arbitrary fields from each of the triplicate migration assays were calculated using a phase-contrast microscope (magnification 200×). (<b>B</b>,<b>E</b>) The absorbance of crystal violet was determined at 570 nm by a microplate reader. The values are displayed as the mean ± SD of separate trials. Significant differences are set at <span class="html-italic">p</span> &lt; 0.001 (***). (<b>C</b>) Isobologram analysis of the parecoxib and 5-FU combination in DLD-1 cells. The trials were conducted at least three times. A descriptive trial is shown.</p> Full article ">Figure 3
<p>(<b>A</b>) After treatment, the cells that migrated to the wounded regions were calculated by a phase-contrast microscope (magnification 200×). (<b>B</b>) Percentages of DLD-1 cells that migrated to the wound area following treatment were evaluated. Significant differences in the untreated group (UN) are denoted as <span class="html-italic">p</span> &lt; 0.001 (***). The * is a statistical symbol. Significant differences in parecoxib (3 μM) alone or 5-FU (20 μM) alone are indicated as <span class="html-italic">p</span> &lt; 0.001 (###).</p> Full article ">Figure 4
<p>Effect of parecoxib and 5-FU on EMT. After treatment, the levels of protein expression were evaluated using the extracted proteins and assessed by Western blot. Actin, tubulin, or GAPDH were used as internal controls.</p> Full article ">Figure 5
<p>Effect of parecoxib and 5-FU on MMP-9 activity. After treatment, the conditional media were used on non-reduced denatured 12% polyacrylamide gel containing gelatin and stained with Coomassie Blue.</p> Full article ">Figure 6
<p>Effect of parecoxib and 5-FU on the p-Akt and NF-κB pathways. The cells were treated with drugs for (<b>A</b>) 24 and 48 h, and for (<b>B</b>) 1 h. After incubation, levels of protein expression were assessed via Western blot analysis. Actin, tubulin, or GAPDH were selected as loading controls.</p> Full article ">Figure 7
<p>Effect of overexpression of Akt phosphorylation in parecoxib- and 5-FU-treated DLD-1 cells. (<b>A</b>,<b>D</b>) Phosphorylation of Akt was detected by Western blot. GAPDH and actin were selected as loading controls. (<b>B</b>,<b>E</b>) Random areas from each of the triplicate migration assays were assessed using a phase-contrast microscope (magnification 200×). (<b>C</b>,<b>F</b>) The absorbance of crystal violet was detected at 570 nm by using a microplate reader. The data are shown as the mean ± SD of separate tests. Significant differences are expressed as <span class="html-italic">p</span> &lt; 0.001 (***).</p> Full article ">Figure 8
<p>Effect of parecoxib and 5-FU on intracellular ROS in DLD-1 cells. After treatment, all cells were incubated with DCFH-DA for intracellular ROS detection and assessed using a flow cytometer. The data in each panel show the mean fluorescence intensity of DCF inside the cells. The data are shown as the mean ± SD (<span class="html-italic">n</span> = 5–8) of individual experiments.</p> Full article ">Figure 9
<p>Effect of parecoxib and 5-FU on cell migration and invasion by transwell and matrix gel assays in SW480 cells. (<b>A</b>,<b>B</b>) Migration assay. (<b>D</b>,<b>E</b>) Invasion assay. (<b>A</b>,<b>D</b>) Random fields from each of the triplicate migration assays were calculated by a phase-contrast microscope (magnification 200×). (<b>B</b>,<b>E</b>) The absorbance of crystal violet was determined at 570 nm by using a microplate reader. The values are displayed as the mean ± SD of separate trials. Significant differences are expressed as <span class="html-italic">p</span> &lt; 0.05 (*), <span class="html-italic">p</span> &lt; 0.01 (**), and <span class="html-italic">p</span> &lt; 0.001 (***). (<b>C</b>) Isobologram analysis of the parecoxib and 5-FU combination in SW480 cells. The trials were conducted at least three times. A descriptive trial is shown.</p> Full article ">

Review

Jump to: Research

29 pages, 2861 KiB  
Review
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
Viewed by 1343
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 [...] Read more.
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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Figure 1

Figure 1
<p>Melanocytes shift from normal to tumor type. The UV radiation and other mutagen factors generate skin damage and induce mutations in the melanocytes’ DNA. The poor efficacy of the DNA repair mechanism allows mutation accumulation in the DNA and at high tumor mutation burden (TMB) the tumor melanocytes express neoantigens. The tumor site is prone to becoming hypoxic and new blood vessels are created which increases the proinflammatory state in the tumor microenvironment (TME) and promotes tumor cells escape and metastasis. Figure created with Biorender.</p> Full article ">Figure 2
<p>Targeted therapies anti PD-1, anti PD-L1 and anti CTLA-4 (CD152) in melanoma. In the TME, the malign melanocytes interact with T cells, and the MHC binds to the antigen and TCR. In the first situation, when PD-1 binds to PD-L1, and CTLA 4 binds to CD80, the T cells will exhaust, will slow in proliferation, and will lose their killing ability. On the other hand, when antibodies designed to target PD-1, PD-L1 or CTLA 4 interact with the target, T cell activity is restored and their proliferation is stimulated, as well as their tumor killing ability.</p> Full article ">Figure 3
<p>CAR T vs. BiTEs vs. TCR-T therapies in melanoma. CAR T targeting surface antigens on tumor cells. TCR-T binding to the tumor antigen presented by MHC. BiTEs engage in the interaction between T cells and tumor cells.</p> Full article ">
16 pages, 2831 KiB  
Review
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 1 | Viewed by 1412
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, [...] Read more.
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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Figure 1

Figure 1
<p>(<b>a</b>,<b>b</b>) Computed tomography reveals lung adenocarcinoma (<b>a</b>) and adrenal metastasis (<b>b</b>) (yellow arrow).</p> Full article ">Figure 2
<p>Physical examination reveals multiple prurigo on extremities, some with ero sions and ulcers in the center and some with hyperpigmentation even after nivolumab was discontinued.</p> Full article ">Figure 3
<p>(<b>a</b>,<b>b</b>) Histopathological examination from nodular prurigo reveals epidermal thickening, liquefaction degeneration, spongiotic dermatitis ((<b>a</b>) hematoxylin and eosin stain (HE) ×100), and inflammatory cellular infiltration around vessels in the dermis ((<b>b</b>) HE ×100).</p> Full article ">
17 pages, 1657 KiB  
Review
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 4 | Viewed by 2128
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 [...] Read more.
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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Figure 1

Figure 1
<p>Outline of the HH signaling pathway [<a href="#B16-biomedicines-12-01448" class="html-bibr">16</a>]. If an Hh ligand is present, SMO is phosphorylated, and SUFU is re-activated, while GLI2 induces Hh target genes of transcription. However, if an Hh ligand is absent, GLI is phosphorylated by PKA, GSK3, and CK1, forming GLI3R (GLI repressor), thus inhibiting the Hh target genes.</p> Full article ">Figure 2
<p>Immune checkpoint inhibitors approved by the FDA. Pembrolizumab, Nivolumab, and Cemiplimab as anti-PD-1 antibodies, Ipilimumab as an anti-CTLA-4 antibody, as well as Atezolizumab, Avelumab, and Durvalumab as anti-PD-L1 antibodies [<a href="#B48-biomedicines-12-01448" class="html-bibr">48</a>].</p> Full article ">Figure 3
<p>Outline of the European guidelines for the main therapeutic options for cSCC [<a href="#B51-biomedicines-12-01448" class="html-bibr">51</a>,<a href="#B52-biomedicines-12-01448" class="html-bibr">52</a>]. This review focuses on systemic treatment for locally advanced and metastatic cSCC, which are considered if the tumor is inoperable or if surgery is insufficient. Within systemic treatment, there are different options, which are described in <a href="#biomedicines-12-01448-t002" class="html-table">Table 2</a> above.</p> Full article ">
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