Trojan-horse inspired nanoblaster: X-ray triggered spot attack on radio-resistant cancer through radiodynamic therapy.

Radiotherapy as a mainstay of in-depth cervical cancer (CC) treatment suffers from its radioresistance. Radiodynamic therapy (RDT) effectively reverses radio-resistance by generating reactive oxygen species (ROS) with deep tissue penetration. However, the photosensitizers stimulated by X-ray have high toxicity and energy attenuation. Therefore, X-ray responsive diselenide-bridged mesoporous silica nanoparticles (DMSNs) are designed, loading X-ray-activated photosensitizer acridine orange (AO) for spot blasting RDT like Trojan-horse against radio-resistance cervical cancer (R-CC). DMSNs can encapsulate a large amount of AO, in the tumor microenvironment (TME), which has a high concentration of hydrogen peroxide, X-ray radiation triggers the cleavage of diselenide bonds, leading to the degradation of DMSNs and the consequent release of AO directly at the tumor site. On the one hand, it solves the problems of rapid drug clearance, adverse distribution, and side effects caused by simple AO treatment. On the other hand, it fully utilizes the advantages of highly penetrating X-ray responsive RDT to enhance radiotherapy sensitivity. This approach results in ROS-induced mitochondria damage, inhibition of DNA damage repair, cell cycle arrest and promotion of cancer cell apoptosis in R-CC. The X-ray responsive DMSNs@AO hold considerable potential in overcoming obstacles for advanced RDT in the treatment of R-CC.

Enhancing radiotherapy for melanoma: the promise of high-Z metal nanoparticles in radiosensitization.

Melanoma is a type of skin cancer that can be challenging to treat, especially in advanced stages. Radiotherapy is one of the main treatment modalities for melanoma, but its efficacy can be limited due to the radioresistance of melanoma cells. Recently, there has been growing interest in using high-Z metal nanoparticles (NPs) to enhance the effectiveness of radiotherapy for melanoma. This review provides an overview of the current state of radiotherapy for melanoma and discusses the physical and biological mechanisms of radiosensitization through high-Z metal NPs. Additionally, it summarizes the latest research on using high-Z metal NPs to sensitize melanoma cells to radiation, both in vitro and in vivo. By examining the available evidence, this review aims to shed light on the potential of high-Z metal NPs in improving radiotherapy outcomes for patients with melanoma.

[Box: see text].

Targeted delivery of napabucasin with radiotherapy improves outcomes in diffuse midline glioma.

BACKGROUND: Diffuse midline glioma (DMG) is the most aggressive primary brain tumor in children. All previous studies examining the role of systemic agents have failed to demonstrate a survival benefit; the only standard of care is radiation therapy (RT). Successful implementation of radiosensitization strategies in DMG remains an essential and promising avenue of investigation. We explore the use of Napabucasin, an NAD(P)H quinone dehydrogenase 1 (NQO1)-bioactivatable reactive oxygen species (ROS)-inducer, as a potential therapeutic radiosensitizer in DMG. METHODS: In this study, we conduct in vitro and in vivo assays using patient-derived DMG cultures to elucidate the mechanism of action of Napabucasin and its radiosensitizing properties. As penetration of systemic therapy through the blood-brain barrier (BBB) is a significant limitation to the success of DMG therapies, we explore focused ultrasound (FUS) and convection-enhanced delivery (CED) to overcome the BBB and maximize therapeutic efficacy. RESULTS: Napabucasin is a potent ROS-inducer and radiosensitizer in DMG, and treatment-mediated ROS production and cytotoxicity are dependent on NQO1. In subcutaneous xenograft models, combination therapy with RT improves local control. After optimizing targeted drug delivery using CED in an orthotopic mouse model, we establish the novel feasibility and survival benefit of CED of Napabucasin concurrent with RT. CONCLUSIONS: As nearly all DMG patients will receive RT as part of their treatment course, our validation of the efficacy of radiosensitizing therapy using CED to prolong survival in DMG opens the door for exciting novel studies of alternative radiosensitization strategies in this devastating disease while overcoming limitations of the BBB.

Bifunctional Metal-Organic Framework Synergistically Enhances Radiotherapy and Activates STING for Potent Cancer Radio-Immunotherapy.

The activation of the stimulator of interferon genes (STING) protein by cyclic dinucleotide metabolites plays a critical role in antitumor immunity. However, synthetic STING agonists like 4-(5,6-dimethoxybenzo[b]thiophen-2-yl)-4-oxobutanoic acid (MSA-2) exhibit suboptimal pharmacokinetics and fail to sustain STING activation in tumors for effective antitumor responses. Here, we report the design of MOF/MSA-2, a bifunctional MSA-2 conjugated nanoscale metal-organic framework (MOF) based on Hf6 secondary building units (SBUs) and hexakis(4'-carboxy[1,1'-biphenyl]-4-yl)benzene bridging ligands, for potent cancer radio-immunotherapy. By leveraging the high-Z properties of the Hf6 SBUs, the MOF enhances the therapeutic effect of X-ray radiation and elicits potent immune stimulation in the tumor microenvironment. MOF/MSA-2 further enhances radiotherapeutic effects of X-rays by enabling sustained STING activation and promoting the infiltration and activation of immune cells in the tumors. MOF/MSA-2 plus low-dose X-ray irradiation elicits strong STING activation and potent tumor regression, and when combined with an immune checkpoint inhibitor, effectively suppresses both primary and distant tumors through systemic immune activation.

Enhancing Radiotherapy Sensitivity in Prostate Cancer with Lentinan-Functionalized Selenium Nanoparticles: Mechanistic Insights and Therapeutic Potential.

Radiation therapy is a cornerstone of prostate cancer (PCa) treatment. However, its limited tumor sensitivity and severe side effects restrict its clinical utility. Lentinan-functionalized selenium nanoparticles (LET-SeNPs) have shown promise in enhancing radiotherapy sensitivity and exhibiting antitumor activity. In this study, we investigated the radiotherapy sensitization mechanism of LET-SeNPs in PCa. Our results demonstrate that the combination of LET-SeNPs and X-ray therapy (4 Gy) significantly inhibited the growth and colony formation of PCa cells by inducing apoptosis, surpassing the effects of individual treatments. This combined approach modulated DNA damage through the p53, MAPK (mitogen-activated protein kinase), and AKT pathways. Furthermore, LET-SeNPs increased PC3 cell sensitivity to X-ray-induced apoptosis by downregulating TrxR (Thioredoxin reductase) expression and inducing reactive oxygen species (ROS) overproduction, thereby activating mitochondria-mediated apoptosis signaling pathways. Additionally, LET-SeNPs regulated PARP (poly (ADP-ribose) polymerase) to prevent DNA damage repair. In vivo studies confirmed that the combination treatment inhibited PCa growth by synergistically activating the p53 pathway to induce cell apoptosis. These findings highlight LET-SeNPs' potential as a radiotherapy sensitizer and suggest that combining LET-SeNPs with X-ray therapy could be a promising strategy for clinical application, leveraging selenium-modified nanoparticles' antitumor effects.

Nanoradiosensitizers in glioblastoma treatment: recent advances and future perspectives.

Glioblastoma (GBM), a highly invasive type of brain tumor located within the central nervous system, manifests a median survival time of merely 14.6 months. Radiotherapy kills tumor cells through focused high-energy radiation and has become a crucial treatment strategy for GBM, especially in cases where surgical resection is not viable. However, the presence of radioresistant tumor cells limits its clinical effectiveness. Radioresistance is a key factor of treatment failure, prompting the development of various therapeutic strategies to overcome this challenge. With the rapid development of nanomedicine, nanoradiosensitizers provide a novel approach to enhancing the effectiveness of radiotherapy. In this review, we discuss the reasons behind GBM radio-resistance and the mechanisms of radiotherapy sensitization. Then we summarize the primary types of nanoradiosensitizers and recent progress in their application for the radiosensitization of GBM. Finally, we elucidate the factors influencing their practical implementation, along with the challenges and promising prospects associated with multifunctional nanoradiosensitizers.

[Box: see text].

Targeting proliferating cell nuclear antigen enhances ionizing radiation-induced cytotoxicity in prostate cancer cells.

BACKGROUND: Proliferating cell nuclear antigen (PCNA) is essential for DNA replication and repair, cell growth, and survival. PCNA also enhances androgen receptor (AR) signaling in prostate cancer (PC) cells. We identified a PCNA interaction protein (PIP) box at the N-terminal domain of AR and developed a small peptide PCNA inhibitor R9-AR-PIP containing AR PIP-box. We also identified a series of small molecule PCNA inhibitors (PCNA-Is) that bind directly to PCNA and interrupt PCNA functions. The present study investigated the effects of the PCNA inhibitors on the sensitivity of PC cells to X-ray radiation. METHODS: The effects of targeting PCNA on radio sensitivity of PC cells were investigated in four lines of castration-resistant PC (CRPC) cells with different AR expression statuses. The cells were treated with the PCNA inhibitors and X-ray radiation alone or in combination. The effects of the treatment on expression of AR target genes, DNA damage response, DNA damage, homologous recombination repair (HRR), and cytotoxicity were evaluated. RESULTS: We found that the androgen response element (ARE) occupancy of the DNA damage response gene PARP1 by AR is significantly attenuated by PCNA-I1S or R9-AR-PIP combined with X-ray radiation, while X-ray radiation alone does not enhance the ARE occupancy. PCNA-I1S or R9-AR-PIP alone significantly inhibits occupancy of the AR-occupied regions (AROR) in PRKDC and XRCC2 genes. R9-AR-PIP and PCNA-I1S inhibit expression of AR-Vs target gene cyclin A2 and show the additive effects with radiation in AR-positive CRPC cells. Targeting PCNA by PCNA-I1S and R9-AR-PIP downregulates expression of DNA damage response genes EXO1, Rad54L, Rad51, and/or PARP1 and shows the additive effects with radiation as compared with their respective controls in AR-positive CRPC LNCaP-AI, 22Rv1, and R1-D567 cells, but not in AR-negative PC-3 cells. R9-AR-PIP and PCNA-I1S elevate the levels of phospho-DNA-PKcs(S2056) and γH2AX, indicating DNA damage in response to radiation in AR-positive cells. The HRR is significantly attenuated by PCNA inhibitors PCNA-I1S, R9-AR-PIP, and T2AA in all four CRPC cells examined, and inhibited by Enzalutamide (Enz) only in 22RV1 cells. The cytotoxicity induced by X-ray radiation in androgen-dependent LNCaP cells is enhanced by Enz and a lower concentration of R9-AR-PIP in the colony formation assay. R9-AR-PIP at higher concentration reduces the colony formation and has an additive effect with X-ray radiation in all AR expressing cells, regardless of AR-FL and AR-Vs, but does not significantly alter the colony formation in AR-negative PC-3 cells. PCNA-I1S attenuates colony formation and has an additive effect with ionizing radiation in all four CRPC cells, regardless of AR expression status. CONCLUSION: These data provide a strong rationale for the therapy studies using PCNA-I1S or R9-AR-PIP in combination with X-ray radiation against CRPC tumors in preclinical models.

MnO2@CeOx-GAMP radiosensitizer with oxygen vacancies depended mimicking enzyme-like activities for radiosensitization-mediated STING pathway activation.

Activation of the stimulator of interferon genes (STING) pathway by radiotherapy (RT) has a significant effect on eliciting antitumor immune responses. The generation of hydroxyl radical (·OH) storm and the sensitization of STING-relative catalytic reactions could improve radiosensitization-mediated STING activation. Herein, multi-functional radiosensitizer with oxygen vacancies depended mimicking enzyme-like activities was fabricated to produce more dsDNA which benefits intracellular 2', 3'-cyclic GMP-AMP (cGAMP) generation, together with introducing exogenous cGAMP to activate immune response. MnO2@CeOx nanozymes present enhanced superoxide dismutase (SOD)-like and peroxidase (POD)-like activities due to induced oxygen vacancies accelerate the redox cycles from Ce4+ to Ce3+ via intermetallic charge transfer. CeOx shells not only serve as radiosensitizer, but also provide the conjugation site for AMP/GMP to form MnO2@CeOx-GAMP (MCG). Upon X-ray irradiation, MCG with SOD-like activity facilitates the conversion of superoxide anions generated by Ce-sensitization into H2O2 within tumor microenvironment (TME). The downstream POD-like activity catalyzes the elevated H2O2 into a profusion of ·OH for producing more damage DNA fragments. TME-responsive decomposed MCG could supply exogenous cGAMP, meanwhile the releasing Mn2+ improve the sensitivity of cyclic GMP-AMP synthase to dsDNA for producing more cGAMP, resulting in the promotion of STING pathway activation.

A multifunctional targeted nano-delivery system with radiosensitization and immune activation in glioblastoma.

Glioblastoma (GBM), the most common primary brain malignancy in adults, is notoriously difficult to treat due to several factors: tendency to be radiation resistant, the presence of the blood brain barrier (BBB) which limits drug delivery and immune-privileged status which hampers effective immune responses. Traditionally, high-dose irradiation (8 Gy) is known to effectively enhance anti-tumor immune responses, but its application is limited by the risk of severe brain damage. Currently, conventional dose segmentation (2 Gy) is the standard radiotherapy method, which does not fully exploit the potential of high-dose irradiation for immune activation. The hypothesis of our study posits that instead of directly applying high doses of radiation, which is risky, a strategy could be developed to harness the immune-stimulating benefits of high-dose irradiation indirectly. This involves using nanoparticles to enhance antigen presentation and immune responses in a safer manner. Angiopep-2 (A2) was proved a satisfactory BBB and brain targeting and Dbait is a small molecule that hijack DNA double strand break damage (DSB) repair proteins to make cancer cells more sensitive to radiation. In view of that, the following two nanoparticles were designed to combine immunity of GBM, radiation resistance and BBB innovatively. One is cationic liposome nanoparticle interacting with Dbait (A2-CL/Dbait NPs) for radiosensitization effect; the other is PLGA-PEG-Mal nanoparticle conjugated with OX40 antibody (A2-PLGA-PEG-Mal/anti-OX40 NPs) for tumor-derived protein antigens capture and optimistic immunoregulatory effect of anti-OX40 (which is known to enhance the activation and proliferation T cells). Both types of nanoparticles showed favorable targeting and low toxicity in experimental models. Specifically, the combination of A2-CL/Dbait NPs and A2-PLGA-PEG-Mal/anti-OX40 NPs led to a significant extension in the survival time and a significant tumor shrinkage of mice with GBM. The study demonstrates that combining these innovative nanoparticles with conventional radiotherapy can effectively address key challenges in GBM treatment. It represents a significant step toward more effective and safer therapeutic options for GBM patients.

Enhancement of gold-curcumin nanoparticle mediated radiation response for improved therapy in cervical cancer: a computational approach and predictive pathway analysis.

Radiotherapy is prevalently applied for highly effective cancer therapy while the low specificity of radiation is deleterious to the nearby healthy cells. High-Z-based nanomaterials offer excellent radio-enhancement properties while natural products provide radioprotection. Modulation of the radiotherapeutic index via applying nanomaterials is feasible for effective treatment however, the scenario changes when simultaneous protection of non-cancerous cells is required. Here, we report the modulatory radiotherapeutic effect of curcumin conjugated gold nanoparticles in a single nanoformulation to pave the long-awaited hope of a single combination-based, cell-selective radio enhancer, and protectant for cancer radiotherapy. We have validated the effective radiation dose along with the combination of the radio-nano-modulator by a reverse experimentation statistical model. The concept was supported by different sets of experiments, like quantification of ROS generation, cell cycle monitoring, mitochondrial membrane potential measurement, etc. along with gene expression study, and predictive modeling of molecular pathways of the killing mechanism. In conclusion, the nanoconjugate showed a promise to become a candidate for the pH-dependent cell-specific radio-modulator.

Microdosimetric Simulation of Gold-Nanoparticle-Enhanced Radiotherapy.

Conventional X-ray therapy (XRT) is commonly applied to suppress cancerous tumors; however, it often inflicts collateral damage to nearby healthy tissue. In order to provide a better conformity of the dose distribution in the irradiated tumor, proton therapy (PT) is increasingly being used to treat solid tumors. Furthermore, radiosensitization with gold nanoparticles (GNPs) has been extensively studied to increase the therapeutic ratio. The mechanism of radiosensitization is assumed to be connected to an enhancement of the absorbed dose due to huge photoelectric cross-sections with gold. Nevertheless, numerous theoretical studies, mostly based on Monte Carlo (MC) simulations, did not provide a consistent and thorough picture of dose enhancement and, therefore, the radiosensitization effect. Radiosensitization by nanoparticles in PT is even less studied than in XRT. Therefore, we investigate the physics picture of GNP-enhanced RT using an MC simulation with Geant4 equipped with the most recent physics models, taking into account a wide range of physics processes relevant for realistic PT and XRT. Namely, we measured dose enhancement factors in the vicinity of GNP, with diameters ranging from 10 nm to 80 nm. The dose enhancement in the vicinity of GNP reaches high values for XRT, while it is very modest for PT. The macroscopic dose enhancement factors for realistic therapeutic GNP concentrations are rather low for all RT scenarios; therefore, other physico-chemical and biological mechanisms should be additionally invoked for an explanation of the radiosensitization effect observed in many experiments.

Role of autophagy in modulating tumor cell radiosensitivity: Exploring pharmacological interventions for glioblastoma multiforme treatment.

Autophagy is an innate cellular process characterized by self-digestion, wherein cells degrade or recycle aged proteins, misfolded proteins, and damaged organelles via lysosomal pathways. Its crucial role in maintaining cellular homeostasis, ensuring development and survival is well established. In the context of cancer therapy, autophagy's importance is firmly recognized, given its critical impact on treatment efficacy. Following radiotherapy, several factors can modulate autophagy including parameters related to radiation type and delivery methods. The concomitant use of chemotherapy with radiotherapy further influences autophagy, potentially either enhancing radiosensitivity or promoting radioresistance. This review article discusses some pharmacological agents and drugs capable of modulating autophagy levels in conjunction with radiation in tumor cells, with a focus on those identified as potential radiosensitizers in glioblastoma multiforme treatment.

MitoTam induces ferroptosis and increases radiosensitivity in head and neck cancer cells.

BACKGROUND AND PURPOSE: Radiotherapy (RT) is an integral treatment part for patients with head and neck squamous cell carcinoma (HNSCC), but radioresistance remains a major issue. Here, we use MitoTam, a mitochondrially targeted analogue of tamoxifen, which we aim to stimulate ferroptotic cell death with, and sensitize radioresistant cells to RT. MATERIALS AND METHODS: We assessed viability, reactive oxygen species (ROS) production, disruption of mitochondrial membrane potential, and lipid peroxidation in radiosensitive (UT-SCC-40) and radioresistant (UT-SCC-5) HNSCC cells following MitoTam treatment. To assess ferroptosis specificity, we used the ferroptosis inhibitor ferrostatin-1 (fer-1). Also, total antioxidant capacity and sensitivity to tert-butyl hydroperoxide were evaluated to assess ROS-responses. 53BP1 staining was used to assess radiosensitivity after MitoTam treatment. RESULTS: Our data revealed increased ROS, cell death, disruption of mitochondrial membrane potential, and lipid peroxidation following MitoTam treatment in both cell lines. Adverse effects of MitoTam on cell death, membrane potential and lipid peroxidation were prevented by fer-1, indicating induction of ferroptosis. Radioresistant HNSCC cells were less sensitive to the effects of MitoTam due to intrinsic higher antioxidant capacity. MitoTam treatment prior to RT led to superadditive residual DNA damage expressed by 53BP1 foci compared to RT or MitoTam alone. CONCLUSION: MitoTam induced ferroptosis in HNSCC cells, which could be used to overcome the elevated antioxidant capacity of radioresistant cells and sensitize such cells to RT. Treatment with MitoTam followed by RT could therefore present a promising effective therapy of radioresistant cancers. STATEMENT OF SIGNIFICANCE: Radiotherapy is applied in the treatment of a majority of cancer patients. Radioresistance due to elevated antioxidant levels can be overcome by promoting ferroptotic cell death combining ROS-inducing drug MitoTam with radiotherapy.

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.

Aqueous extracts from Dioscorea sansibarensis Pax show cytotoxic and radiosensitizing potential in 3D growing HPV-negative and HPV-positive human head and neck squamous cell carcinoma models.

Numerous natural substances have anti-cancer properties. Especially indigenous people use aqueous plant extracts for tea or ointments including Dioscorea sansibarensis Pax to treat various diseases. The aim of this study was to evaluate the cytotoxic and radiosensitizing potential of aqueous extracts from Dioscorea sansibarensis Pax collected from Kenya in a panel of HPV-negative and -positive head and neck squamous cell carcinoma (HNSCC) cells grown in three-dimensional laminin-rich extracellular matrix (3D lrECM). The results show cytotoxicity, radiosensitization and increased levels of residual double strand breaks (DBS) by Dioscorea sansibarensis Pax extracts in HPV-negative and -positive HNSCC models in a concentration- and cell model-dependent manner. Application of ROS scavengers indicated an association between ROS-induced DSB and radiosensitization through Dioscorea sansibarensis Pax pretreatment. High-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) based characterization of Dioscorea sansibarensis Pax identified the main components of the extract including camptothecin. Overall, Dioscorea sansibarensis Pax aqueous extracts alone and in combination with X-ray irradiation showed effective anticancer properties, which are worthy of further mechanistic investigation.

Dihydroartemisinin enhances the radiosensitivity of breast cancer by targeting ferroptosis signaling pathway through hsa_circ_0001610.

OBJECTIVE: This study aimed to elucidate how DHA enhances the radiosensitivity of BC and to explain its potential mechanisms of action. METHODS: The circular structure of hsa_circ_0001610 was confirmed by Sanger sequencing, RNase R treatment, RT-PCR analysis using gDNA or cDNA. Cellular localization of hsa_circ_0001610 and microRNA-139-5p (miR-139-5p) was detected by fluorescence in situ hybridization. Cell counting kit-8 assay, wound healing and colony formation tests for assessing cell proliferation, while flow cytometry was utilized to estimate cell cycle progression and apoptosis. Reactive oxygen species and malondialdehyde experiments were conducted to validate ferroptosis of BC cells. The expression of ncRNAs and mRNAs was quantified via qRT-PCR, and protein expression was analyzed using Western blot. The effects of hsa_circ_0001610 and DHA on radiosensitivity of BC in vivo were studied by establishing BC mice model. RESULTS: In vivo and in vitro experimental results indicate that DHA promotes ferroptosis of BC cells at least partly by inhibiting hsa_circ_0001610/miR-139-5p/SLC7A11 pathway, thereby enhancing the radiosensitivity of BC cells. CONCLUSIONS: Our findings showed that DHA can induce ferroptosis of BC cells by down-regulation of hsa_circ_0001610, thus enhancing radiosensitivity, suggesting a promising therapeutic strategy for enhancing BC radiosensitivity that is worthy of further exploration.

Radiosensitizing effects of CDK4/6 inhibitors in hormone receptor-positive and HER2-negative breast cancer mediated downregulation of DNA repair mechanism and NF-κB-signaling pathway.

CDK4/6 inhibitors combined with endocrine therapy prolonged survival in hormone receptor (HR)-positive and HER2-negative advanced breast cancer. We investigated whether CDK4/6 inhibitors enhance radiosensitivity and their underlying mechanisms of this subtype of breast cancer. In vitro and in vivo experiments were conducted using two HR-positive and HER2-negative breast cancer cell lines (MCF-7 and T-47D), CDK4/6 inhibitors (ribociclib and palbociclib) and radiotherapy (RT) to assess the biological functions and mechanisms. The radiation-enhancing effect was assessed using clonogenic assays; γH2AX and 53BP1 levels were assessed by immunofluorescence to evaluate DNA damage. The levels of phospho (p)-ERK, c-Myc, and DNA-double strand break (DSB)-related molecules, p-DNA-PKcs, Rad51, and p-ATM, were assessed by western blotting. We used an NF-κB p65 transcription factor assay kit to evaluate NF-κB activity. We evaluated the antitumor effect of the combination of RT and ribociclib through the MCF-7 orthotopic xenograft model. The synergistic effects of combining RT with ribociclib and palbociclib pretreatment were demonstrated by clonogenic assay. CDK4/6 inhibitors synergistically increased the numbers of RT-induced γH2AX and 53BP1, downregulated the expression of p-DNA-PKcs, Rad51 and p-ATM activated by RT, and reduced RT-triggering p-ERK expression, NF-κB activation, and its down-streaming gene, c-Myc. Combined ribociclib and RT reduced the growth of MCF-7 cell xenograft tumors, and downregulated the immunohistochemical expression of p-ERK, p-NF-κB p65, and c-Myc compared to that in the control group. Combining CDK4/6 inhibitors enhanced radiosensitivity of HR-positive and HER2-negative breast cancer cells at least by reducing DNA-DSB repair and weakening the activation of ERK and NF-κB signaling by RT.

Integrating serum metabolomics analysis and network pharmacology to reveal the potential mechanism of Shengmai Jianghuang San in the treatment of nasopharyngeal carcinoma.

Shengmai Jianghuang San (SMJHS) is a traditional Chinese herbal compound reported to inhibit Nasopharyngeal Carcinoma (NPC) progression and enhance radiosensitivity. However, the specific active ingredients and regulatory mechanisms of SMJHS against NPC, particularly under hypoxic conditions, remain unclear. In this study, Sprague-Dawley (SD) rats were gavaged with Shengmai Jianghuang San (SMJHS), and their blood was collected from the abdominal aorta. UHPLC-Q-Exactive orbitrap MS/MS was used to identify the metabolite profiles of SMJHS drug-containing serum. A molecular network of the active compositions in SMJHS targeting NPC was constructed through network pharmacology and molecular docking. The HIF-1α/VEGF pathway was in key positions. The effects of SMJHS on the proliferation, migration, and radiosensitivity of hypoxic NPC cells were assessed by in vitro experiments. NPC cell lines stably overexpressing HIF-1α were established using a lentivirus to investigate the regulation of HIF-1α/VEGF signaling in hypoxic NPC cells by SMJHS. Through a combination of network pharmacological analysis, cellular biofunctional validation, and molecular biochemical experiments, our study found that SMJHS had an anti-proliferative effect on NPC cells cultured under hypoxic conditions, inhibiting their migration and increasing their radiosensitivity. Additionally, SMJHS suppressed the expression of HIF-1α and VEGFA, exhibiting potential as an effective option for improving NPC treatment.

Radiosensitization treatment using hydrogen peroxide for inoperable rectal cancer.

The treatment outcomes of patients with unresectable rectal cancer are complex, and concurrent chemoradiation therapy is the main treatment option. Radiosensitizers can enhance the effect of localized intratumoral hypoxia, contributing to local control and symptomatic relief. The present study evaluated the feasibility and safety of radiosensitization using hydrogen peroxide combined with radiation therapy (RT) in patients with unresectable rectal cancer. A total of 13 patients with rectal cancer were recruited in the present study. Radiosensitization was performed twice weekly in combination with RT. Gauze soaked in 3% hydrogen peroxide solution was inserted into the anus, ensuring firm contact with the lesion. In total, 45-65 Gy was delivered in 25-33 fractions to the whole pelvis from four directions using 10 MV X-rays 5 days per week. Acute and late adverse events were evaluated 1 and 6 months after the completion of RT. Treatment was well tolerated, with no acute grade 3 or worse events noted, and no patient developed rectal fistula, necrosis, obstruction, perforation, stenosis, ulcer or retroperitoneal hemorrhage. No notable late adverse events, beyond 6 months, were observed at the end of the analysis. All patients experienced pain relief, hemostatic effects and tumor shrinkage. Therefore, the use of a hydrogen peroxide solution-soaked gauze in the rectum may be a promising option for patients with inoperable rectal tumors. The limitations of the present study are that the patient population was small and the observation time was relatively short. This study was retrospectively registered with the University Hospital Medical Information Network Center (trial registration no. R000061902) on April 21, 2024.

NEO212, temozolomide conjugated to NEO100, exerts superior therapeutic activity over temozolomide in preclinical chemoradiation models of glioblastoma.

Background: The chemotherapeutic standard of care for patients with glioblastoma (GB) is radiation therapy (RT) combined with temozolomide (TMZ). However, during the twenty years since its introduction, this so-called Stupp protocol has revealed major drawbacks, because nearly half of all GBs harbor intrinsic treatment resistance mechanisms. Prime among these are the increased expression of the DNA repair protein O6-guanine-DNA methyltransferase (MGMT) and cellular deficiency in DNA mismatch repair (MMR). Patients with such tumors receive very little, if any, benefit from TMZ. We are developing a novel molecule, NEO212 (TMZ conjugated to NEO100), that harbors the potential to overcome these limitations. Methods: We used mouse models that were orthotopically implanted with GB cell lines or primary, radioresistant human GB stem cells, representing different treatment resistance mechanisms. Animals received NEO212 (or TMZ for comparison) without or with RT. Overall survival was recorded, and histology studies quantified DNA damage, apoptosis, microvessel density, and impact on bone marrow. Results: In all tumor models, replacing TMZ with NEO212 in a schedule designed to mimic the Stupp protocol achieved a strikingly superior extension of survival, especially in TMZ-resistant and RT-resistant models. While NEO212 displayed pronounced radiation-sensitizing, DNA-damaging, pro-apoptotic, and anti-angiogenic effects in tumor tissue, it did not cause bone marrow toxicity. Conclusions: NEO212 is a candidate drug to potentially replace TMZ within the standard Stupp protocol. It has the potential to become the first chemotherapeutic agent to significantly extend overall survival in TMZ-resistant patients when combined with radiation.