Prodrugs of paclitaxel improve in situ photo-vaccination.

Photodynamic therapy (PDT) effectively kills cancer cells and initiates immune responses that promote anticancer effects locally and systemically. Primarily developed for local and regional cancers, the potential of PDT for systemic antitumor effects [in situ photo-vaccination (ISPV)] remains underexplored. This study investigates: (1) the comparative effectiveness of paclitaxel (PTX) prodrug [Pc-(L-PTX)2] for PDT and site-specific PTX effects versus its pseudo-prodrug [Pc-(NCL-PTX)2] for PDT combined with checkpoint inhibitors; (2) mechanisms driving systemic antitumor effects; and (3) the prophylactic impact on preventing cancer recurrence. A bilateral tumor model was established in BALB/c mice through subcutaneous injection of CT26 cells. Mice received the PTX prodrug (0.5 µmole kg-1, i.v.), and tumors were treated with a 690-nm laser (75 mW cm-2 for 30 min, drug-light interval 0.5 h, light does 135 J cm-1), followed by anti-CTLA-4 (100 µg dose-1, i.p.) on days 1, 4, and 7. Notable enhancement in both local and systemic antitumor effectiveness was observed with [Pc-(L-PTX)2] compared to [Pc-(NCL-PTX)2] with checkpoint inhibitor. Immune cell depletion and immunohistochemistry confirmed neutrophils and CD8+ T cells are effectors for systemic antitumor effects. Treatment-induced immune memory resisted newly rechallenged CT26, showcasing prophylactic benefits. ISPV with a PTX prodrug and anti-CTLA-4 is a promising approach for treating metastatic cancers and preventing recurrence.

Antitumor effects of intracranial injection of B7-H3-targeted Car-T and Car-Nk cells in a patient-derived glioblastoma xenograft model.

BACKGROUND: Glioblastoma multiforme (GBM) is the most lethal primary brain tumor for which novel therapies are needed. Recently, chimeric antigen receptor (CAR) T cell therapy has been shown to be effective against GBM, but it is a personalized medicine and requires high cost and long time for the cell production. CAR-transduced natural killer (NK) cells can be used for "off-the-shelf" cellular immunotherapy because they do not induce graft-versus-host disease. Therefore, we aimed to analyze the anti-GBM effect of CAR-T or NK cells targeting B7-H3, which is known to be highly expressed in GBM. METHODS: CAR-T cells targeting B7-H3 were generated using previously reported anti-B7-H3 scFv sequences. Cord blood (CB)-derived NK cells transduced with the B7-H3 CAR were also generated. Their anti-GBM effect was analyzed in vitro. The antitumor effect of intracranial injection of the B7-H3 CAR-T or NK cells was investigated in an in vivo xenograft model with patient-derived GBM cells. RESULTS: Both B7-H3 CAR-T cells and CAR-NK cells exhibited marked cytotoxicity against patient-derived GBM cells in vitro. Furthermore, intracranial injection of CAR-T cells and CAR-NK cells targeting B7-H3 resulted in a significant antitumor effect against patient-derived GBM xenografts. CONCLUSION: Not only CAR-T cells but also CB-derived CAR-NK cells targeting B7-H3 may have the potential to eliminate GBM cells.

Identification of GPNMB in endometrial cancer based on pan-cancer analysis and in vitro validation.

BACKGROUND: GPNMB is a type I transmembrane protein, and emerging evidence supports the relationship between GPNMB and cancers. OBJECTIVE: Through a comprehensive pan-cancer analysis, we examined the expression levels, prognostic significance, and mutation profiles of GPNMB in different cancer types. Subsequently, utilizing in vitro experiments, we elucidated the impact of GPNMB in endometrial cancer (EC). METHODS: TIMER2, GEPIA2, UALCAN and cBioPortal were used to analyze the expression pattern, prognostic values, and mutation status of GPNMB. HEC-1B and Ishikawa cells were used to conduct in vitro analyses of GPNMB overexpression. GeneMANIA and TIMER2 were used to evaluate the potential functions and correlations between GPNMB expression and tumor-infiltrating immune cells in EC. RESULTS: GPNMB was found to be highly expressed in multiple cancers, where it was associated with poor prognosis. Additionally, GPNMB was downregulated at both mRNA and protein levels in EC. Overexpression of GPNMB inhibited the proliferation, migration, and invasion of HEC-1B and Ishikawa cells. Functional analysis showed that GPNMB was enriched in pathways associated with regulation of plasma lipoprotein particle levels. The expression of GPNMB was positively connected with B cell, CD8+ T cell, CD4+ T cell, Macrophage, Neutrophil, and Dendritic cell levels. CONCLUSION: Through pan-cancer analysis, we identified the antitumor effect of GPNMB in EC and predicted the potential mechanisms between GPNMB expression and EC.

In Vitro Cytotoxic Potential and In Vivo Antitumor Effects of NOS/PDK-Inhibitor T1084.

Previously, we showed the antitumor activity of the new NOS/PDK inhibitor T1084 (1-isobutanoyl-2-isopropylisothiourea dichloroacetate). The present study included an assessment of in vitro cytotoxicity against human malignant and normal cells according to the MTT-test and in vivo antitumor effects in solid tumor models in comparison with precursor compounds T1023 (NOS inhibitor; 1-isobutanoyl-2-isopropylisothiourea hydrobromide) and Na-DCA (PDK inhibitor; sodium dichloroacetate), using morphological, histological, and immunohistochemical methods. The effects of T1084 and T1023 on the in vitro survival of normal (MRC-5) and most malignant cells (A375, MFC-7, K562, OAW42, and PC-3) were similar and quantitatively equal. At the same time, melanoma A375 cells showed 2-2.5 times higher sensitivity (IC50: 0.39-0.41 mM) to the cytotoxicity of T1023 and T1084 than other cells. And only HeLa cells showed significantly higher sensitivity to the cytotoxicity of T1084 compared to T1023 (IC50: 0.54 ± 0.03 and 0.81 ± 0.02 mM). Comparative studies of the in vivo antitumor effects of Na-DCA, T1023, and T1084 on CC-5 cervical cancer and B-16 melanoma in mice were conducted with subchronic daily i.p. administration of these agents at an equimolar dose of 0.22 mmol/kg (33.6, 60.0, and 70.7 mg/kg, respectively). Cervical cancer CC-5 fairly quickly evaded the effects of both Na-DCA and T1023. So, from the end of the first week of Na-DCA or T1023 treatment, the tumor growth inhibition (TGI) began to decrease from 40% to an insignificant level by the end of the observation. In contrast, in two independent experiments, CC-5 showed consistently high sensitivity to the action of T1084: a significant antitumor effect with high TGI (43-58%) was registered throughout the observation, without any signs of neoplasia adaptation. The effect of precursor compounds on melanoma B-16 was either minimal (for Na-DCA) or moderate (for T1023) with TGI only 33%, which subsequently decreased by the end of the experiment. In contrast, the effect of T1084 on B-16 was qualitatively more pronounced and steadily increasing; it was accompanied by a 3-fold expansion of necrosis and dystrophy areas, a decrease in proliferation, and increased apoptosis of tumor cells. Morphologically, the T1084 effect was 2-fold superior to the effects of T1023-the TGI index reached 59-62%. This study suggests that the antitumor effects of T1084 develop through the interaction of NOS-dependent and PDK-dependent pathophysiological effects of this NOS/PDK inhibitor. The NOS inhibitory activity of T1084 exerts an anti-angiogenic effect on neoplasia. At the same time, the PDK inhibitory activity of T1084 enhances the cytotoxicity of induced intratumoral hypoxia and suppresses the development of neoplasia adaptation to anti-angiogenic stress. Such properties allow T1084 to overcome tumor resistance and realize a stable synergistic antitumor effect.

Ribavirin in Modern Antitumor Therapy: Prospects for Intranasal Administration.

Ribavirin has been used as an antiviral agent to treat a variety of viral infections since the 1970s. Over the past few decades, studies have been conducted on the pharmacology of ribavirin, and the possibility of its use in new indications has been explored. According to the results of a number of studies, ribavirin efficacy in the therapy of malignant neoplasms of various genesis has been proven. Furthermore, due to the complexity of brain tumor therapy using surgical methods, targeted delivery of ribavirin to the brain becomes a promising alternative to existing treatment methods. Targeting of active pharmaceutical ingredient (API) to the brain tumor is achieved by intranasal drug delivery via a Nose-to-Brain mechanism. In addition, using this delivery mechanism, it is possible to reach the brain while bypassing the blood-brain barrier (BBB), thus avoiding the effects of the first passage through the liver. Despite the significant advantages of the method, there are limiting factors to its application - mucociliary clearance, which aims to remove foreign bodies from the surface of the nasal mucosa. In situ, systems are able to reduce the intensity of interfering factors on API and allow the achievement of maximum bioavailability during intranasal administration.

Anti-HER2 Cancer-Specific mAb, H2Mab-250-hG1, Possesses Higher Complement-Dependent Cytotoxicity than Trastuzumab.

Cancer-specific monoclonal antibodies (CasMabs) that recognize cancer-specific antigens with in vivo antitumor efficacy are innovative therapeutic strategies for minimizing adverse effects. We previously established a cancer-specific anti-human epidermal growth factor receptor 2 (HER2) monoclonal antibody (mAb), H2Mab-250/H2CasMab-2. In flow cytometry and immunohistochemistry, H2Mab-250 reacted with HER2-positive breast cancer cells but did not show reactivity to normal epithelial cells. In contrast, a clinically approved anti-HER2 mAb, trastuzumab, strongly recognizes both breast cancer and normal epithelial cells in flow cytometry. The human IgG1 version of H2Mab-250 (H2Mab-250-hG1) possesses compatible in vivo antitumor effects against breast cancer xenografts to trastuzumab despite the lower affinity and effector activation than trastuzumab in vitro. This study compared the antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cellular cytotoxicity (CDC) between H2Mab-250-hG1 and trastuzumab. Both H2Mab-250-hG1 and trastuzumab showed ADCC activity against HER2-overexpressed Chinese hamster ovary -K1 and breast cancer cell lines (BT-474 and SK-BR-3) in the presence of human natural killer cells. Some tendency was observed where trastuzumab showed a more significant ADCC effect compared to H2Mab-250-hG1. Importantly, H2Mab-250-hG1 exhibited superior CDC activity in these cells compared to trastuzumab. Similar results were obtained in the mouse IgG2a types of both H2Mab-250 and trastuzumab. These results suggest the different contributions of ADCC and CDC activities to the antitumor effects of H2Mab-250-hG1 and trastuzumab, and indicate a future direction for the clinical development of H2Mab-250-hG1 against HER2-positive tumors.

Preparation, characterization and cytotoxic activity of selenium nanoparticles stabilized with a heteropolysaccharide isolated from Sanghuangporus vaninii residue.

Selenium nanoparticles (SeNPs) possess unique features with excellent bioavailability and bioactivity, but the poor stability limits its application. A combination of polysaccharides and SeNPs is an effective strategy to overcome the limitation. Herein, a heteropolysaccharide (SVL-3) with an average molecular weight of 2.428 × 104 Da was purified from the fruiting body residue of Sanghuangporus vaninii after soaking in sorghum wine, which was composed of fucose, galactose, glucose, fructose and 3-O-methyl-galactose. The main chain of SVL-3 was composed of →6)-α-3-MeO-Galp-(1→, →4)-α-D-Galp-(1→, →2,6)-ß-D-Glcp-(1 â†’ and →3)-α-D-Glcp-(1→, and the branched chain was composed of →4)-α-D-Xylp-(1 â†’ and α-L-Fucp-(1→. For enhancing bioactivity of SVL-3 and stability of SeNPs, SVL-3-functionalized SeNPs (SVL-3-SeNPs) was prepared, which contained 45.31 % polysaccharide and 48.49 % selenium. SVL-3-SeNPs maintained an emphatic stability over 28 days at 4 °C and pH 6-8, and exhibited a higher cytotoxic effect on MCF-7 cells than SVL-3 and SeNPs. The inhibitory effect of SVL-3-SeNPs on the cancer cells may be associated with the mechanisms by inducing S-phase arrest, triggering apoptosis and elevating the protein levels of Cytochrome c, Caspases and cleaved caspases 3 and 9. These results indicated that SeNPs modified by S. vaninii polysaccharides can be utilized as a potential material for targeted antitumor drugs.

Biological Evaluation of Dinuclear Platinum(II) Complexes with Aromatic N-Heterocycles as Bridging Ligands.

The history of effective anti-cancer medications begins with the discovery of cisplatin's anti-cancer properties. Second-generation analogue, carboplatin, with a similar range of effectiveness, made progress in improving these drugs with fewer side effects and better solubility. Renewed interest in platinum-based drugs has been increasing in the past several years. These developments highlight a revitalized enthusiasm and ongoing exploration in platinum chemotherapy based on the series of dinuclear platinum(II) complexes, [{Pt(L)Cl}2(µ-bridging ligand)]2+, which have been synthesized and evaluated for their biological activities. These complexes are designed to target various cancerous conditions, exhibiting promising antitumor, antiproliferative, and apoptosis-inducing activities. The current work aims to shed light on the potential of these complexes as next-generation platinum-based therapies, highlighting their enhanced efficacy and reduced side effects, which could revolutionize the approach to chemotherapy.

Basic Fibroblast Growth Factor Accumulation in Culture Medium Masks the Direct Antitumor Effect of Anti-VEGF Agent Bevacizumab.

The direct antitumor effect of bevacizumab (BEV) has long been debated. Evidence of the direct antitumor activities of drugs are mainly obtained from in vitro experiments, which are greatly affected by experimental conditions. In this study, we evaluated the effect of BEV-containing medium renewal on the results of in vitro cytotoxicity experiments in A549 and U251 cancer cells. We observed starkly different results between the experiments with and without BEV-containing medium renewal. Specifically, BEV inhibited the tumor cell growth in the timely replacement with a BEV-containing medium but promoted tumor cell growth without medium renewal. Meanwhile, compared with the control, a significant basic fibroblast growth factor (bFGF) accumulation in the supernatant was observed in the group without medium renewal but none in that with replaced medium. Furthermore, bFGF neutralization partially reversed the pro-proliferative effect of BEV in the medium non-renewed group, while exogenous bFGF attenuated the tumor cell growth inhibition of BEV in the medium-renewed group. Our data explain the controversy over the direct antitumor effect of BEV in different studies from the perspective of the compensatory autocrine cytokines in tumor cells.

Design, synthesis, and evaluation of antitumor activity of 2-arylmethoxy-4-(2-fluoromethyl-biphenyl-3-ylmethoxy) benzylamine derivatives as PD-1/PD-l1 inhibitors.

A series of novel 2-arylmethoxy-4-(2-fluoromethyl-biphenyl-3-ylmethoxy) benzylamine derivatives was designed, synthesized, and evaluated for their antitumor effects as PD-1/PD-L1 inhibitors both in vitro and in vivo. Firstly, the ability of these compounds to block the PD-1/PD-L1 immune checkpoint was assessed using the homogeneous time-resolved fluorescence (HTRF) assay. Two of the compounds can strongly block the PD-1/PD-L1 interaction, with IC50 values of less than 10 nM, notably, compound HD10 exhibited significant clinical potential by inhibiting the PD-1/PD-L1 interaction with an IC50 value of 3.1 nM. Further microscale thermophoresis (MST) analysis demonstrated that HD10 had strong interaction with PD-L1 protein. Co-crystal structure (2.7 Å) analysis of HD10 in complex with the PD-L1 protein revealed a strong affinity between the compound and the target PD-L1 dimer. This provides a solid theoretical basis for further in vitro and in vivo studies. Next, a typical cell-based experiment demonstrated that HD10 could remarkably prevent the interaction of hPD-1 293 T cells from human recombinant PD-L1 protein, effectively restoring T cell function, and promoting IFN-γ secretion in a dose-dependent manner. Moreover, HD10 was effective in suppressing tumor growth (TGI = 57.31 %) in a PD-1/PD-L1 humanized mouse model without obvious toxicity. Flow cytometry, qPCR, and immunohistochemistry data suggested that HD10 inhibits tumor growth by activating the immune system in vivo. Based on these results, it seems likely that HD10 is a promising clinical candidate that should be further investigated.

Novel Piperazine Derivatives of Vindoline as Anticancer Agents.

A series of novel vindoline-piperazine conjugates were synthesized by coupling 6 N-substituted piperazine pharmacophores at positions 10 and 17 of Vinca alkaloid monomer vindoline through different types of linkers. The in vitro antiproliferative activity of the 17 new conjugates was investigated on 60 human tumor cell lines (NCI60). Nine compounds presented significant antiproliferative effects. The most potent derivatives showed low micromolar growth inhibition (GI50) values against most of the cell lines. Among them, conjugates containing [4-(trifluoromethyl)benzyl]piperazine (23) and 1-bis(4-fluorophenyl)methyl piperazine (25) in position 17 of vindoline were outstanding. The first one was the most effective on the breast cancer MDA-MB-468 cell line (GI50 = 1.00 µM), while the second one was the most effective on the non-small cell lung cancer cell line HOP-92 (GI50 = 1.35 µM). The CellTiter-Glo Luminescent Cell Viability Assay was performed with conjugates 20, 23, and 25 on non-tumor Chinese hamster ovary (CHO) cells to determine the selectivity of the conjugates for cancer cells. These compounds exhibited promising selectivity with estimated half-maximal inhibitory concentration (IC50) values of 2.54 µM, 10.8 µM, and 6.64 µM, respectively. The obtained results may have an impact on the design of novel vindoline-based anticancer compounds.

GuiErBai: a potent inhibitor, exhibiting broadly antitumor effect against cervical cancer in vitro and in vivo.

Introduction: Cervical cancer (CC) ranks as the fourth most prevalent malignant tumor among women worldwide, and is the fourth leading cause of cancer-related mortality. GuiErBai (GEB), a compound preparation developed by our research team, is derived from the ancient Chinese medicine of the Miao nationality and is comprised of podophyllotoxin (PTOX), imperatorin, isoimperatorin, and A. dahurica alkaloids. These individual components have demonstrated notable efficacy in tumor treatment. However, the specific anti-tumor effect of the compound Chinese medicine GEB in the context of CC has yet to be validated. Methods: HeLa and SiHa cell lines were utilized for in vitro experiments and treated with 5 mg/mL and 10 mg/mL GEB concentrations, respectively. The cell cycle changes after GEB treatment were assessed using flow cytometry. Transmission electron microscopy was employed to observe autophagic bodies and apoptotic bodies, while MDC staining evaluated the occurrence of autophagy. CCK-8 was used to observe the effect of GEB on cell proliferation, and Transwell assays assessed cell migration and invasion. Western blotting detected cell cycle and apoptosis-related protein expression, along with the expression level of autophagy-related protein LC3I/II. Changes in ROS and mitochondrial membrane potential in cervical cancer cells following GEB treatment were determined using ROS detection and mitochondrial membrane potential detection kits. For the in vivo experiment, a nude mouse model of cervical cancer transplantation based on HeLa cells was established. Experimental animals were divided into negative control, positive control, high-dose GEB (10 mg/mL), and low-dose GEB (5 mg/mL) groups. Results: In HeLa and SiHa cell lines, the G0/G1 phase of tumor cells significantly decreased (p < 0.001), while the G2/M phase increased notably (p < 0.001) following various GEB treatments. Electron microscopy showed GEB promoted apoptotic body and autophagosome formation in both cell lines. Compared to untreated HeLa and SiHa cells, GEB-treated cells exhibited significantly reduced caspase3 protein expression, and substantially increased autophagy-related protein LC3I/II expression. GEB treatment significantly reduced migration and invasion capabilities in both cell lines (p < 0.001), while ROS content and mitochondrial membrane potential were significantly elevated (p < 0.001). GEB effectively inhibited cervical cancer cell proliferation, with the optimal concentration being 10 mg/mL. A successful nude mouse model of cervical cancer transplantation was established using HeLa cells. Post-GEB treatment, the tumor volume and weight in nude mice significantly decreased (p < 0.001), with diminished expression of CD34, VEGF, and caspase3 proteins in tumor tissues. Discussion: GEB exhibits a robust antitumor effect against cervical cancer, both in vitro and in vivo, in a concentration-dependent manner, by regulating autophagy and apoptosis of tumor cells.

Development of stemness-related signature to optimize prognosis prediction and identify XMD8-85 as a novel therapeutic compound for glioma.

Glioma is a highly invasive and aggressive type of brain cancer with poor treatment response. Stemness-related transcription factors form a regulatory network that sustains the malignant phenotype of gliomas. We conducted an integrated analysis of stemness-related transcription factors using The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) datasets, established the characteristics of stemness-related transcription factors, including Octamer-Binding Protein 4 (OCT4), Meis Homeobox 1 (MEIS1), E2F Transcription Factor 1 (E2F1), Transcription Factor CP2 Like 1 (TFCP2L1), and RUNX Family Transcription Factor 1 (RUNX1). The characteristic of stemness-related transcription factors was identified as an independent prognostic factor for glioma patients. Patients in the high-risk group have a worse prognosis than those in the low-risk group. The glioma microenvironment in the high-risk group exhibited a more active immune status. Single-cell level analysis revealed that stem cell-like cells exhibited stronger intercellular communication than glioma cells. Meanwhile, patients in different risk stratification exhibited varying sensitivities to immunotherapy and small molecule drug therapy. XMD8-85 was more effective in the high-risk group, and its antitumor effects were validated both in vivo and in vitro. Our results indicate that this prognostic feature will assist clinicians in predicting the prognosis of glioma patients, guiding immunotherapy and personalized treatment, as well as the potential clinical application of XMD8-85 in glioma treatment, and helping to develop effective treatment strategies.

Enhanced Efficacy against Drug-Resistant Tumors Enabled by Redox-Responsive Mesoporous-Silica-Nanoparticle-Supported Lipid Bilayers as Targeted Delivery Vehicles.

Multidrug resistance (MDR) is frequently induced after long-term exposure to reduce the therapeutic effect of chemotherapeutic drugs, which is always associated with the overexpression of efflux proteins, such as P-glycoprotein (P-gp). Nano-delivery technology can be used as an efficient strategy to overcome tumor MDR. In this study, mesoporous silica nanoparticles (MSNs) were synthesized and linked with a disulfide bond and then coated with lipid bilayers. The functionalized shell/core delivery systems (HT-LMSNs-SS@DOX) were developed by loading drugs inside the pores of MSNs and conjugating with D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) and hyaluronic acid (HA) on the outer lipid surface. HT-LMSNs-SS and other carriers were characterized and assessed in terms of various characteristics. HT-LMSNs-SS@DOX exhibited a dual pH/reduction responsive drug release. The results also showed that modified LMSNs had good dispersity, biocompatibility, and drug-loading capacity. In vitro experiment results demonstrated that HT-LMSNs-SS were internalized by cells and mainly by clathrin-mediated endocytosis, with higher uptake efficiency than other carriers. Furthermore, HT-LMSNs-SS@DOX could effectively inhibit the expression of P-gp, increase the apoptosis ratios of MCF-7/ADR cells, and arrest cell cycle at the G0/G1 phase, with enhanced ability to induce excessive reactive oxygen species (ROS) production in cells. In tumor-bearing model mice, HT-LMSNs-SS@DOX similarly exhibited the highest inhibition activity against tumor growth, with good biosafety, among all of the treatment groups. Therefore, the nano-delivery systems developed herein achieve enhanced efficacy towards resistant tumors through targeted delivery and redox-responsive drug release, with broad application prospects.

Traditional Chinese Medicine for Cancer Treatment.

In recent years, due to advancements in medical conditions and the development of scientific research, the fundamental research of TCM antitumor treatments has progressed from the cellular level to the molecular and genetic levels. Previous studies have demonstrated the significant role of traditional Chinese medicine (TCM) in antitumor therapy through various mechanisms and pathways. Its mechanism of action is closely associated with cancer biology across different stages. This includes inhibiting tumor cell proliferation, blocking invasion and metastasis to surrounding tissues, inducing tumor cell apoptosis, inhibiting tumor angiogenesis, regulating immune function, maintaining genome stability, preventing mutation, and regulating cell energy metabolism. The use of TCM for eliciting antitumor effects not only has a good therapeutic effect and low side effects, it also provides a solid theoretical basis for clinical treatment and medication. This paper reviews the mechanism of the antitumor effects of TCM based on tumor characteristics. Through our review, we found that TCM not only directly inhibits tumors, but also enhances the body's immunity, thereby indirectly inducing an antitumor effect. This function aligns with the TCM theory of "strengthening the body's resistance to eliminate pathogenic factors". Furthermore, TCM will play a significant role in tumor treatment in clinical settings.

Research progress on the antitumor effects of harmine.

Harmine is a naturally occurring ß-carboline alkaloid originally isolated from Peganum harmala. As a major active component, harmine exhibits a broad spectrum of pharmacological properties, particularly remarkable antitumor effects. Recent mechanistic studies have shown that harmine can inhibit cancer cell proliferation and metastasis through epithelial-to-mesenchymal transition, cell cycle regulation, angiogenesis, and the induction of tumor cell apoptosis. Furthermore, harmine reduces drug resistance when used in combination with chemotherapeutic drugs. Despite its remarkable antitumor activity, the application of harmine is limited by its poor solubility and toxic side effects, particularly neurotoxicity. Novel harmine derivatives have demonstrated strong clinical application prospects, but further validation based on drug activity, acute toxicity, and other aspects is necessary. Here, we present a review of recent research on the action mechanism of harmine in cancer treatment and the development of its derivatives, providing new insights into its potential clinical applications and strategies for mitigating its toxicity while enhancing its efficacy.

Current Trends on the Involvement of Zinc, Copper, and Selenium in the Process of Hepatocarcinogenesis.

Numerous nutritional factors increase the risk of hepatocellular carcinoma (HCC) development. The dysregulation of zinc, copper, and selenium homeostasis is associated with the occurrence of HCC. The impairment of the homeostasis of these essential trace elements results in oxidative stress, DNA damage, cell cycle progression, and angiogenesis, finally leading to hepatocarcinogenesis. These essential trace elements can affect the microenvironment in HCC. The carrier proteins for zinc and copper and selenium-containing enzymes play important roles in the prevention or progression of HCC. These trace elements enhance or alleviate the chemosensitivity of anticancer agents in patients with HCC. The zinc, copper, or selenium may affect the homeostasis of other trace elements with each other. Novel types of cell death including ferropotosis and cupropotosis are also associated with hepatocarcinogenesis. Therapeutic strategies for HCC that target these carrier proteins for zinc and copper or selenium-containing enzymes have been developed in in vitro and in vivo studies. The use of zinc-, copper- or selenium-nanoparticles has been considered as novel therapeutic agents for HCC. These results indicate that zinc, copper, and selenium may become promising therapeutic targets in patients with HCC. The clinical application of these agents is an urgent unmet requirement. This review article highlights the correlation between the dysregulation of the homeostasis of these essential trace elements and the development of HCC and summarizes the current trends on the roles of these essential trace elements in the pathogenesis of hepatocarcinogenesis.

Discovery of sesquiterpene from Youngia japonica with antitumor effect.

Fourteen sesquiterpenes, including one undescribed sesquiterpene lactone, were isolated from Youngia japonica, and their structures were identified by NMR, HRESIMS, ECD and calculated ECD. Cytotoxic activities of all isolates against A549, HeLa, and 4 T1 cell lines were detected by CCK8 assay. Among them, 2 showed obvious cytotoxic activity against A549 cells. Subsequently, the production of ROS, and apoptosis of A549 cells treated with 2 were evaluated. The result showed that 2 distinctly increased the ROS level, and induced the apoptosis of A549 cells. Further anticancer mechanism studies showed that 2 increased the expression of cleaved caspase 3. Taken together, our results demonstrated that 2 might become potential leading compounds for the treatment of lung cancer.

FLASH radiotherapy: A new milestone in the field of cancer radiotherapy.

Radiotherapy plays a pivotal role in the control and eradication of tumors, but it can also induce radiation injury to surrounding normal tissues while targeting tumor cells. In recent years, FLASH-Radiotherapy (FLASH-RT) has emerged as a cutting-edge research focus in the field of radiation therapy. By delivering high radiation doses to the treatment target in an ultra-short time, FLASH-RT produces the FLASH effect, which reduces the toxicity to normal tissues while achieving comparable tumor control efficacy to conventional radiotherapy. This review provides a brief overview of the development history of FLASH-RT and its impact on tumor control. Additionally, it focuses on introducing the protective effects and molecular mechanisms of this technology on various normal tissues, as well as exploring its synergistic effects when combined with other tumor therapies. Importantly, this review discusses the challenges faced in translating FLASH-RT into clinical practice and outlines its promising future applications.

Anti-tumor effect and mechanisms of Timosaponin AIII across diverse cancer progression.

Timosaponin AIII (TAIII), a steroidal saponin derived from Anemarrhena asphodeloides Bunge, has gained attention for its versatile therapeutic properties. While well-established for its anti-inflammatory, antidepressant, and anticoagulant properties, emerging research highlights its potent anti-tumor capabilities. This review synthesizes recent findings on the intricate mechanisms and diverse functions of TAIII in cancer therapy, elucidating its impact on various tumor cells, encompassing the effects of TAIII on critical aspects of cancer progression, including metastasis, apoptosis, and autophagy. Additionally, the shared features of TAIII-induced anti-tumor activities, the factors contributing to the multifaceted anti-cancer activities of TAIII, and an exploration of the advantages and disadvantages associated with the regulation of multiple anti-tumor pathways by TAIII are discussed. Furthermore, the detailed regulation of signaling pathways is delineated and tailored to specific cancer types, providing a comprehensive overview of the potential development of TAIII as a promising anti-tumor agent.