Chemotherapy-induced different cell fates play crucial roles in cancer treatment outcomes; however, the cross-talk between the cell fates during cancer recurrence remains unclear. Here, we found that the transition from cellular senescence to pyroptosis promoted small cell lung cancer (SCLC) recurrence after cisplatin and etoposide treatment. Parts of the senescent SCLC cells induced by chemotherapy showed positive cytoplasmic chromatin fragments (CCFs), and CCFs activated the ubiquitin-editing enzyme A20, which stabilized NLRP3 through its deubiquitinating activity, resulting in senescent cells undergoing pyroptosis. Subsequent inflammatory factors [such as interleukin-1 (IL-1)] released by pyroptosis promoted the acquisition of stem-like properties in CCF-negative senescent cells, ultimately promoting tumor recurrence. We also found that a combination of IL-1 receptor antagonist anakinra with chemotherapy delayed recurrence of SCLC, suggesting previously unidentified therapeutic strategies for SCLC.

Ganoderma is a genus of medically important fungus that contains at least 80 species, many of which have not been properly evaluated for their anticancer potential. This study was conducted to assess the cytotoxic activity of the mycelial biomass of Ganoderma weberianum-sichuanese isolated from the Lower Volta River Basin of Ghana. The nuclear ribosomal internal transcribed spacer (ITS) region was analyzed to determine the phylogenetic position of this native ganoderma isolate. We then tested its cytotoxic activity against the human carcinoma cell line PC-3 (human prostate), Jurkat (human T lymphoblastoid cell line), derived from an acute T cell leukemia, and PMDC05, a plasmacytoid dendritic cell (pDC) derived from acute leukemia using the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. The ITS phylogenetic analysis demonstrated that this native Ghanaian ganoderma isolate belongs to the Ganoderma weberianum-sichuanese species complex. Fractions of the mycelial biomass were found to inhibit significantly (≤ 0.05%) the proliferation and survival of the three cancer cell lines, PC-3, PMDC05, and Jurkat with increasing concentrations and with IC50 values of 27.73 ± 5.25, 21.31 ± 2.40 and 17.09 ± 0.86 μg/mL, respectively compared to Chang liver cells (CVCL_0238) with IC50 value of 75.41 ± 1.95 μg/mL. To the best of our knowledge, these findings demonstrated for the first time, that specific constituents of Ganoderma weberianum-sichuanese are selectively cytotoxic to the three human cancer cell lines, suggesting their potential efficacy in the treatment of malignancies. Future studies to isolate and characterize the biologically active molecules are warranted.

Propolis, a natural resinous substance rich in bioactive compounds, has been traditionally used for its therapeutic properties. This study investigates the cytotoxic and anticancer effects of Anatolian propolis on ovarian cancer cells, focusing on its modulation of the AKT/mTOR pathway and its ability to enhance cisplatin efficacy. Its antimicrobial and antibiofilm properties were also assessed, addressing infection risks in immunocompromised cancer patients. In epithelial ovarian cancer (A2780) cell line, apoptosis, cell cycle progression, and cell viability were evaluated using flow cytometric analysis, propidium iodide/annexin V staining, and MTS assay, respectively. The signaling pathways were analyzed using Western blotting. The IC50 value of propolis was determined as 0.342 ± 0.180 mg/mL in the A2780 cell line and 1.11 ± 0.31 mg/mL in the MCF-10A cell line. Apoptosis in the cells was evaluated using annexin V/PI staining and Caspase-3 expression via flow cytometry after treatment with varying concentrations of propolis and cisplatin. The combination of propolis at IC50 and cisplatin at IC25 demonstrated the highest apoptotic activity. Propolis treatment upregulated pro-apoptotic Bax while downregulating survival proteins (Bcl-2, mTOR/p-mTOR, and AKT/p-AKT) in A2780 cells, demonstrating AKT/mTOR pathway-mediated anticancer activity. Propolis exhibited potent antibacterial and antibiofilm activity against clinically relevant pathogens including MRSA and MDR E. coli, confirming its antimicrobial potential. Anatolian propolis demonstrates anticancer activity by modulating the AKT/mTOR pathway and enhancing cisplatin efficacy. Its antibacterial and antibiofilm properties further highlight its potential as a dual-function therapeutic agent, especially in cancer contexts where secondary infections are a common complication.

Resistance to antimicrobial agents has become a global threat, estimated to cause 10-million deaths annually by 2050. Antimicrobial peptides are emerging as an alternative and offer advantages over traditional antibiotics. Antimicrobial peptides generated by artificial intelligence (AI) strategies are potential alternatives that reduce costs and development time. This work optimized a set of peptides generated by two deep learning algorithms. The modifications made to the peptides were evaluated with bioinformatic and other AI tools as predictors of antimicrobial activity, hemolytic capacity, and toxicity. As a result, 26 synthetic peptides generated in silico were obtained with a high probability of being antimicrobial and biologically safe. Finally, 12 peptides were synthesized to perform in vitro tests against four bacterial species, Candida albicans, and cancer cells. Results indicate that 9 of the peptides have a MIC below 10 μM, and some have an inhibitory concentration at 2 μM, such as OrP1M for Escherichia coli, OrP9M for Pseudomonas aeruginosa, and VeP1 for Staphylococcus aureus. In addition, six peptides have activity against the breast cancer cell line (MCF-7), and peptide OrP1M had an IC50 of < 6.25 μM. It is concluded that the synthetic-generated peptides have high antimicrobial activity, but in most cases, their MICs were improved after the modifications were made.

Immunotherapy targeting the immune functions of the tumor microenvironment (TME) is beneficial for colorectal cancer; however, the response rate is poor. Ciprofloxacin is a fluoroquinolone-class antibiotic that is used to treat bacterial infections. The purpose of this study is to assess the mechanism of ciprofloxacin that enhances anti-PD1 in colorectal cancer. We found that ciprofloxacin induced cytosolic DNA, including single-stranded and double-stranded DNA, formation in mouse CT26 colorectal adenocarcinoma cells. Molecules in DNA-sensing signaling such as cGAS, STING, and IFNβ mRNA and protein expression were elicited after ciprofloxacin treatment in CT26 cells. STING siRNA abrogated the cGAS-STING pathway activation by ciprofloxacin. In vivo, ciprofloxacin exhibited a synergistic effect with anti-PD1 to suppress tumor growth in a CT26 syngeneic animal model without biological toxicity. The examination of TME revealed that ciprofloxacin, alone and in combination therapy, induced M1 and red pulp macrophage production in the spleen. In tumors, M1 and M2 macrophage levels were increased by ciprofloxacin, and CD8+ T cell granzyme B expression was increased after combination therapy. STING showed the highest expression in tumor specimens after combination treatment. Ciprofloxacin may enhance the anti-PD1 efficacy and modulate the TME through the cGAS-STING pathway.

High-grade osteosarcoma (HGOS) is the most common primary malignant bone tumor in children and adolescents. Poor response to chemotherapy is linked to worse prognosis and increased risk of recurrence and metastasis. However, current assessment methods, such as tumor necrosis evaluation, are time-consuming and delay treatment decisions. Thus, identifying molecular pathways and predictive biomarkers is essential for guiding early therapeutic strategies. In this study, RNA-seq analysis of HGOS tissues revealed enrichment of cholesterol biosynthesis and mitotic pathways in poor responders. Additionally, high HMGCR expression, as analyzed from TCGA data, was associated with poor prognosis in sarcoma. Functional validation using SaOS-2 cells, which exhibited poor drug sensitivity and elevated HMGCR levels, demonstrated that simvastatin enhanced the efficacy of cisplatin and doxorubicin by inducing mitochondrial-mediated apoptosis and downregulating anti-apoptotic proteins. Simvastatin also reduced cell migration and invasion by suppressing epithelial-mesenchymal transition and extracellular matrix degradation. Mechanistically, simvastatin disrupted Ras prenylation and inhibited downstream oncogenic signaling pathways, including Akt/mTOR and Akt/GSK3, which regulate survival and metastasis-associated gene expression. These findings suggest that the cholesterol biosynthesis pathway particularly plays a critical role in chemoresistance and metastasis in HGOS and may serve as a promising predictive molecular target for guiding early therapeutic strategies.

Urothelial carcinoma (UC) is a common genitourinary malignancy. Smoking, exposure to arsenic in drinking water, and age can increase the risk of developing UC. Neoadjuvant cisplatin-based chemotherapy prior to radical cystectomy is the standard treatment for the muscle invasive form of UC (MIUC). Tumors of the basal/squamous (Ba/Sq) subtype of MIUC are aggressive, express basal keratins (KRT5, 6, and 14), are associated with squamous differentiation (SD), and frequently develop chemotherapy resistance. The SOX2 transcription factor is a marker of UC stem cells, and its expression is associated with poor overall and disease-free survival. We hypothesized that the attenuation of SOX2 would reduce the expression of basal keratins and increase the chemotherapy response in human UC cells. For this study, we performed lentiviral knockdown (KD) of SOX2 expression in two separate arsenite (As3+)-transformed UROtsa (As_I, As_II), 5637, and RT4 cells. Cellular growth and colony-forming ability was inhibited in all UC cell lines after SOX2 KD. We demonstrate that SOX2 KD in the UC cells of the Ba/Sq subtype (As_I, As_II, 5637) decreased the expression of stem-associated proteins, oncoproteins, and basal keratins. Additionally, there was an induction of several luminal markers and enhanced cisplatin sensitivity following the repression of SOX2. Lastly, proteomics revealed reductions in lipid-, cholesterol-, and interferon-signaling pathways after SOX2 KD. This study provides a better understanding of the regulation of key genes responsible for defining the Ba/Sq subtype of UC and demonstrates that the inhibition of SOX2 improves chemotherapy response in UC.

Medication-related osteonecrosis of the jaw (MRONJ), associated with antiresorptive and antiangiogenic/immunomodulatory therapies, is a severe condition affecting the jawbones. It most commonly occurs as a side effect of treatments for malignant tumors, osteological, and rheumatological diseases. Spontaneous healing is uncommon, and no definitive causal therapy exists. Surgical interventions, such as sequestrectomy or segmental resection, provide only temporary solutions, as the unpredictable involvement of the entire jawbone complicates the progression of the disease. The development of MRONJ is primarily linked to impaired bone remodeling, especially following trauma, such as tooth extractions. Patients over 65 years of age, those with weakened conditions, diabetes, ongoing steroid therapy, or poor oral hygiene are particularly affected, with the mandibular molar region being especially at risk. This study reviews the causative medications, risk factors, and the importance of early diagnosis and prevention. It also explores research directions aimed at achieving more effective treatments.

Eight new LQFM's Aplysinopsin analogs (12a-h) were synthesized and were evaluated for their anticancer profile on MCF-7 (breast cancer), SiHA and HeLa (cervical cancer). The compounds were obtained through the rational drug design strategy, bioisosterism, by changing the indole scaffold of Aplysinopsin by phenylpyrazole, a subunit extensively explored for designing potent and selective anticancer agents. The synthesis was performed in three simple steps, followed by structural elucidation through nuclear magnetic resonance, infrared spectroscopy, and mass spectrometry, and global yield ranged from 10% to 93%. Regarding the biological assay, the best result was achieved with 12g, which showed antiproliferative activity against all cell lines evaluated, with IC50 59.22, 58.33, and 55.32 μM for MCF-7, SiHA and HeLa, respectively. The safety profile, in the Zebrafish-based model, showed the mortality rate for 12g in concentration-time-dependent, from 87 μM, over 120 h. All Aplysinopsin analogs demonstrated drug-likeness in agreement to Lipinski and Veber rules. Although the moderate antiproliferative activity displayed by 12g, our results include new Aplysinopsin analogs that may be promising lead compounds for further studies, since chemical structures related to this marine compound have provided satisfactory results as anticancer agents against a variety of human tumor cell lines.

Immune checkpoint inhibitors (ICIs) have transformed the therapeutic landscape of malignant melanoma; however, they are frequently associated with immune-related adverse events (irAEs). Emerging evidence suggests that genetic predispositions, including interleukin-7 (IL-7) gene variants, may influence the risk of these toxicities.

The impact of H. pylori infection on the efficacy of trastuzumab in HER2-positive gastric cancer (GC) remains poorly understood, despite growing evidence that tumor microenvironment and host-pathogen interactions influence therapeutic outcomes. This study aimed to investigate how H. pylori strains of differing virulence, one high (HV-HP) and one low (LV-HP), affect GC cell behavior, particularly in the context of ERBB2 (HER2) amplification and Trastuzumab (TRAS)-resistance.

The incorporation of immune checkpoint inhibitors (ICIs) into cancer treatment has revolutionized oncology, providing marked advantages in managing various types of cancer. Nevertheless, the increasing use of ICIs has led to the emergence of immune‑related side effects, including autoimmune diseases such as inflammatory arthritis. IL‑6 signaling is crucial in the development of inflammatory arthritis and is linked to both the benefits and adverse effects of ICIs. The present review summarizes the latest progress in the IL‑6 pathway in inflammatory arthritis and discusses the therapeutic potential of IL‑6 pathway inhibitors for ICI‑induced inflammatory arthritis.

The aim of the present study was to investigate the direct effects of BMS‑202 on melanoma cells. The small molecule programmed cell death ligand 1 (PD‑L1) inhibitor BMS‑202 was used to treat A375 melanoma cells. The cell distribution of BMS‑202 was examined using low‑power and high‑resolution confocal microscopy, focusing on its localization in mitochondria. The impact of BMS‑202 on mitochondrial gene expression levels, the activity of respiratory chain complexes, and the levels of reactive oxygen species and apoptosis‑related genes, including Bax, Bcl‑2, PARP and caspase‑3, were assessed by quantitative PCR and western blotting. Additionally, tumor cell viability, proliferation, migration and invasion were evaluated in vitro, with in vivo experiments conducted through the construction of tumor‑bearing mouse models and Ki‑67 immunohistochemical staining to validate tumor proliferation. The function of mitochondria was inhibited using a pyruvate carrier inhibitor to examine how this affected the action of BMS‑202. The results revealed that BMS‑202 can inhibit tumor cell function and promote apoptosis. Furthermore, BMS‑202 was shown to enter the mitochondria where it may bind to PD‑L1 and improve mitochondrial function. By inhibiting mitochondrial function, the antitumor effects of BMS‑202 can be enhanced. Overall, the present study provides information on the potential antitumor mechanisms of BMS‑202 as well as a theoretical basis for its application in melanoma therapy.

In this review, the role of microRNA‑21 (miRNA‑21) as an oncogene in lung cancer was investigated. Studies have shown that miRNA‑21 can promote the progression of lung cancer by targeting downstream target genes, and its expression can be modulated by transcription factors, DNA methylation or competitive endogenous RNA as an upstream regulator. This review highlights that miRNA‑21 can promote the progression of lung cancer through multiple signaling pathways, with a focus on the PI3K/AKT, MEK/ERK, TGF‑β/SMAD, Hippo, NF‑κB and STAT3 signaling pathways. Mechanistically, miRNA‑21 plays an important role in the progression of lung cancer by regulating multiple biological processes, such as proliferation, invasion, metastasis, apoptosis and angiogenesis in lung cancer cells. Higher expression of miRNA‑21 is associated with chemotherapy, radiotherapy and immune resistance in lung cancer. Targeting these molecular pathways may be a novel therapeutic strategy for treating lung cancer. Additionally, miRNA‑21 can serve as a biomarker for lung cancer diagnosis, prognosis and treatment response. This review also summarized the following: i) Current methods employed to inhibit the expression of miRNA‑21 in lung cancer, including CRISPR/Cas9 technology; ii) the application of natural anticancer agents, oligonucleotides, small molecules and miRNA sponges; and iii) the nano‑delivery systems developed for miRNA‑21 inhibitors. Finally, the advancements in research on miRNA mimics and inhibitors in clinical trials, which may promote the application of miRNA‑21 in clinical trials in lung cancer, were discussed. Given that lung cancer is a considerable public health challenge, these studies provide new ways of treating patients with lung cancer.

This study reports a green, efficient, and high-yielding synthesis of novel imidazole derivatives 5a-i via a one-pot, four-component reaction under microwave irradiation. The optimized protocol demonstrates satisfactory yields (86%-92%), short reaction times (9-14 min), easy workup, and avoidance of toxic solvents, in accordance with sustainable chemistry principles. The antiproliferative efficacy of derivatives 5a-i was evaluated against H1975, A549, and A431 cells, using the MTT assay. The results indicated that derivatives 5b and 5g exhibited the greatest antiproliferative activity, with IC50 values of 5.22 and 6.34 µM. The values obtained were markedly inferior to those of recognized EGFR inhibitors, such as osimertinib, gefitinib, and erlotinib. Compound 5b was exhibited as the most potent inhibitor of both EGFRWT and EGFRT790M kinases, with IC50 values of 30.1 and 12.8 nM, respectively. The findings exceeded those of osimertinib and gefitinib, which demonstrated IC50 values of 54.3, 19.1, 9.1, and 356.8 nM, respectively, which may explain its notable antiproliferative effect against the H1975 cell line. Molecular docking and dynamics simulations confirmed the stable binding of derivatives 5b and 5g within the EGFR active sites, aligning with experimental findings. Furthermore, in silico ADME properties for the promising EGFR inhibitors 5b and 5g, conducted using the egg-boiled technique, demonstrated favorable lipophilicity, G.I.T. absorption, and BBB permeability. As a result, imidazoles 5a-i, particularly 5b and 5g, exhibited promising antiproliferative properties, targeting EGFRWT and EGFRT790M kinase inhibitors.

Phosphoglycerate dehydrogenase (PHGDH) is the rate-limiting enzyme in the de novo Serine synthesis pathway (SSP), a highly regulated pathway overexpressed in several tumors. Specifically, PHGDH expression is dynamically regulated during different stages of tumor progression, promoting cancer aggressiveness. Previously, we demonstrated that high Serine (Ser) availability, obtained by increased exogenous uptake or increased PHGDH expression, supports 5-Fluorouracil (5-FU) resistance in colorectal cancer (CRC). Beyond its metabolic role in sustaining Ser biosynthesis, different "non-enzymatic roles" for PHGDH have recently been identified. The present study aims to investigate non-enzymatic mechanisms through which PHGDH regulates 5-FU response in CRC.

Unresectable hepatocellular carcinoma (uHCC) with portal vein tumor thrombosis (PVTT) has poor prognoses. This study evaluated the efficacy and safety of lenvatinib (LEN) combined with anti-PD-1 antibodies (PD-1) and locoregional therapy (LRT) in uHCC patients with PVTT.

Chemotherapy-induced peripheral neuropathy (CIPN), hand-foot syndrome (HFS), and nail changes are common adverse effects associated with chemotherapy, significantly impacting the quality of life of cancer patients, and effective interventions remain an unmet need in oncologic care. Regional limb cooling is an emerging non-pharmacological approach used to prevent or reduce the severity of these adverse side effects. Although the awareness of regional limb cooling is rather prevalent, the overall use and efficacy of this non-pharmacological therapy in preventing chemotoxicities is not universally agreed upon. This paper reviews the current evidence regarding the use, efficacy, limitations, and safety of regional limb cooling in preventing or reducing CIPN, HFS, and nail changes in clinical settings.

The increasing global incidence of cancer emphasizes the vital role of machine learning algorithms and artificial intelligence (AI) in identifying novel anticancer targets and developing new drugs. Computational approaches can significantly quicken research on complex disorders, enabling the discovery of effective treatments. This study explores anticancer targets by assessing the potential of naturally occurring compounds derived from various plants to cure colorectal cancer. Twenty compounds were sourced from PubChem, and the RPS20 protein structure was obtained from AlphaFold, and mutation "V50S" was added. Validation of mutated RPS20 protein was performed using the Ramachandran plot and ERRAT. Binding sites on the mutated RPS20 protein were identified with DeepSite, followed by virtual screening to pinpoint the most promising natural lead drug candidate. Indirubin emerged as the lead drug candidate, fulfilling all ADMET criteria and exhibiting a good binding affinity. Further development included designing an AI-based drug using the WADDAICA server, which was validated through molecular docking, molecular dynamics (MD) simulation, and MMGBSA. The electronic properties of indirubin were studied using DFT calculations. The results show a moderate HOMO-LUMO gap, indicating its potential reactivity and the possible capability for biological target interactions. These findings indicate that indirubin could serve as a potent and effective cancer inhibitor, offering high efficacy with minimal side effects.

Triple-negative breast cancer (TNBC) is the most aggressive among the breast cancer subtypes and poses unique therapeutic challenges due to its distinct characteristics like lack of specific therapeutic targets. TNBC demonstrates poor survival rate enhanced immunogenic characteristics and a more favorable tumor microenvironment than other breast cancer variants. Also, TNBC patients show elevated levels of programmed death ligand-1 (PD-L1) expression in contrast to non-TNBC patients. Binding of PD-L1 with PD-1 produces an inhibitory signal, resulting in suppression of T-cell. Therapeutic approaches utilizing immunotherapies against PD-L1 exhibit promising outcomes in the treatment of TNBC. Limitations like suboptimal efficacy, inadequate oral bioavailability, and associated immune-related adverse effects of antibody-mediated anti PD-1/PD-L1 therapies have necessitated the exploration of alternative therapeutic approaches. Thus, small molecules become an alternate option for PD-1/PD-L1 inhibition. In the present study, we have used virtual screening to identify potential phytochemicals from selected Indian medicinal plants as PD-L1 inhibitors. A total of 953 phytochemicals derived from eleven selected medicinal plants were initially screened through molecular docking using the PyRx tool. Among the 953 identified phytochemicals, the top 20 compounds exhibiting the highest binding affinities in docking study were selected for further analysis. Following comprehensive ADMET analyses, 2 compounds were ultimately identified as suitable candidates for a molecular dynamics (MD) simulation study. The study identified 4-hydroxychalcone and flavylium from Glycyrrhiza glabra and Catharanthus roseus, respectively as potential PD-L1 inhibitors with enhanced stability relative to the reference molecule. Both compounds also showed enhanced gastrointestinal absorption with no predicted cytotoxic and immunotoxic effects. Consequently, these compounds present promising candidates for novel PD-L1 inhibitor development in TNBC therapy. Further experimental investigations are necessary to facilitate their clinical translation.