Ginsenoside Rh2 (Rh2) is one of the main bioactive ginsenosides that act as a natural antitumor drug. However, the clinical application of Rh2 is limited by its low solubility in water. In this study, a novel ginsenoside Rh2 pH-sensitive liposome was constructed for targeted liver cancer therapy. Rh2 nanoparticles (NPs) exhibited an acid responsive mode, where cumulative release increased with the decrease in pH value. Rh2 and Rh2 NPs showed a dose-dependent inhibitory effect on Huh7 and MHCC97H cells. Rh2 and Rh2 NPs significantly inhibited tumor cell proliferation, migration, invasion and epithelial-mesenchymal transition, and promoted cell apoptosis and immunogenic cell death. Moreover, compared to Rh2 monomers, the Rh2 NPs exhibited improved antitumor effects in vitro. In vivo antitumor efficacy studies indicated that the Rh2 and Rh2 NPs significantly inhibited tumor growth, thereby decreasing tumor volume and weight at the end of the experiment compared with that in the control mice. Furthermore, Rh2 NPs had a more significant inhibitory effect on tumor growth compared with Rh2 monomers. Rh2 NPs might serve as a novel drug delivery system to enhance the antitumor potentials of Rh2 for effective liver cancer therapy.

Silver nanoparticles (AgNPs) have garnered great attention due to their biocompatibility and environmental safety. However, no prior study has focused on the synthesis, characterization, and biological evaluation of AgNPs prepared with Bingol propolis (PrAgNPs).

Epigenetic changes drive gene expression alterations, contributing to oncogenesis and drug resistance. Lysosomes play a key role in cell signaling and sequestering toxins, including chemotherapeutic agents, which are then expelled through lysosomal exocytosis-a process linked to drug resistance. However, the epigenetic regulation of lysosomal exocytosis is poorly understood. We hypothesize that epigenetic modifier drugs (epidrugs) inhibiting this exocytosis could serve as potential cancer therapeutics. To explore this, we screened more than 150 epidrugs targeting various epigenetic proteins for their combined cytotoxic effects with cisplatin, their impact on lysosomal exocytosis, and lysosomal biogenesis. Two type I PRMT inhibitors, MS023 and GSK3368715, showed synergy with cisplatin, reduced cell viability, and inhibited lysosomal exocytosis without altering lysosomal biogenesis gene expression. RNA-seq analysis revealed differentially expressed genes involved in vesicular trafficking and lysosome dynamics, suggesting novel regulatory mechanisms. These inhibitors also synergized with other lysosome-sequestered drugs, indicating a broader application in overcoming drug resistance. Analysis of patient data further linked lower type I PRMT levels to better responses, highlighting their potential as combination therapy candidates to enhance chemotherapy efficacy and improve cancer survival rates.

Although immune checkpoint inhibitors (ICIs) are efficacious, they often cause immune-related adverse events (irAEs), most commonly cutaneous irAEs (CirAEs). The mechanisms underlying CirAEs remain unclear.

The review highlights the synthesis, coordination behavior, and extensive biological activities of selenosemicarbazones and their metal complexes. Over 110 selenosemicarbazone ligands coordinated with metals such as Cu, Ni, Zn, Pt, and Pd are discussed, showcasing significant structural diversity. These compounds uniquely combine the pharmacophoric semicarbazone moiety with selenium, a redox-active trace element, resulting in enhanced stability, reactivity, and biological performance. Coordinated metal complexes demonstrate potent antibacterial, anticancer, antioxidant, and antiparasitic activities. Mechanistic insights include reactive oxygen species (ROS) generation, metalloenzyme inhibition, and DNA binding. Recent developments in structure-activity relationships and therapeutic targeting are emphasized.

BET inhibitor is a novel strategy in tumor therapy based on targeting epigenetic mechanism. In recent decades, dozens of clinical trials have been conducted to validate the potential efficacy of the first-generation BET inhibitors in refractory cancer and non-cancerous ailments. However, limited efficacy and significant toxicity were observed in clinical trials for treating solid tumors. Here, we proposed a novel inhibitor strategy as well as an effective and low toxicity agent that can effectively kill tumor cells and exhibited low toxicity. A ring-closure scaffold hopping approach and high-precision deep learning models was leveraged to furnish a series of rationally designed carboline derivatives as desired BET inhibitors. These most potent compounds were synthesized by an efficient and facile multistep route. Subsequent evaluations identified a potent BET inhibitor YD-851 and it can effectively inhibit tumor cell proliferation. In addition, YD-851 causes tumor shrinkage and significantly suppresses tumor growth in multiple xenograft solid tumor models. Moreover the results of toxicity texting and pharmacokinetic properties support further development of YD-851. We obtain an effective and low toxicity preclinical candidate for BET inhibitor to treat solid tumors. And the success of our strategy encourages the implementation of similar methods in the drug discovery of other targets.

Homoharringtonine (HHT), a natural product used clinically to treat acute myeloid leukemia (AML) in combination with chemotherapy, induced transient remission in 25 % of unclassified AML patients when administered alone. Recent studies showed that HHT could be combined with targeting agents for AML treatment. However, the rationales of these combinations require further exploration to optimize therapeutic efficacy.

Brusatol (BRU), a compound derived from Brucea javanica, has demonstrated notable antitumour activity across various cancer types. However, its precise mechanisms and functional roles in glioma remain incompletely understood.

Breast cancer is a leading cause of death among women globally, with triple-negative breast cancer (TNBC) being the most aggressive subtype. To develop effective and safe chemotherapeutic drugs, we identified TOP2A as a potential target due to its differential expression between breast cancer and normal tissues. By targeting hydrogen bond-van der Waals sites, we discovered three active amino acid sites in TOP2A (E461, D463, and D543) and designed a β-carboline derivative, DM1, targeting DNA and TOP2A using a molecular generation model, local docking, and optimization. Molecular dynamics simulations showed that DM1 binds effectively to DNA and TOP2A, with its amide linker co-anchoring E461 and D543 alongside Mg2+, while the β-carboline ring interacts with DNA and stabilizes the connection with D463. This binding disrupts Mg2+-mediated ATP stabilization and blocks DNA reconnection. DM1 shows strong antiproliferative activity against 4T1 cells (IC50 = 1.12 ± 0.13 μM), outperforming etoposide (IC50 = 9.37 ± 0.52 μM), and inhibits cell migration. Further experiments demonstrated that DM1 selectively binds to TOP2A, not TOP2B, induces DNA damage, and increases reactive oxygen species (ROS) in TNBC cells. Proteomics analysis confirmed that DM1's mechanism involves nucleosomes, replication forks, and heterochromatin related to the two targets. In a 4T1 xenograft model, DM1 achieves a 71.50 % tumor growth inhibition (TGI) at 20 mg/kg, compared to etoposide's 30.93 % TGI at the same dose. DM1 interacts with DNA and TOP2A to form a stable DM1-TOP2A-DNA ternary complex. This blocks DNA's normal function, induces double-strand breaks, causes ROS accumulation, and triggers apoptosis, thereby inhibiting TNBC progression.

CD44, a cell surface glycoprotein, plays a crucial role in cancer progression by enhancing cell proliferation and resistance to apoptosis. Targeting CD44 with small molecules is a promising cancer therapy strategy. Building on our previous work with the tetrahydroisoquinoline (THIQ) derivative SRT1, we designed and synthesized a series of analogues (SRT2-SRT10) to explore their anticancer potential. Among these, the sulfonate esters SRT5 and SRT6 were the most promising in CD44+ MDA-MB-231 breast cancer cells. They effectively inhibited the HA-CD44 interaction, as demonstrated by binding assays and cell viability studies. In addition, molecular dynamics simulations predict that these esters interact with the same key residues within the CD44-HABD domain as those involved in HA recognition. In CD44+ lung cancer cell lines (A549 and NCI-H23), SRT1 exhibited the strongest antiproliferative activity (EC50 = 0.88 and 0.42 μM, respectively), while SRT5 and SRT6 also showed significant efficacy, particularly in NCI-H23 cells. Interestingly, only SRT1 induced apoptosis, suggesting distinct mechanisms of cell death. Kinase profiling revealed that SRT5 and SRT6 inhibited CD44-associated kinases, particularly SRC, contributing to their anticancer effects. In contrast, SRT1 appeared to act through a kinase-independent pathway. All compounds displayed high selectivity for cancer cells over non-tumoral lung cells. ADME predictions suggested favorable pharmacokinetic properties. Overall, our results underscore the potential of N-benzylTHIQ derivatives, as selective agents for targeted therapy of lung cancer and support further in vivo validation and mechanistic investigations.

We introduce a mathematical model of the cancer-immunity cycle and use it to test several hypotheses regarding the combination, timing, and optimization associated with chemotherapy and immunotherapy dosing schedules in the context of competition and time-dependent selection pressure. A key idea is the value of synchronizing the dosing schedules with the fundamental period of the cancer-immunity cycle. The competitors in the population dynamics evolutionary game are the cancer cells, healthy (normal) cells, and T cells, which conceptually form a nontransitive rock-paper-scissor chain. The chemotherapy and immunotherapy dosing schedules each act as control functions whose timing and magnitudes we synchronize with the fundamental period of the underlying nonlinear dynamical system. With the model, we show among other more detailed results, that chemotherapy and immunotherapy pulse-dosing schedules do not commute; the best duration of the chemotherapy is one-quarter of the cancer-immunity cycle, whereas for immunotherapy it is one-half cycle; immunotherapy dosing should precede chemotherapy dosing and last twice as long. A general conclusion is that optimized timing of the dosing schedules can make up for lower total dose, opening up new possibilities for designing less toxic and more efficacious dosing regimens with drugs currently in use. Obtaining and calibrating more accurate measurements of the cycle-period across patient populations would be an important step in making some of these ideas clinically actionable.

Bendamustine, an alkylating agent used in treating hematological cancers like non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukemia (CLL), has recently garnered attention for its potential in breast cancer therapy. This study explores its anticancer effects and molecular mechanisms in breast cancer cells. MDA-MB-231 cells were exposed to various concentrations of bendamustine (0-50 µM), and cytotoxicity was assessed using Alamar Blue and LDH assays, revealing a dose-dependent reduction in cell viability with an IC50 value of 16.98 μM at 24 h (p < 0.001). Intracellular reactive oxygen species (ROS) were quantified by DCF-DA flow cytometry, showing a significant elevation following treatment (p < 0.01). Downregulation of major antioxidant enzymes (SOD, CAT, GPx1, GST; p < 0.01) and upregulation of TRPC6 (1.8-fold at 10 μM, 2.5-fold at 20 μM; p < 0.01) were detected by qPCR. Markers of apoptosis were evaluated by Annexin V/PI staining, revealing significant increases in both early and late apoptotic cell populations (p < 0.01), and by gene expression analysis showing increased BAX:BCL-2 ratio (1.5-fold at 10 μM, 7.8-fold at 20 μM; p < 0.01). CHOP mRNA, an ER stress-related pro-apoptotic gene, was significantly upregulated (2.5-fold at 20 μM; p < 0.01), supporting activation of the ER stress pathway. The results demonstrated that bendamustine exerted a dose-dependent cytotoxic effect, decreasing cell viability and increasing LDH release. It significantly increased ROS levels and altered the expression of apoptotic genes, promoting apoptosis in breast cancer cells. Furthermore, bendamustine-induced ER stress, shown by upregulated Chop expression, suggests that ER stress plays a role in its anticancer activity. These findings highlight bendamustine as a promising therapeutic agent for breast cancer treatment.

Human epidermal growth factor receptor-2 (HER2) is an essential biomarker in oncology. It is highly expressed in many tumors, especially in breast cancer and gastric cancer, and is associated with the malignant progression of tumors. Trastuzumab is a targeted drug for HER2-positive tumors, which can improve the efficacy of HER2-positive tumors, initiate precise treatment of HER2-positive tumors, and play an essential role in first-line therapy and second-line therapy. However, resistance to Trastuzumab is a limiting factor for its efficacy and a necessary factor for short patient survival and poor prognosis. The resistance mechanism to trastuzumab is complex, and non-coding RNA (ncRNA), a type of RNA that does not encode genes, mediates resistance, and plays important roles in of trastuzumab resistance. In clinical practice, ncRNA can be a biomarker for tumor progression, prognosis, and trastuzumab resistance. This article systematically summarizes the key mechanisms of ncRNA resistance to trastuzumab in HER2-positive tumors and its clinical application potential. Especially in this article, for the first time, ncRNA is integrated to regulate of trastuzumab resistance through epigenetic modification crosstalk, insulin-like growth factor 1 receptor (IGF1R) targets, exosome delivery, and ceRNA network regulation aimed to provide insights and references for basic research, drug development, and biomarker determination of trastuzumab resistance in HER2-positive tumors.

Over the past decade, convolutional neural networks (CNNs) have revolutionized predictive modeling of data containing spatial correlations, specifically excelling at image analysis tasks due to their embedded feature extraction and improved generalization. However, outside of image or sequence data, datasets typically lack the structural correlation needed to exploit the benefits of CNN modeling. This is especially true regarding anticancer drug sensitivity prediction tasks, as the data used is often tabular without any embedded information in the ordering or locations of the features when utilizing data other than DNA or RNA sequences. This chapter provides a computational procedure, REpresentation of Features as Images with NEighborhood Dependencies (REFINED), that maps high-dimensional feature vectors into compact 2D images suitable for CNN-based deep learning. The pairing of REFINED mappings with CNNs enables enhanced predictive performance through reduced model parameterization and improved embedded feature extraction as compared to fully connected alternatives utilizing the high-dimensional feature vectors.

Combination CTLA-4 (ipilimumab) and PD-1 (nivolumab) checkpoint inhibition (dual-ICI) improves survival in patients with advanced melanoma. However, many patients also experience immune-related adverse events (irAE) that require systemic treatment with corticosteroids. Corticosteroids dampen the anti-tumoral response and may impair survival. Here, we investigated the association between irAE and overall survival as well as exposure to corticosteroids and second line immunosuppressants in dual ICI-treated patients with advanced melanoma (n = 205). Patients with irAE (n = 113) had superior OS compared to patients with no irAE (n = 92). The survival benefit persisted after adjusting for immortal time bias. Regarding specific irAE, patients with colitis, hepatitis, rheumatic irAE, hypophysitis, and skin-related irAE had improved OS after adjusting for negative baseline factors. A survival benefit persisted for hypophysitis (p = 0.03) and hepatitis (p = 0.04) after adjusting for immortal time bias, whereas rheumatic (p = 0.05) and skin-related irAE (p = 0.06) where borderline significant. Hepatitis and colitis required higher doses of corticosteroids for longer times and more often second-line immunosuppression compared to other irAE. In conclusion, irAE are associated with superior OS in patients with advanced melanoma treated with dual ICI. Hepatitis and hypophysitis were most strongly associated with better survival outcomes. Studies investigating the mechanisms underlying hepatitis and hypophysitis may identify important response mechanisms.

Pluronic F-127 (PF-127) has low mechanical strength at low concentrations and a high gel-sol transition temperature at high concentrations, which limits its use as a controlled drug-release carrier. To address this issue while preserving the hydrogel's high biocompatibility, we developed a hydrogel system consisting of polydopamine nanoparticles (PDA NPs), agarose, and PF-127 (PDA/APF) in which agarose forms a secondary network and PDA NPs enhance hydrogen bonding in the network, thereby improving the mechanical strength and stability of the hydrogel. This modification prolonged the hydrogel's degradation period to approximately seven days and maintained gel-sol transition temperature at 59.0 °C. We incorporated SN-38-cholesterol NPs into the hydrogel system for sustained chemotherapy. Upon 808 nm near infrared (NIR) irradiation, the hydrogel system behaved as expected by releasing SN-38-cholesterol NPs through subsequent hydrogel degradation induced by the embedded PDA NPs. In vivo studies showed that the hydrogel system effectively inhibited tumor growth in mice following photothermal therapy with NIR light. The use of the PDA/APF hydrogel system is a promising strategy for controlled localized cancer therapy, combining chemotherapy and photothermal therapy for enhanced efficacy.

Immune checkpoint inhibitors (ICIs) are therapy for many malignancies including hepatocellular carcinoma (HCC), yet the impact of HCC on immune-mediated liver injury from checkpoint inhibitors (ILICI) remains poorly understood and no direct comparison exists for hepatotoxicity rates between ICI and sorafenib in HCC.

Mitochondria and lysosomes are key organelles involved in cell survival and death. Mitochondria regulate energy production, reactive oxygen species (ROS) levels, and apoptosis, while lysosomes manage waste degradation and also play a role in cell death through enzyme release when damaged. Cancer cells often contain more active lysosomal enzymes, making them more vulnerable to lysosome-related cell death. Targeting these organelles with photosensitizers (PSs) in photodynamic therapy (PDT) can achieve enhanced anticancer effects. Dual-targeting PSs, especially those that affect both mitochondria and lysosomes, are rare but highly promising. By simultaneously damaging both organelles, such PSs may trigger stronger therapeutic responses. In this study, we present a novel dual-targeting photosensitizer, MCQ-1, which localizes to both mitochondria and lysosomes and serves as an efficient type I PS for cancer cell treatment. Additionally, MCQ-1 demonstrates remarkable antibacterial activity against Gram-positive bacteria, including Staphylococcus aureus (S. aureus) and methicillin-resistant S. aureus (MRSA), under white LED irradiation.

Acute myeloid leukemia (AML) is extremely difficult to cure due to the challenges in accurately targeting it, as it is characterized by rapid progression, high aggressiveness, and high drug resistance. In this study, biomimetic sustained release nanoparticles (PLGA-C-M) were designed and prepared to inhibit the survival and resistance pathways of AML. PLGA-C-M targeted AML cells by wrapping leukemia cell membranes, achieving sustained slow drug release in the blood, and then progressively affecting intracellular Ca2+ signaling by targeting TRPM2 ion channels that were highly expressed in AML in a step-by-step manner. PLGA-C-M can inhibit the growth of AML cells from three aspects: destroying mitochondrial function, reducing autophagy, and overcoming the drug resistance of cancer cells. Biomimetic nanoparticles achieved simultaneous regulation of intracellular ROS and Ca2+ signals to inhibit the growth of leukemia cells and provided ideas for the regulation of ion channel-related signal transduction in AML.

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment landscape for advanced cancers, yet their efficacy remains heterogeneous among patients. Tumor mutation burden (TMB) has been extensively explored as a potential biomarker for predicting ICI response. However, its application is limited by several factors, including inconsistent predictive power across different tumor types and the lack of a clear relationship with overall survival (OS). This study aimed to explore the complex interplay between TMB and the tumor microenvironment (TME) and to identify novel predictive biomarkers that can enhance the precision of ICI therapy across multiple cancer types.