Small molecule activators of the mitochondrial caseinolytic protease P (ClpP agonists) can disrupt tumor metabolism and deprive tumors of their energy needs. The imipridone, ONC201, is a ClpP agonist currently undergoing clinical evaluation across multiple cancer types, while additional analogs with improved potency and selectivity are in preclinical development. Preclinical studies in mice have demonstrated a unique pharmacokinetic-pharmacodynamic (PK-PD) relationship for ONC201 characterized by prolonged pharmacology following a single dose. This motivated the selection of an initial human dosing regimen of every three weeks, and subsequent dose exploration studies in mice led to dose intensification in human patients. However, a systematic analysis of ClpP agonist PK-PD relationships has not been performed, and the optimal exposure profile for ClpP agonists remains undefined. To address this gap, we combined PK-PD modeling with a microfluidic perfusion platform as an animal-alternative approach for translational PK-PD of ClpP agonists. We demonstrate that the anti-proliferative effect on triple negative breast cancer cells correlates with the magnitude and duration of ClpP agonist exposure above a threshold concentration required for ClpP activation. Moreover, we demonstrate that PK-PD model simulations using parameters derived from microfluidic perfusion datasets can successfully predict the anti-tumor efficacy of a ClpP agonist in a mouse tumor xenograft study. These studies support the translational relevance of the animal-alternative in vitro PK-PD platform and its utility to help guide dose optimization of ClpP agonists as cancer therapeutics.

Objective responses to immune checkpoint inhibitors (ICI) in leiomyosarcoma (LMS) are rare. Response rates may be increased by combination with other drugs known to promote immune infiltration, such as poly(ADP-ribose) polymerase (PARP) inhibitors, which have led to benefit in BRCA-altered uterine LMS. We therefore evaluated the combination of a PARP inhibitor, rucaparib, and the anti-programmed death receptor-1 monoclonal antibody, nivolumab, in patients with advanced LMS and investigated its effects on the tumor immune microenvironment.

In this study, we designed and synthesized a novel polysaccharide-based fluorescent nanocarrier system, HPMC-AuNPs@1, for the delivery of plant extract compound 1. The HPMC-AuNPs@1 system was synthesized by functionalizing gold nanoparticles (AuNPs) with hydroxypropyl methylcellulose (HPMC) and loading Compound 1 into the system. The resulting nanocarrier exhibited a typical aggregation-induced emission (AIE) effect in aqueous media, showing strong green fluorescence in a DMSO-H2O (5:95) solution. Host-guest sensing experiments revealed that HPMC-AuNPs@1 demonstrated high selectivity for detecting carcinoembryonic antigen (CEA) among 14 different metallic ions and antigen molecules. A noticeable fluorescence shift occurred upon binding with CEA, and the detection limit for CEA was as low as 2.56 × 10-6 M. Additionally, we explored the potential therapeutic applications of HPMC-AuNPs@1 in cancer treatment, particularly in inducing pyroptosis, a form of programmed cell death. In vitro experiments with SNU-16 cells showed that HPMC-AuNPs@1 nanoparticles inhibited cancer cell proliferation by inducing pyroptosis. These findings suggest that HPMC-AuNPs@1 holds great promise as a therapeutic platform for cancer treatment, particularly in targeting cell proliferation pathways via pyroptosis induction.

Cell-free DNA (cfDNA) found in biofluids is increasingly being used in the diagnosis and treatment of a variety of disease states, including cancer. Though DNA is known to be susceptible to damage by many different chemotherapeutic compounds and genotoxic agents, the fact that cfDNA may be damaged and contain DNA adducts associated with specific exposures has not previously been considered to any significant extent. Here, using differential centrifugation of culture medium from cells treated with the anti-cancer drug cisplatin, we show that DNA containing cisplatin adducts is readily detectable in the extracellular milieu and is enriched in fractions known to contain small extracellular vesicles and cfDNA. However, our data indicates that this damaged cfDNA is non-vesicular in nature and likely represents fragments of chromatin. Dose and time course experiments suggest that the release of cfDNA containing cisplatin-DNA adducts is correlated with the activation of apoptotic signaling. Indeed, the generation of cisplatin-damaged cfDNA is exacerbated by the loss of nucleotide excision repair and is abrogated by caspase inhibition. Finally, we show that native cisplatin-damaged cfDNA, but not purified, protein-free cfDNA, can be taken up by cells by phagocytosis to result in the presence of cisplatin-DNA adduct-containing DNA in non-cisplatin-treated cells. These results indicate that tumors from patients undergoing cisplatin-based chemotherapy may shed damaged cfDNA that could have additional biological effects in bystander cells, which could both impact chemotherapeutic responses and lead to improved treatments and diagnostic tools for monitoring therapeutic efficacy.

Two marine actinomycete-like strains, MCC20T and MCC57, were isolated from Chanthaburi (Thailand) mangrove sediment. Their taxonomic classifications were established through a polyphasic approach. Despite differences in colony morphotypes, genetic and chemotaxonomic analyses confirmed them as the same species within the genus Streptomyces. Both strains contained ll-diaminopimelic acid in their cell wall, with glucose, mannose, ribose and rhamnose identified as whole-cell sugars. Their phospholipid profile comprises phosphatidylethanolamine, diphosphatidylglycerol, phosphatidylglycerol, phosphatidylinositol and phosphatidylinositol mannoside. The predominant fatty acids were iso-C15:0, anteiso-C15:0, iso-C16:0 and anteiso-C17:0 with MK-9(H8) as the primary menaquinone, while MK-9(H6) and MK-9(H4) were unique to strain MCC57. Both strains exhibited anticancer activity against colorectal (HCT116) and lung (A549) cancer cells, with strain MCC20T being more potent. Their 16S rRNA gene sequences showed 100% similarity, with 99.2% similarity to Streptomyces fumigatiscleroticus NBRC 12999T. Nevertheless, a phylogenomic tree placed them closer to Streptomyces spinosirectus CRSS-Y-16T, Streptomyces plumbidurans KC 17012T and Streptomyces spinosisporus 7R016T. Nearly 100% average nucleotide identity (ANI) and digital DNA-DNA hybridization (dDDH) values highlighted the identity of strains MCC20T and MCC57, while ANI (89.4%) and dDDH (35.5%) values were well below the respective 95 and 70% thresholds for related species. This supported their novelty. Based on their genotypes and phenotypes, strains MCC20T (=NBRC 117131T=TBRC 19240T) and MCC57 (=NBRC 117132=TBRC 19241) are identified as phenotypic variants of a new species, Streptomyces sediminimaris sp. nov., with strain MCC20T designated as the type strain (~9.2 Mb genome, 72.0 mol% G+C content).

Genomic instability is a hallmark of cancer and is associated with tumor progression and therapeutic resistance. Centrioles and centrosomes are a critical determinant of genomic stability. Polo-like kinase 4 (PLK4) is a serine-threonine kinase that plays a critical role in the regulation of centrosome duplication. PLK4 overexpression drives tumorigenesis and has been shown to be overexpressed in a wide variety of human tumors, where it is associated with more advanced disease and worse clinical outcomes. As such, there has been significant interest in pharmacologically targeting PLK4 using small-molecule inhibitors for therapeutic gain in multiple cancer types. In this review, we will discuss the functions of PLK4 in normal and oncogenic processes. We will further discuss the current state of PLK4 as a therapeutic target in cancer by reviewing the current literature on PLK4 inhibitors in both the preclinical and clinical space. Finally, we will discuss the emerging data exploring rational combinations of PLK4 inhibitors with DNA-damaging agents and immunotherapies as a means to unlock the potential of these agents in cancer therapy.

Paclitaxel is a potent agent against ovarian cancer. Hydrogen sulfide (H2S) is of particular interest in cancer treatment research. It is known that H2S has apoptotic and antiproliferative effects.

Inflammation is a hallmark of cancer, significantly contributing to tumor progression and therapeutic outcomes. Among the diverse cellular components of the tumor microenvironment, fibroblasts have been recognized as key regulators of inflammatory processes. Under tumor‑specific conditions, cancer‑associated fibroblasts (CAFs) undergo differentiation and promote tumor proliferation, metastasis and immune evasion via highly intricate mechanisms. This review provides a comprehensive analysis of the reciprocal interactions between CAFs and inflammation, elucidating the mechanisms by which CAFs induce pro‑inflammatory signaling and how inflammatory mediators, in turn, potentiate CAF activation and function. Furthermore, innovative therapeutic strategies, including the inhibition of stromal proteins, hypoxia‑inducible factor 1α and metabolic pathways associated with CAFs, as well as the application of nanoparticle‑based drug delivery systems, are examined for their potential to impede CAF‑mediated tumor progression. Pharmacological agents targeting CAF‑associated signaling pathways or inflammatory cytokines show dual efficacy by concurrently modulating inflammatory responses and CAF activity. These approaches frequently demonstrate improved therapeutic efficacy compared to interventions solely directed at CAF surface proteins, highlighting the therapeutic potential of concurrently addressing both inflammation and CAFs to enhance cancer treatment efficacy.

Immune checkpoint blockade therapy has revolutionized cancer treatment, yet its clinical efficacy remains limited to a subset of patients with specific tumor types. The present review provides a comprehensive analysis of T cell‑mediated antitumor immunity from both local and systemic perspectives, with particular emphasis on CD8+ T cells as primary effectors. The review discusses how the complex trafficking between the tumor microenvironment (TME), surrounding lymphoid tissues and peripheral circulation creates multiple opportunities for tumors to evade immune surveillance. Within the TME, T‑cell exclusion mechanisms, antigen specificity and the spectrum of T‑cell exhaustion states, from progenitor exhausted T cells to terminally exhausted T‑cell phenotypes, are reviewed. Beyond the local TME, the crucial roles of tumor‑draining lymph nodes and tertiary lymphoid structures in maintaining sustainable antitumor immunity, as well as the significance of circulating T cells as both biomarkers and therapeutic targets, are analyzed. This systemic perspective provides insights into the dynamic nature of antitumor immunity and suggests potential strategies for next‑generation immunotherapies, including combination approaches targeting multiple immune compartments to achieve optimal therapeutic outcomes.

Triple‑negative breast cancer (TNBC) is a lethal subtype of breast cancer with a poor prognosis and limited existing treatment options. The immune checkpoint inhibitor, anti‑programmed death ligand 1 (PD‑L1), has recently emerged as a promising alternative in treating TNBC. PD‑L1 is critical in tumor immune evasion and is therefore a key target for cancer immunotherapy. Although anti‑PD‑L1 therapy is effective in breast cancer based on clinical trials, the relationship between PD‑L1 expression levels and treatment response remains unclear. To investigate this, a 4T1 breast cancer cell line that stably overexpressed PD‑L1 was established and was used to create a tumor model in mice. Mice were treated with anti‑PD‑L1 antibodies, and tumor growth was compared between the control and treated groups. PD‑L1 overexpressing tumors did not exhibit an antitumor response to anti‑PD‑L1 therapy compared with the control tumors. Additionally, immune cell infiltration and activation were significantly altered, as shown by immunohistochemical staining and bulk RNA sequencing. In PD‑L1‑overexpressing tumors that did not respond to treatment, immune cell markers and antitumor immune pathways were downregulated. These results demonstrated that excessive PD‑L1 expression creates an immunosuppressive tumor microenvironment, which impairs the efficacy of anti‑PD‑L1 therapy. The present study suggests that excessive PD‑L1 expression reduces the effectiveness of antitumor immunotherapy, and that PD‑L 1 expression levels are essential in predicting the response to antitumor immunotherapy.

Acute myeloid leukemia (AML), originating from myeloid hematopoietic stem/progenitor cells, is a malignant hematological disorder. Resistance to current treatments, especially in FLT3-ITD AML cases, urgently demands the development of novel therapeutics. In this study, we pinpointed fostamatinib, an orally delivered small molecule SYK inhibitor for chronic immune thrombocytopenia (ITP), as a promising candidate for drug repurposing. It effectively inhibited FLT3-ITD+ AML cell proliferation and induced leukemic cell apoptosis. Network pharmacology analysis further deciphered the associated pharmacological mechanism related to the PI3K-AKT signaling pathway. Moreover, fostamatinib downregulated the expression of immune checkpoints such as PD-L1 and CD47. Overall, this study provided a conceptual foundation for evaluating the advantages of drug repurposing in AML drug development.

The efficacy of regorafenib or fruquintinib in combination with PD-1/PD-L1 inhibitors for metastatic colorectal cancer (mCRC) treatment has not been elucidated. This study aims to systematically evaluate the efficacy and safety of this combination therapy.

Canine oral papillomatosis, caused by canine papilloma virus 1, is a benign condition primarily affecting young or immunosuppressed dogs. While most cases regress spontaneously, severe cases often require surgical intervention due to extensive lesions and associated discomforts. However, surgical excision is associated with a high risk of recurrence, necessitating adjuvant therapies. This report presents the case of a 1-year-old German Shepherd with severe oral papilloma unresponsive to prior treatments, managed through surgical excision followed by topical mitomycin C (MMC) application. MMC, applied intraoperatively and during follow-up, effectively prevented recurrence over a 1-year period. This case demonstrates the potential of MMC as an effective adjuvant therapy for severe canine oral papillomatosis, providing a novel approach in veterinary medicine.

Withanolides are a class of naturally occurring C-28 ergostane steroidal lactones with an abundance of biological activities, and their members are promising candidates for antineoplastic drug development. The ADMET properties of withanolides are still largely unknown, and in silico predictions can play a crucial role highlighting these characteristics for drug development, shortening time and resources spent on the development of a drug lead. In this work, ADMET properties of promising antitumoral withanolides were assessed. Each chemical structure was submitted to the prediction tools: SwissADME, pkCSM-pharmacokinetics, admetSAR v2.0, and Molinspiration Cheminformatics. The results indicate a good gastrointestinal absorption rate, inability to cross the blood-brain barrier, CYP3A4 metabolization, without inhibition of other P450 cytochromes, high interaction with nuclear receptors, and a low toxicity. It was also predicted for the inhibition of pharmacokinetics transporters and some ecotoxicity. This demonstrates a viability for oral drug development, with low probabilities of side effects.

Aminosteroid derivative RM-581 stands out as an anticancer agent, supported by positive in vitro and in vivo studies on resistant cancers of the breast, prostate, and pancreas. A synthetic route has already been developed to obtain aminosteroid RM-581 in small quantities (scale of milligrams to a few grams). However, this route has significant limitations in view of its transposition to scaling up to larger quantities to support late preclinical and clinical trials. Among the problems are the use of toxic reagents, the moderate overall yield, and the need for multiple purifications through chromatographic columns. The development of a new synthetic route has therefore been explored. Starting from commercially available estrone, 2,4-dibromo-estrone was rapidly formed, followed by the regioselective introduction of a nitro group at the C2 position and by the methylation of phenol at the C3 position. The 4-bromo-2-nitro-3-O-methylestrone was then reduced to 2-amino-3-O-methylestrone and the primary amine was used to form the piperazine ring. Once the cyclization step was carried out, the last two steps were identical to the first synthetic route previously reported, i.e., introducing an ethynyl group at the C-17α position and then adding the quinoline-proline side chain with an N-acylation, assisted by a peptide coupling reagent. Importantly, no purification by chromatography was necessary during the whole sequence of reactions and only a final silica gel filtration, followed by recrystallization, led to RM-581 at a very high level of purity. The structure was also fully characterized by 2D NMR analysis.

Colorectal cancer (CRC) remains a major global health challenge, necessitating the development of more effective and environmentally sustainable treatments. This study presents a novel green synthetic protocol for 1,3,5-triazine derivatives with anticancer potential, employing both microwave-assisted and ultrasound-assisted methods. The synthesis was optimized using 4-chloro-N-(2-chlorophenyl)-6-(morpholin-4-yl)-1,3,5-triazin-2-amine as the key intermediate, with sodium carbonate, TBAB, and DMF providing optimal yields under microwave conditions. To enhance sustainability, a modified sonochemical method was also developed, enabling efficient synthesis in aqueous media with a minimal use of organic solvents. A series of nine morpholine-functionalized derivatives were synthesized and evaluated for cytotoxic activity against SW480 and SW620 colorectal cancer cell lines. Compound 11 demonstrated superior antiproliferative activity (IC₅₀ = 5.85 µM) compared to the reference drug 5-fluorouracil, while compound 5 showed promising dual-line activity. In silico ADME analysis supported the drug likeness of the synthesized compounds, and biomimetic chromatography analysis confirmed favorable physicochemical properties, including lipophilicity and membrane affinity. These results underscore the potential of the developed protocol to produce bioactive triazine derivatives through an efficient, scalable, and environmentally friendly process, offering a valuable strategy for future anticancer drug development.

Cisplatin (CIS) is a widely used chemotherapeutic agent that is highly effective against various cancers. However, its clinical application is frequently limited by its substantial nephrotoxic side effects. The gastrin-releasing peptide receptor (GRPR), a critical regulator in inflammatory diseases, has been identified as a promising therapeutic target. Our previous studies have demonstrated that the GRPR antagonists PD176252 and RH-1402 can mitigate CIS-induced nephrotoxicity through anti-inflammatory mechanisms. Based on these findings, we designed and synthesized a series of 2-arylpropanoic acid-L-tryptophan derivatives to enhance the therapeutic effects. Among these compounds, 3m exhibited superior renal protection by significantly improving mouse renal tubular epithelial cell (mRTEC) viability from 50.2 ± 2.6% to 80.5 ± 3.9%, surpassing PD176252 (70.8 ± 1.4%) and RH-1402 (73.9 ± 3.7%). Moreover, compound 3m markedly reduced the expression of kidney injury molecule-1 (KIM-1) and inflammatory cytokines [Tumor Necrosis Factor-α (TNF-α), Interleukin-6 (IL-6), Monocyte Chemoattractant Protein-1 (MCP-1)]. Finally, molecular docking results revealed that 3m exhibited a high binding affinity for GRPR. Computational predictions using SwissADME further indicated that 3m possesses favorable drug-like properties, thereby supporting its potential as a promising candidate for mitigating CIS-induced nephrotoxicity.

Flavonoids and chalcones, widely recognised for their diverse biological activities, have garnered attention due to their potential therapeutic applications. This review discusses fluorinated flavonoids and chalcones, focusing on their prospective anti-inflammatory, antidiabetic, anticancer, antiosteoporotic, cardioprotective, neuroprotective, hepatoprotective, antimicrobial, and antiparasitic applications. The enhanced biological activities of fluorinated derivatives, particularly the antibacterial, antiviral, and anticancer properties, are attributed to the introduction of fluorine groups, which increase lipophilicity and metabolic stability. Key findings indicate that fluorinated flavonoids and chalcones exhibit synergistic effects with antibiotics, inhibit bacterial efflux pumps, and reveal potent antiviral and anticancer properties. However, challenges such as cytotoxicity and structural optimisation have to be addressed. The synthesis of fluorinated flavonoids and chalcones is discussed, with emphasis on various synthetic methods such as condensation and cyclisation reactions starting from fluorinated precursors, as well as fluorination strategies, including the use of molecular fluorine or fluorinating agents. Fluorinated flavonoids and chalcones represent candidates for therapeutic development and have the potential to overcome drug resistance. However, further studies are necessary to adjust their pharmacological profiles.

The Fabaceae family is known for the presence of isoflavones-phytoestrogens with potential chemopreventive effects against hormone-dependent cancers. This study aimed to optimize isoflavones extraction using a fractional factorial design and to quantitatively and qualitatively analyze 32 Fabaceae species native to Polish flora by HPLC-UV-VIS to indicate new, rich plant sources of isoflavones. The optimal extraction method was a 60 min reflux with 50% methanol and a plant material-to-solvent ratio of 1:125. The highest isoflavone levels were found in Trifolium medium (26.70 mg/g d.m.), Genista tinctoria (19.65 mg/g d.m.), and Trifolium pratense (12.56 mg/g d.m.). The obtained extracts were further evaluated for cytotoxic and antiproliferative activity against MCF7 and MDA-MB-231 human breast cancer cells. Genista tinctoria showed the highest cytotoxicity against MCF7, while Cytisus scoparius and Ononis arvensis were most effective against MDA-MB-231 at a dose of 500 µg/mL. The extracts were also characterized by varied, potent antioxidant properties, important in chemoprevention. A strong correlation was observed between isoflavone content and cytotoxic and antiproliferative activity exclusively in the estrogen receptor-positive MCF7 cell line. Importantly, the tested extracts demonstrated no toxic effects on normal human liver (HepG2), thyroid (Nthy-ori 3-1), or breast (MCF10A) cells, indicating a favorable safety profile.

Cervical cancer remains a major threat to women's health, with advanced cases often exhibiting recurrence and metastasis due to cancer stem cells driving therapy resistance. This study evaluated fenbendazole (FBZ), a repurposed veterinary anthelmintic, for its antitumor activity dual targeting cervical cancer cells (CCCs) and cervical cancer stem cells (CCSCs). CD133+CD44+ CCSCs were isolated from HeLa and C-33 A cell lines via immunomagnetic sorting and validated for stemness. Cell proliferation, cell cycle and apoptosis, and protein expression were detected by MST assay, flow cytometry, and Western blot analysis, respectively. FBZ dose-dependently inhibited proliferation, induced G2/M arrest, and triggered apoptosis in both CCCs and CCSCs. Mechanistically, FBZ upregulated cyclin B1 and phosphorylation of cdc25C-Ser198, while downregulating Wee1, phosphorylation of CDK1, and phosphorylation of cdc25C-Ser216, collectively enforcing G2/M blockade. In vivo, FBZ (100 mg/kg) significantly suppressed tumor growth in xenograft models without weight loss, contrasting with cisplatin-induced toxicity. Survival analysis revealed 100% survival in FBZ-treated mice versus 40% in cisplatin and 0% in untreated controls. These findings demonstrate FBZ's unique ability to simultaneously target bulk tumor cells and therapy-resistant CCSCs via cell cycle disruption, supported by its preclinical safety and efficacy, positioning it as a promising therapeutic candidate for cervical cancer.