Novel Arf1 Inhibitors Drive Cancer Stem Cell Aging and Potentiate Anti-Tumor Immunity.

The small G protein Arf1 has been identified as playing a selective role in supporting cancer stem cells (CSCs), making it an attractive target for cancer therapy. However, the current Arf1 inhibitors have limited translational potential due to their high toxicity and low specificity. In this study, two new potent small-molecule inhibitors of Arf1, identified as DU101 and DU102, for cancer therapy are introduced. Preclinical tumor models demonstrate that these inhibitors triggered a cascade of aging in CSCs and enhance anti-tumor immunity in mouse cancer and PDX models. Through single-cell sequencing, the remodeling of the tumor immune microenvironment induced by these new Arf1 inhibitors is analyzed and an increase in tumor-associated CD8+ CD4+ double-positive T (DPT) cells is identified. These DPT cells exhibit superior features of active CD8 single-positive T cells and a higher percentage of TCF1+PD-1+, characteristic of stem-like T cells. The frequency of tumor-infiltrating stem-like DPT cells correlates with better disease-free survival (DFS) in cancer patients, indicating that these inhibitors may offer a novel cancer immunotherapy strategy by converting the cold tumor immune microenvironment into a hot one, thus expanding the potential for immunotherapy in cancer patients.

Anti-tumor and anti-metastasis of water-soluble sulfated ß-glucan derivatives from Saccharomyces cerevisiae.

Traditional fungi ß-glucan commonly possesses high molecular weight with poor water solubility, which remains significant challenge in the drug development and medical application. Water-soluble ß-glucan with high molecular weight (dHSCG) of 560 kDa, low molecular weight (dLSCG) of 60 kDa, and sulfated derivative (SCGS) with a molecular weight of 146 kDa and sulfate degree at 2.04 were obtained through well-controlled degradation and sulfated modification from Saccharomyces cerevisiae in this study. The structural characteristics were confirmed as ß-1,3/6-glucan by FT-IR and NMR spectroscopy. Carbohydrate microarrays and surface plasmon resonance revealed distinct and contrasting binding affinities between the natural ß-glucans and sulfated derivatives. SCGS exhibited strong binding to FGF and VEGF, while natural ß-glucan showed no response, suggesting its potential as a novel antitumor agent. Moreover, SCGS significantly inhibited the migration rate of the highly metastatic melanoma (B16F10) cells. The lung metastasis mouse model also demonstrated that SCGS significantly reduced and eliminated the nodules, achieving an inhibition rate of 86.7% in vivo, with a dramatic improvement in IFN-α, TNF-α, and IL-1ß levels. Through analysis of protein content and distribution in lung tissues, the anti-tumor and anti-metastasis mechanism of SCGS involves the regulation of degrading enzymes to protect extracellular matrix (ECM), as well as the reduction of angiogenic factor release. These findings provide a foundation for exploring the potential of SCGS in the development of new anti-tumor and anti-metastasis drugs and open up a new field in cancer research.

Ginseng polysaccharide promotes the apoptosis of colon cancer cells via activating the NLRP3 inflammasome.

BACKGROUND: Ginseng polysaccharide (GPS) is an ingredient of ginseng with documented anti-tumor properties. However, its effect on colon cancer and the underlying molecular mechanisms have not been investigated clearly. METHODS: Cell viability of HT29 and CT26 cells treated with different concentrations of GPS was assessed using the Cell Counting Kit-8 (CCK-8) assay. Western blot assay was used to detect the expression of apoptotic proteins, while the mRNA levels were assessed by real-time quantitative polymerase chain reaction (RT-qPCR). Transwell migration assays were used to examine the migration and invasion of cells. RESULTS: The results revealed that GPS effectively suppressed the proliferation of HT29 and CT26 cells. We demonstrated an upregulation of apoptotic proteins in GPS-treated cells, including Bax, cleaved Caspase-3, and p-p53. GPS treatment also increased the mRNA levels of cytochrome C and Bax. Furthermore, the results showed that GPS treatment concurrently promoted the activation of nucleotide-binding domain leucine-rich family pyrin-containing 3 (NLRP3) inflammasome. Transwell migration assays showed that GPS inhibited the migratory and invasive abilities of colon cancer cells. As expected, inhibition of NLRP3 expression using INF39 attenuated the inhibitory effect of GPS on migration and invasion. Upon NLRP3 inhibition, GPS-induced apoptosis was dramatically alleviated, accompanied by a reduction in the expression of apoptotic proteins. CONCLUSION: In conclusion, this research provides compelling evidence that the GPS-induced NLRP3 signaling pathway plays a pivotal role in apoptosis of colon cells, suggesting potential clinical implications for the therapeutic intervention of colon cancer. Thus, GPS might be a promising anti-tumor drug for the treatment of colorectal cancer.

FN-1501 Inhibits Diffuse Large B-Cell Lymphoma Tumor Growth by Inducing Cell Cycle Arrest And Apoptosis.

BACKGROUND: Due to its high degree of aggressiveness, diffuse large B-cell lymphoma (DLBCL) presents a treatment challenge because 30% to 50% of patients experience resistance or relapse following standard chemotherapy. FN-1501 is an effective inhibitor of cyclin-dependent kinases and Fms-like receptor tyrosine kinase 3. OBJECTIVE: This study aimed to examine the anti-tumor impact of FN-1501 on DLBCL and clarify its molecular mechanism. METHODS: This study used the cell counting kit-8 assay to evaluate cell proliferation, along with western blotting and flow cytometry to analyze cell cycle progression and apoptosis influenced by FN-1501 in vitro. Afterward, the effectiveness of FN-1501 was evaluated in vivo utilizing the xenograft tumor model. In addition, we identified the potential signaling pathways and performed rescue studies using western blotting and flow cytometry. RESULTS: We found that FN-1501 inhibited cell proliferation and induced cell cycle arrest and apoptosis in DLBCL cells in vitro. Its anti-proliferative effects were shown to be time- and dose-dependent. The effect on cell cycle progression resulted in G1/S phase arrest, and the apoptosis induction was found to be caspase-dependent. FN-1501 treatment also reduced tumor volumes and weights and was associated with a prolonged progressionfree survival in vivo. Mechanistically, the MAPK and PI3K/AKT/mTOR pathways were significantly inhibited by FN-1501. Additional pathway inhibitors examination reinforced that FN-1501 may regulate cell cycle arrest and apoptosis through these pathways. CONCLUSION: FN-1501 shows promising anti-tumor activity against DLBCL in vivo and in vitro, suggesting its potential as a new therapeutic option for patients with refractory or relapsed DLBCL.

Heteroaryl Group Containing Trisubstituted Alkenes: Synthesis and Anti-tumor Activity.

Pancreatobililary cancers are fatal solid tumors that pose a significant threat to human life. It is imperative to investigate novel small molecule active compounds for controlling these cancers. Heterocyclic compounds (e.g. gemcitabine) and multi-substituted alkenes (e.g. resveratrol) are commonly applied in tumor treatment. Researchers have proposed that the synthesis of new trisubstituted alkenes containing heteroaromatic rings by combining these two scaffolds may be a fresh strategy to develop new active molecules. In this study, we utilized alkenyl bromide and heteroaryl boronic acid as substrates, employing Suzuki coupling to generate a series of triarylethylenes featuring nitrogen, oxygen, and sulfur atoms. Through in vitro experiments, the results indicated that some compounds exhibited remarkable anti-tumor efficacy (e.g. IC50[3be, GBC-SD] = 0.13 µM and IC50[3be, PANC-1] = 0.27 µM). The results further demonstrated that the antitumor efficacy of these compounds was dependent on the heteroatom, π-system, skeleton-bonding site, and substituent type.

Loss of histone deubiquitinase Bap1 triggers anti-tumor immunity.

PURPOSE: Immunotherapy using PD-L1 blockade is effective in only a small group of cancer patients, and resistance is common. This emphasizes the importance of understanding the mechanisms of cancer immune evasion and resistance. METHODS: A genome-scale CRISPR-Cas9 screen identified Bap1 as a regulator of PD-L1 expression. To measure tumor size and survival, tumor cells were subcutaneously injected into both syngeneic WT mice and immunocompromised mice. The phenotypic and transcriptional characteristics of Bap1-deleted tumors were examined using flow cytometry, RNA-seq, and CUT&Tag-seq analysis. RESULTS: We found that loss of histone deubiquitinase Bap1 in cancer cells activates a cDC1-CD8+ T cell-dependent anti-tumor immunity. The absence of Bap1 leads to an increase in genes associated with anti-tumor immune response and a decrease in genes related to immune evasion. As a result, the tumor microenvironment becomes inflamed, with more cDC1 cells and effector CD8+ T cells, but fewer neutrophils and regulatory T cells. We also found that the elimination of Bap1-deleted tumors depends on the tumor MHCI molecule and Fas-mediated CD8+ T cell cytotoxicity. Our analysis of TCGA data further supports these findings, showing a reverse correlation between BAP1 expression and mRNA signatures of activated DCs and T-cell cytotoxicity in various human cancers. CONCLUSION: The histone deubiquitinase Bap1 could be used as a biomarker for tumor stratification and as a potential therapeutic target for cancer immunotherapies.

Extracellular vesicles in anti-tumor drug resistance: Mechanisms and therapeutic prospects.

Drug resistance presents a significant challenge to achieving positive clinical outcomes in anti-tumor therapy. Prior research has illuminated reasons behind drug resistance, including increased drug efflux, alterations in drug targets, and abnormal activation of oncogenic pathways. However, there's a need for deeper investigation into the impact of drug-resistant cells on parental tumor cells and intricate crosstalk between tumor cells and the malignant tumor microenvironment (TME). Recent studies on extracellular vesicles (EVs) have provided valuable insights. EVs are membrane-bound particles secreted by all cells, mediating cell-to-cell communication. They contain functional cargoes like DNA, RNA, lipids, proteins, and metabolites from mother cells, delivered to other cells. Notably, EVs are increasingly recognized as regulators in the resistance to anti-cancer drugs. This review aims to summarize the mechanisms of EV-mediated anti-tumor drug resistance, covering therapeutic approaches like chemotherapy, targeted therapy, immunotherapy and even radiotherapy. Detecting EV-based biomarkers to predict drug resistance assists in bypassing anti-tumor drug resistance. Additionally, targeted inhibition of EV biogenesis and secretion emerges as a promising approach to counter drug resistance. We highlight the importance of conducting in-depth mechanistic research on EVs, their cargoes, and functional approaches specifically focusing on EV subpopulations. These efforts will significantly advance the development of strategies to overcome drug resistance in anti-tumor therapy.

Small molecule inhibitors as adjuvants in cancer immunotherapy: enhancing efficacy and overcoming resistance.

Adjuvant therapy is essential in cancer treatment to enhance primary treatment effectiveness, reduce adverse effects, and prevent recurrence. Small molecule inhibitors as adjuvants in cancer immunotherapy aim to harness their immunomodulatory properties to optimize treatment outcomes. By modulating the tumor microenvironment, enhancing immune cell function, and increasing tumor sensitivity to immunotherapy, small molecule inhibitors have the potential to improve patient responses. This review discusses the evolving use of small molecule inhibitors as adjuvants in cancer treatment, highlighting their role in enhancing the efficacy of immunotherapy and the opportunities for advancing cancer therapies in the future.

Reprogramming the immunosuppressive tumor microenvironment through nanomedicine: an immunometabolism perspective.

Increasing evidence indicates that immunotherapy is hindered by a hostile tumor microenvironment (TME) featured with deprivation of critical nutrients and pooling of immunosuppressive metabolites. Tumor cells and immunosuppressive cells outcompete immune effector cells for essential nutrients. Meanwhile, a wide range of tumor cell-derived toxic metabolites exerts negative impacts on anti-tumor immune response, diminishing the efficacy of immunotherapy. Nanomedicine with excellent targetability offers a novel approach to improving cancer immunotherapy via metabolically reprogramming the immunosuppressive TME. Herein, we review recent strategies of enhancing immunotherapeutic effects through rewiring tumor metabolism via nanomedicine. Attention is drawn on immunometabolic tactics for immune cells and stromal cells in the TME via nanomedicine. Additionally, we discuss future directions of developing metabolism-regulating nanomedicine for precise and efficacious cancer immunotherapy.

Iridium(III) Photosensitizers Induce Simultaneous Pyroptosis and Ferroptosis for Multi-Network Synergistic Tumor Immunotherapy.

The integration of pyroptosis and ferroptosis hybrid cell death induction to augment immune activation represents a promising avenue for anti-tumor treatment, but there is a lack of research. Herein, we developed two iridium(III)-triphenylamine photosensitizers, IrC and IrF, with the capacity to disrupt redox balance and induce photo-driven cascade damage to DNA and Kelch-like ECH-associated protein 1 (KEAP1). The activation of the absent in melanoma 2 (AIM2)-related cytoplasmic nucleic acid-sensing pathway, triggered by damaged DNA, leads to the induction of gasdermin D (GSDMD)-mediated pyroptosis. Simultaneously, iron homeostasis, regulated by the KEAP1/nuclear factor erythroid 2-related factor 2 (NRF2)/heme oxygenase 1 (HO-1) pathway, serves as a pivotal bridge, facilitating not only the induction of gasdermin E (GSDME)-mediated non-canonical pyroptosis, but also ferroptosis in synergy with glutathione peroxidase 4 (GPX4) depletion. The collaborative action of pyroptosis and ferroptosis generates a synergistic effect that elicits immunogenic cell death, stimulates a robust immune response and effectively inhibits tumor growth in vivo. Our work introduces the first metal-based small molecule dual-inducers of pyroptosis and ferroptosis for potent cancer immunotherapy, and highlights the significance of iron homeostasis as a vital hub connecting synergistic effects of pyroptosis and ferroptosis.

Effect of the presence of berberine/curcumin on the binding of limonin to human serum albumin and antitumor activity in vitro.

The competition among drugs for binding to plasma proteins is regarded as a pharmacokinetic drug interaction. Competition between antitumor agents and other drugs for plasma protein binding can alter the free concentration of the drug, potentially impacting its efficacy and increasing the risk of toxic side effects. Through a range of spectroscopic techniques, this study examined the interaction between limonin and human serum albumin (HSA) in the context of berberine (Ber) and curcumin (Cur) under physiological conditions to clarify the binding mechanisms of binary and ternary systems at the molecular level. As demonstrated by fluorescence quenching experiments, Static quenching was identified as the mechanism of interaction between HSA and limonin. The results of site competition experiments indicated that the binding site between limonin and HSA was site I, a result further supported by molecular docking simulations. Through the use of thermodynamic data calculations, it was determined that limonin forms a stable complex with HSA by establishing hydrogen bonds and van der Waals forces. Circular dichroism (CD) spectroscopy, three-dimensional (3D) fluorescence spectroscopy, and synchronous fluorescence spectroscopy (SFS) employed to validate the notion that limonin perturbed the microenvironment of amino acids and induced conformational changes in HSA. What's more, the presence of Ber or Cur was found to have further modified the alterations observed in the interaction between the original HSA-limonin binary system. In vitro cellular experiments showed that interaction with HSA reduced the antitumor activity of limonin. In contrast, adding Ber or Cur increased the inhibition rate of tumor cells. The coexistence of both Ber and Cur significantly diminished limonin's binding affinity to HSA. The current investigation enhances comprehension regarding the binding characteristics and interaction mechanisms involving limonin, Ber, Cur, and HSA. It explores the potential of HSA as a versatile drug carrier and furnishes theoretical underpinnings for co-administrative strategies.

Recent advances in biomaterials based near-infrared mild photothermal therapy for biomedical application: A review.

Mild photothermal therapy (MPTT) generates heat therapeutic effect at the temperature below 45 °C under near-infrared (NIR) irradiation, which has the advantages of controllable treatment efficacy, lower hyperthermia temperatures, reduced dosage, and minimized damage to surrounding tissues. Despite significant progress has been achieved in MPTT, it remains primarily in the stage of basic and clinical research and has not yet seen widespread clinical adoption. Herein, a comprehensive overview of the recent NIR MPTT development was provided, aiming to emphasize the mechanism and obstacles, summarize the used photothermal agents, and introduce various biomedical applications such as anti-tumor, wound healing, and vascular disease treatment. The challenges of MPTT were proposed with potential solutions, and the future development direction in MPTT was outlooked to enhance the prospects for clinical translation.

Clinical and molecular correlates of tumor aneuploidy in metastatic non-small cell lung cancer.

Recent studies have linked elevated tumor aneuploidy to anti-tumor immune suppression and adverse survival following immunotherapy. Herein, we provide supportive evidence for tumor aneuploidy as a biomarker of response to immunotherapy in patients with non-small cell lung cancer (NSCLC). We identify a dose-response relationship between aneuploidy score and patient outcomes. In two independent NSCLC cohorts (n = 659 patients), we demonstrate a novel association between elevated aneuploidy and non-smoking-associated oncogenic driver mutations. Lastly, we report enrichment of TERT amplification and immune-suppressive phenotypes of highly aneuploid NSCLC. Taken together, our findings emphasize a potentially critical role for tumor aneuploidy in guiding immunotherapy treatment strategies.

Structural characteristics and anti-tumor activity of alcohol-precipitated polysaccharides from Cordyceps militaris under different ethanol concentrations.

Six Cordyceps militaris polysaccharides (named CMP-1, CMP-2, CMP-3, CMP-4, CMP-9, and CMP-A) were obtained by fractional alcohol precipitation. The experimental results showed that the six Cordyceps militaris polysaccharides had similar chemical composition and spectral features, and different molecular weights, monosaccharide compositions and anti-tumor activities. Purification of CMP-9 yielded the small molecule polysaccharide LMW-CMP (3.06 kDa). Structural experiments showed that LMW-CMP is an α-glucan with (1 â†’ 4)-α-D-Glcp as the main chain and a glucose branched chain attached at the O-6 position. The results of cell experiments showed that LMW-CMP could effectively inhibit the growth and proliferation of HepG2 cells, activate the downstream NF-κB signaling pathway through the MAPK pathway to induce apoptosis of HepG2 cells, and block apoptosis at the G1 phase. Animal experiments showed that LMW-CMP inhibited the proliferation of tumor cells in H22 tumor-bearing mice by improving the state of immune organs, increasing the activity of immune cells and cytokine levels in the body, and regulating the distribution of lymphocyte subpopulations, with a tumor inhibition rate of 45.70 % (200 mg/kg).

Unlocking the intricacies: Exploring the complex interplay between platelets and ovarian cancer.

Ovarian cancer, an aggressive malignancy of the female reproductive tract, is frequently linked to an elevated risk of thrombotic events. This association is manifested by a pronounced rise in platelet counts and activation levels. Current research firmly supports the pivotal role of platelets in the oncogenic processes of ovarian cancer, influencing tumor cell proliferation and metastasis. Platelets influence these processes through direct interactions with tumor cells or by secreting cytokines and growth factors that enhance tumor growth, angiogenesis, and metastasis. This review aims to thoroughly dissect the interactions between platelets and ovarian cancer cells, emphasizing their combined role in tumor progression and associated thrombotic events. Additionally, it summarizes therapeutic strategies targeting platelet-cancer interface which show significant promise. Such approaches could not only be effective in managing the primary ovarian tumor but also play a pivotal role in preventing metastasis and attenuating thrombotic complications associated with ovarian cancer.

The cytokine Meteorin-like inhibits anti-tumor CD8+ T cell responses by disrupting mitochondrial function.

Tumor-infiltrating lymphocyte (TIL) hypofunction contributes to the progression of advanced cancers and is a frequent target of immunotherapy. Emerging evidence indicates that metabolic insufficiency drives T cell hypofunction during tonic stimulation, but the signals that initiate metabolic reprogramming in this context are largely unknown. Here, we found that Meteorin-like (METRNL), a metabolically active cytokine secreted by immune cells in the tumor microenvironment (TME), induced bioenergetic failure of CD8+ T cells. METRNL was secreted by CD8+ T cells during repeated stimulation and acted via both autocrine and paracrine signaling. Mechanistically, METRNL increased E2F-peroxisome proliferator-activated receptor delta (PPARδ) activity, causing mitochondrial depolarization and decreased oxidative phosphorylation, which triggered a compensatory bioenergetic shift to glycolysis. Metrnl ablation or downregulation improved the metabolic fitness of CD8+ T cells and enhanced tumor control in several tumor models, demonstrating the translational potential of targeting the METRNL-E2F-PPARδ pathway to support bioenergetic fitness of CD8+ TILs.

Anti-tumor effect of antibody-drug conjugate targeting cell adhesion molecule 1 on GIST cells representing small intestinal GIST.

Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the alimentary tract. The prognosis depends on the primary site, and small intestinal GISTs have a worse prognosis than gastric GISTs. Molecularly targeted drugs to inhibit tyrosine kinase activity of KIT were used for unresectable or recurrent GISTs. However, secondary resistance to the drugs is often acquired, and treatments based on other mechanisms are needed. Previously, we reported that cell adhesion molecule 1 (CADM1) was highly expressed in most of small intestinal GISTs but not in most of gastric GISTs. In the present study, we examined whether the antibody-drug conjugate (ADC) with anti-CADM1 antibody and monomethyl auristatin E (anti-CAD-ADC) shows anti-tumor effect on CADM1-expressing human GIST cells. The ADC adhibited in this study was previously used for CADM1-expressing human mesothelioma cells and showed anti-tumor effect for them in vitro. GIST-T1 cell line of gastric origin which scarcely expresses CADM1 and GIST-T1 cells transfected with CADM1 cDNA (GIST-T1-CAD cells) which highly expresses CADM1 and represents small intestinal GIST were used. In vitro, anti-CAD-ADC showed remarkable cytotoxic activity on GIST-T1-CAD cells, but control ADC did not. Both anti-CAD-ADC and control ADC did not show anti-tumor effect on original GIST-T1 cells. When GIST-T1-CAD cells were subcutaneously injected to the nude mice, intravenous administration of anti-CAD-ADC showed inhibitory effect for tumor enlargement. Tumor of GIST-T1 cells grew even after anti-CAD-ADC injection. When GIST-T1-CAD cells were injected into peritoneal cavity of the SCID mice, intraperitoneal administration of anti-CAD-ADC showed reduction of the peritoneal tumor. On the other hand, peritoneal tumor grew after control ADC administration. Tissue and organ damage due to administration of anti-CAD-ADC was not apparent by macroscopic and histological examinations in mice. These results indicate that anti-CAD-ADC could have apparent anti-tumor effect on CADM1-expressing human GIST cells both in in vitro and in vivo mouse models.

Synthesis of Isatin-derived Heterocycles with Promising Anticancer Activities.

Isatin or 1H-indole-2,3-dione skeleton has been playing a significant role in drug de-sign and development. Isatin itself and many of its derivatives are widely distributed in naturally occurring bioactive compounds. Various synthetic isatin derivatives were found to possess a broad range of significant pharmacological efficacies especially anti-cancer activity against a wide variety of cancer cell lines. Interestingly, on a few occasions, some isatin-derived scaffolds were reported as more potent than the tested reputed drug molecules. As a result, isatin-derived compounds have been gaining significant attention in cancer-based drug developments. In this re-view, we have summarized literature reported during the last two decades related to the synthesis of structurally diverse isatin-derived scaffolds with promising anti-cancer activities.

Study on the sensitizing effect of SM-1 combined with irradiation on head and neck squamous cell carcinoma.

PURPOSE: Head and neck squamous cell carcinoma (HNSCC) is globally prevalent with high recurrence, low survival rate, and poor quality of life for patients. Derived from PAC-1, SM-1 can activate procaspase-3 and induce apoptosis in cancer cells to exert anti-tumor effects. However, the inhibitory effect of SM-1 on HNSCC after combination with radiation are unclear. This study aims to investigate the radiosensitizing effect of SM-1 on HNSCC in vitro and in vivo. METHODS: MTT method was used to detect the effect of SM-1 on the viability of HNSCC cell lines (HONE1, HSC-2, and CAL27). The effects of SM-1 combined with radiation on the survival index of HONE1, HSC-2, and CAL27 cell lines were determined by colony formation assay. Flow cytometry was used to investigate the effects of SM-1 and radiation combination on cell apoptosis and cell cycle, and western blot experiments were performed to detect the expression of apoptosis and cell cycle-related proteins. Finally, a xenograft tumor model of CAL27 was established to evaluate the anti-tumor effect of SM-1 combined with radiation in vivo. RESULTS: In vitro, SM-1 effectively inhibited the activity of HNSCC cell lines HONE1, HSC-2, and CAL27 cells, and synergistically showed anti-proliferation activity during combined irradiation. Meanwhile, anti-tumor effect of SM-1 on HNSCC was higher than that of Debio1143, and the radiosensitivity of cells was greatly increased. Flow cytometry and western blot analysis showed that SM-1 induced G2/M phase arrest of head and neck squamous cell carcinoma cells via inhibiting the expression of CyclinB1 and CDC2. Moreover, SM-1 activated caspase-3 activity and up-regulated the cleaved form of PARP1 to induce cell apoptosis. In vivo, SM-1 combined irradiation showed a good anti-tumor effect. CONCLUSION: SM-1 enhances HNSCC cell radiation sensitivity in vitro and in vivo, supporting its potential as a radiosensitizer for clinical trials in combination with radiotherapy.

Strategies for the development of stimuli-responsive small molecule prodrugs for cancer treatment.

Approved anticancer drugs typically face challenges due to their narrow therapeutic window, primarily because of high systemic toxicity and limited selectivity for tumors. Prodrugs are initially inactive drug molecules designed to undergo specific chemical modifications. These modifications render the drugs inactive until they encounter specific conditions or biomarkers in vivo, at which point they are converted into active drug molecules. This thoughtful design significantly improves the efficacy of anticancer drug delivery by enhancing tumor specificity and minimizing off-target effects. Recent advancements in prodrug design have focused on integrating these strategies with delivery systems like liposomes, micelles, and polymerosomes to further improve targeting and reduce side effects. This review outlines strategies for designing stimuli-responsive small molecule prodrugs focused on cancer treatment, emphasizing their chemical structures and the mechanisms controlling drug release. By providing a comprehensive overview, we aim to highlight the potential of these innovative approaches to revolutionize cancer therapy.