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Killing It Softly–New Approaches to Overcome Cancer Chemoresistance 2.0

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Dear Colleagues,

This Special Issue, “Killing It Softly—New Approaches to Overcome Cancer Chemoresistance 2.0”, will mainly focus on new strategies to eliminate chemoresistant cancer types.

Oncological therapy is an unequal fight with a dangerous opponent who cleverly adapts to changes in the environment, such as activation of the immune response, the presence of cytostatics, and weakening or eliminating their effects. In response to chemotherapeutic drugs or radiotherapy, cancer cells activate several molecular mechanisms that ensure survival and further cancer progression. Examples of mechanisms determining chemo- and radio-resistance include the constitutive activity of survival factors, namely: NF-kB, pSTAT3, expression of MDR multidrug resistance proteins, glycolytic phenotype, shedding of TNF family death-ligand receptors, and many others. Because of the wealth of protective mechanisms, the available chemotherapeutic agents do not meet the need for effective cancer elimination. Therefore, there is an urgent need for the continuous improvement of anti-cancer therapy to reduce the phenomenon of chemoresistance and to effectively attack cancer cells. In the development of medicine, biotechnology, nanomedicine, and molecular biology techniques, anti-cancer therapy progress is also significant.

We cordially invite authors in the field to submit original research or review articles pertaining to this important and fast-progressing field of biomedicine.

Dr. Beata Pajak
Dr. Anna Jaśkiewicz
Guest Editors

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Research

18 pages, 4028 KiB

Open AccessArticle

p38 Mitogen-Activated Protein Kinase Inhibition of Mesenchymal Transdifferentiated Tumor Cells in Head and Neck Squamous Cell Carcinoma

by Julia Federspiel, Maria do Carmo Greier, Andrea Ladányi and Jozsef Dudas

Biomedicines 2023, 11(12), 3301; https://doi.org/10.3390/biomedicines11123301 - 13 Dec 2023

Viewed by 777

Abstract

High mortality in head and neck squamous cell carcinoma (HNSCC) is due to recurrence, metastasis, and radiochemotherapy (RCT) resistance. These phenomena are related to the tumor cell subpopulation undergoing partial epithelial to mesenchymal transition (pEMT). Repeated transforming growth factor-beta (TGF-beta-1) treatment via the p38 mitogen-activated protein kinase (p38 MAPK) signaling pathway induces pEMT in SCC-25 HNSCC cells, and activates and stabilizes the pro-EMT transcription factor Slug. We investigated the growth inhibitory, cisplatin-sensitizing, and pro-apoptotic effects of p38 MAPK inhibition in cisplatin-resistant (SCC-25) and -sensitive (UPCI-SCC090) HNSCC cell lines, using two specific p38 MAPK inhibitors, SB202190 and ralimetinib. Cell viability was measured by MTT assay; cell cycle distribution and cell death were evaluated by flow cytometry; p38 MAPK phosphorylation, Slug protein stabilization, and p38 MAPK downstream targets were investigated by Western blot. p-p38 inhibitors achieved sustained phosphorylation of p38 MAPK (Thr180/Tyr182) and inhibition of its function, which resulted in decreased phosphorylation (Thr69/71) of the downstream target pATF2 in pEMT cells. Subsequently, the p-p38 inhibition resulted in reduced Slug protein levels. In accordance, p-p38 inhibition led to sensitization of pEMT cells to cisplatin-induced cell death; moreover, p-p38 inhibitor treatment cycles significantly decreased the viability of cisplatin-surviving cells. In conclusion, clinically relevant p38 inhibitors might be effective for RCT-resistant pEMT cells in HNSCC patients. Full article

(This article belongs to the Special Issue Killing It Softly–New Approaches to Overcome Cancer Chemoresistance 2.0)

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15 pages, 6363 KiB

Open AccessArticle

WP1234—A Novel Anticancer Agent with Bifunctional Activity in a Glioblastoma Model

by Beata Pająk, Ewelina Siwiak-Niedbalska, Anna Jaśkiewicz, Maja Sołtyka and Tomasz Domoradzki

Biomedicines 2022, 10(11), 2799; https://doi.org/10.3390/biomedicines10112799 - 03 Nov 2022

Cited by 1 | Viewed by 1425

Abstract

Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor in adults with a poor prognosis. Despite significant progress in drug development, the blood–brain barrier (BBB) continues to limit the use of novel chemotherapeutics. Thus, our attention has been focused on the design, synthesis, and testing of small-molecule anticancer agents that are able to penetrate the BBB. One such compound is the D-glucose analog, 2-deoxy-D-glucose (2-DG), which inhibits glycolysis and induces GBM cell death. 2-DG has already been tested in clinical trials but was not approved as a drug, in part due to inadequate pharmacokinetics. To improve the pharmacokinetic properties of 2-DG, a series of novel derivatives was synthesized. Herein, we report the biological effects of WP1234, a 2-ethylbutyric acid 3,6-diester of 2-DG that can potentially release 2-ethylbutyrate and 2-DG inside the cells when metabolized. Using biochemical assays and examining cell viability, proliferation, protein synthesis, and apoptosis induction, we assessed the cytotoxic potential of WP1234. WP1234 significantly reduced the viability of GBM cells in a dose- and time-dependent manner. The lactate and ATP synthesis assays confirmed the inhibition of glycolysis elicited by released 2-DG. Furthermore, an evaluation of histone deacetylases (HDAC) activity revealed that the 2-ethylbutyrate action resulted in HDAC inhibition. Overall, these results demonstrated that WP1234 is a bifunctional molecule with promising anticancer potential. Further experiments in animal models and toxicology studies are needed to evaluate the efficacy and safety of this new 2-DG derivative. Full article

(This article belongs to the Special Issue Killing It Softly–New Approaches to Overcome Cancer Chemoresistance 2.0)

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