The guanosine triphosphatase (GTPase) activity of the mitochondrial dynamin-related protein Optic Atrophy 1 (OPA1) regulates cristae remodeling, cytochrome c release, and apoptosis. Elevated OPA1 levels in multiple cancers correlate with reduced therapy sensitivity and poor survival, calling for specific OPA1 GTPase inhibitors. A high-throughput screening of ~10,000 compounds identified MYLS22, a heterocyclic N-pyrazole derivative as a reversible, noncompetitive OPA1 GTPase inhibitor. MYLS22 engaged with OPA1 in vitro and in cells where it induced cristae remodeling and mitochondrial fragmentation contingent on intactness of its predicted OPA1 binding site. MYLS22 enhanced proapoptotic cytochrome c release and sensitized breast adenocarcinoma cells to anti-Bcl-2 therapy, without toxicity on noncancer cells. By MYLS22 structure-activity relationship studies, we obtained Opa1 inhibitor 0 (Opitor-0) that inhibited OPA1, promoted cytochrome c release, and restored anti-Bcl-2 therapy sensitivity more efficiently than MYLS22. These chemical probes validate OPA1 as a therapeutic target to increase cancer cell apoptosis at the mitochondrial level.

DNA double-strand break (DSB) is a highly toxic lesion that can generate genome instability, a major source of tumorigenesis. DSBs are mainly repaired by non-homologous end joining (NHEJ) or homologous recombination (HR). The selection of the DSB repair pathway primarily depends on the DNA resection of the DSB ends. Indeed, HR is initiated by resection at the DSB, generating 3' single-stranded overhang. The shieldin complex prevents resection fostering DSB repair toward NHEJ. Here, we reveal that the inflammasome sensor NLRP3 facilitates DNA end resection to promote the HR pathway in an inflammasome-independent manner. Strikingly, NLRP3 silencing decreases HR efficiency, as evidenced by RAD51 foci and functional HR assays. Mechanistically, we describe that NLRP3 interacts with REV7, a subunit of the shieldin complex, and its depletion increases REV7 recruitment to IR-induced DSBs. Similar to cancer cells harboring HR-mutated genes, we find that NLRP3-deficient cells are sensitive to Poly-ADP-ribose polymerase (PARP) inhibitors (PARPi) and exhibit an epistatic relationship with BRCA1 deficiency. Remarkably, loss of REV7 in NLRP3-depleted cells induces PARPi resistance by restoring HR. This study unravels the crucial role of the innate immune receptor NLRP3 in regulating the selection of DSB repair pathways to maintain genome integrity.

The proliferation of colon cancer is influenced by alterations in epigenetic, reactive oxygen species (ROS), and dysregulation of signaling pathways, especially via the involvement of DNMT1, mTOR, and KEAP1 axis. The current investigation examined the antiproliferative capabilities of fisetin (FisT) in a rat model and in colon cancer cell lines HCT116, CT-26, and Caco-2. Our findings show that FisT modulated the DNMT1, mTOR, KEAP1, and IL-6 signaling pathways to enhance the antiproliferative effects against in vitro and in vivo preclinical model. In-silico based anticancer potential of fisetin were revealed through SwissTargetPrediction, Cytoscape, STRING, Schrodinger, molecular dynamics simulations, KEGG, and network analysis. In-vitro MTT assay, cell cycle analysis, ROS level, immunocytofluorescence, western blot analysis, and in vivo immunohistofluorescence, western blot analysis, ELISA-based assays were performed to evaluate anticancer property of fisetin. Our findings revealed that FisT has a strong anticancer property by demethylating DNA, enhancing ROS, KEAP1 level. Simultaneously downregulated the DNMT1 & mTOR expression, and preventing angiogenesis, cell proliferation, invasion, and migration against in vitro & in vivo models. FisT enhances the anticancer response of tumor development and reduces the size of crypt foci. FisT has potential as a cytotoxic drug, improving and intensifying anticancer responses in colon cancer.

Nasopharyngeal carcinoma (NPC) is a kind of malignant tumour originating from the mucosal epithelium of the nasopharynx, which has apparent regional distribution characteristics, and its incidence is increasing yearly. At present, the primary treatment method for nasopharyngeal carcinoma is radiotherapy, but radioresistance has become a complex problem to overcome to improve the therapeutic effect. Recently, ferroptosis has been proposed as a new type of iron-dependent programmed cell death, distinct from apoptosis, cell necrosis and autophagy. Many studies have shown that ferroptosis is involved in the occurrence, development, invasion and metastasis of nasopharyngeal carcinoma cells, and promoting the occurrence of ferroptosis of the same cells is a promising treatment method that should be written in the prospect. Therefore, this paper summarizes the mechanism of action of ferroptosis and its role in treating the same as above.

Plant-mediated iron nanoparticles are increasingly utilized in biomedical and health applications due to their biocompatibility and nontoxicity. The therapeutic characteristics of these nanoparticles are extensively diverse.

Doxorubicin(DOX), which is a first-line broad-spectrum chemotherapeutic agent remains constrained clinical efficacy by dose-dependent cardiotoxicity, multidrug resistance, and systemic toxicity. Recent advancements in nanocarrier-based drug delivery systems have demonstrated remarkable potential to enhance tumor-specific accumulation, modulate drug release kinetics, and mitigate off-target effects through innovative engineering strategies. Contemporary nanocarrier researchers have expanded beyond conventional efforts to enhance tumor targeting and optimize drug release kinetics, which emphasizes the pathophysiological roles of the tumor microenvironment (TME) in mediating oncogenesis, neoplastic progression, and therapeutic resistance. This review emphasizes two pivotal strategies: (1) Structural innovation in tumor-targeting nanocarrier design through stimuli-responsive release mechanisms and molecular recognition targeting; (2) Therapeutic reprogramming of the TME via combinatorial extracellular matrix modulation. Through systematic analysis of 2019-2022 literatures from major scientific databases, this review synthesizes the advances in DOX-loaded nanocarriers targeting TME reprogramming and immunomodulation, and evaluates novel delivery platforms that overcome DOX's dose-limiting toxicity while potentiating antitumor efficacy.

Vascular endothelial growth factor (VEGF) is an endothelial cell‑specific angiogenic factor. VEGF is involved in vasodilatation, nerve protection and retinal development and maturation. Over‑expression of VEGF is closely associated with retinopathies, such as retinal vein occlusion, diabetic retinopathy, age‑related macular degeneration and diabetic macular edema. Intravitreal injections of anti‑VEGFs are widely used in the treatment of retinopathies to reduce the angiogenesis and the macular edema. Hypothetically, repeated anti‑VEGF injections for retinopathies should interfere with the neuroprotective function of VEGF and might induce the vasoconstriction with a subsequent decrease in the ocular perfusion. These two could affect the optic nerve. The peripapillary retinal nerve fiber layer (p‑RNFL) thinning and the decreased papillary/peripapillary blood circulation can show the optic nerve damage earlier. In the present review, the effects of anti‑VEGFs on p‑RNFL and papillary/peripapillary blood circulation in retinopathies were comprehensively summarized and analyzed to explore whether the anti‑VEGFs cause damages to the optic nerve. The present review provided a detailed evaluation and analysis of the changes in p‑RNFL thickness, papillary/peripapillary blood circulation and intraocular pressure and the correlations between these changes with the number and type of anti‑VEGFs in 3,078 affected eyes and 520 fellow eyes with retinopathies. The present review sought to establish a foundation for the intravitreal administration of anti‑VEGFs and efficacy monitoring of the possible side effects on the optic nerve.

Aurora-A is often overexpressed in lung cancer and is associated with poor prognosis, making it a potential therapeutic target for non-small cell lung cancer (NSCLC) treatment. This study aimed to evaluate the therapeutic potential of nanomedicine-based delivery of the Aurora-A inhibitor Danusertib (Danu) in NSCLC treatment.

Plant-based phytochemicals have shown potential as agents against cancer through various biological pathways, including immune system modulation. Combining natural compounds with synergistic interactions enhances the identification of molecular targets in cancer cells, demonstrating anticancer capabilities. The "miracle tree," Moringa oleifera (Moringa), possesses remarkable nutritional and medicinal properties.

Our previous research demonstrated that SIC-19, an innovative inhibitor of salt-inducible kinase 2 (SIK2), effectively reduces SIK2 protein levels through the ubiquitin-proteasome pathway and exhibits synthetic lethal effects with poly ADP-ribose polymerase (PARP) inhibitors in ovarian cancer. However, the role of SIC-19 in triple-negative breast cancer (TNBC) and pancreatic cancer (PC) remains poorly defined. This study aims to investigate whether SIC-19 combined with PARP inhibitors can induce synthetic lethal effects in TNBC and PC.

Targeted cancer therapy has emerged as a promising alternative to conventional chemotherapy, which is often plagued by poor selectivity, off-target effects, and drug resistance. Among the various targeting agents in development, peptides stand out for their unique advantages, including minimal immunogenicity, high tissue penetration, and ease of modification. Their small size, specificity, and flexibility allow them to target cancer cells while minimizing damage to healthy tissue selectively. Peptide-based therapies have shown great potential in enhancing the efficacy of drug delivery, improving tumor imaging, and reducing adverse effects. With cancer responsible for millions of deaths worldwide, the development of peptide-based therapeutics offers new hope in addressing the limitations of current treatments. As detailed studies on different aspects of targeting peptides are crucial for optimizing drug development, this review provides a comprehensive overview of the literature on tumor-targeting peptides, including their structure, sources, modes of action, and their application in cancer therapy-both as standalone agents and in fusion drugs. Additionally, various computational tools for peptide-based tumor-targeting drug design and validation are explored. The promising results from these studies highlight peptides as ideal candidates for targeted cancer therapies, offering valuable insights for researchers and accelerating the discovery of novel anti-tumor peptide base drug candidates.

Neuroblastoma (NB) is frequently associated with high-risk pediatric cases that demonstrate limited response to cisplatin, contributing to a poor prognosis. Recent studies have explored the role of tumor cell senescence in increasing sensitivity to this chemotherapy agent. This study aims to identify genes related to cell senescence in children diagnosed with NB, evaluate their influence on cisplatin sensitivity, and investigate potential strategies to enhance the efficacy of chemotherapy.

The increasing incidence of cancers and infectious diseases worldwide presents a significant public health challenge that requires immediate intervention. Our strategy to tackle this issue involves the development of pharmaceutical formulations that combine phytopolyphenols (P), targeted drugs (T), and metal ions (M), collectively referred to as PTM regimens. The diverse pharmacological properties of PTM regimens are hypothesized to effectively reduce the risk factors associated with both cancers and infectious diseases.

There is an urgent need for new therapeutic strategies against aggressive triple-negative breast cancer (TNBC), and drug repurposing offers a promising, time- and cost-effective solution. We previously reported that TGFβ leads to the tumorigenic role of NDRG1 in TNBC. Here, we aimed to identify drugs that mimic the transcriptomic signature after the inhibition of TGFβ-induced NDRG1 and to determine their antitumor properties. The transcriptomic signature was obtained by RNA sequencing after gene silencing of TGFβ-induced NDRG1 expression in TNBC cells. For the drug repositioning study, the transcriptome was further computationally analyzed by using the Connectivity Map tool. Efavirenz, ouabain, and vinburnine were selected as the repurposed drug candidates to evaluate their therapeutic potential in TNBC models as monotherapies and pairwise combinations. We determined that the candidate drugs significantly reduced tumor cell proliferation, cancer stem cells, self-renewal, clonogenic properties, and migration abilities in TNBC cell lines through the blockade of AKT. Importantly, we validated their translational potential in TNBC patient-derived xenograft organoids in combination with docetaxel. After validating that the drugs decreased p-AKT and Ki67, we demonstrated their antitumor activity in combination with docetaxel in organoids. In addition, drugs also showed efficacy in a docetaxel-resistant TNBC model, supporting their potential to overcome chemoresistance. In conclusion, these findings demonstrate the potential of efavirenz, ouabain, and vinburnine as repurposed agents capable of inhibiting TNBC cell proliferation, stemness, and migration. Their synergistic effects with docetaxel in organoid cultures further underscore their translational relevance and highlight a promising strategy for combination therapies to improve TNBC treatment.

Three-dimensional (3D) self-assembly of organoids or tumoroids based on 3D rebuilding environment (3DRE) aims to preserve the biological characteristics of original tumors, but whether the self-assembly process is influenced by 3DREs remains unknown. We here compared the colorectal cancer (CRC) tumoroids cultured using different 3DREs, including dome culture (DG), ultra-low adherence culture without Matrigel(UA) or with Matrigel (UAG), and hanging-drop without Matrigel (HD) and with Matrigel (HDG).

The development of novel therapeutic drugs with enhanced efficacy has gained significant attention in recent years. In this study, we aimed to enhance the radical scavenging and antitumor activities of centaureidin through computationally guided structural modifications. Centaureidin was initially isolated through extensive phytochemical fractionation from Centaurea scoparia. We employed Density Functional Theory (DFT) and multitarget molecular modeling to explore how modifying the carbon-8 (C-8) position influences bond dissociation enthalpies, radical scavenging mechanisms, and the structure-antitumor activity relationships. Guided by computational analysis, we then modified the core skeleton of centaureidin using a facile multicomponent Mannich-type synthesis, resulting in two newly substituted centaureidin analogues. The radical scavenging properties of centaureidin and its analogues CA1 and CA4 were investigated using DPPH and ABTS assays. CA1 and CA4 revealed more potent radical scavenging activities. In addition, both analogues were more effective in inhibiting the proliferation of the MCF-7 cancer cell line. All tested compounds exhibited binding affinity towards caspase-3 and the receptors EGFR, HER2 and VEGFR. In conclusion, structural modification of centaureidin resulted in enhanced antioxidant and cytotoxic activities. This comprehensive approach offers a streamlined and cost-effective pathway for drug design and development, providing valuable insights for researchers in the field of therapeutic drug production.

Polo-like kinase 1 (PLK1) functionally mediates tumorigenesis of pancreatic cancer (PC) and associates with its drug resistance to gemcitabine, but related inhibitor therapies were poorly explored. MLN0905 is a novel small molecule inhibitor targeting PLK1. Here we investigate the therapeutic capacity for gemcitabine-resistant pancreatic cancer and related molecular mechanism of MLN0905.

Oral mucositis (OM), as a common adverse effect in patients with chemotherapies, affects the convalescent quality of life. Currently, an increasing number of mouthwashes have been used to improve the incidence of OM in patients undergoing with radiotherapy and chemotherapy. Most studies are comparisons of two arms or three groups, resulting in the lack of direct comparative trial evidence for all care fluids.Therefore, it is not clear which mouthwash is better for preventing the occurrence of OM in patients. This study compares the preventive effects of13 mouthwashes currently used to treat OM in different countries.

Postoperative osimertinib for EGFR mutant non-small cell lung cancer has become the standard of care. However, its adverse events in clinical practice remain unclear. We report a case of interstitial lung disease and pulmonary embolism occurring simultaneously as adverse events during adjuvant osimertinib treatment.

To assess the efficacy and tolerability of transarterial chemoembolization (TACE) plus immune checkpoint inhibitors (ICIs) plus molecular targeted therapies (MTT) in elderly patients with hepatocellular carcinoma (HCC) (≥ 65 years).