Ononin promotes radiosensitivity in lung cancer by inhibiting HIF-1α/VEGF pathway.

BACKGROUND: In our previous study, we provided evidence that Astragalus mongholicus Bunge(AM) and its extracts possess a protective capability against radiation-induced damage, potentially mediated through the reduction of reactive oxygen species (ROS) and nitric oxide (NO). However, we were pleasantly surprised to discover during our experimentation that AM not only offers protection against radiation damage but also exhibits a radiation sensitization effect. This effect may be attributed to a specific small molecule present in AM known as ononin. Currently, radiation sensitizers are predominantly found in nitrazole drugs and nanomaterials, with no existing reports on the radiation sensitization properties of ononin, nor its underlying mechanism. PURPOSE: This study aims to investigate the sensitization effect of the small molecule ononin derived from AM on lung cancer radiotherapy, elucidating its specific molecular mechanism of action. Additionally, the safety profile of combining astragalus small molecule ononin with radiation therapy will be evaluated. METHODS: The effective concentration of ononin was determined through cell survival experiments, and the impact of ononin combined with varying doses of radiation on lung cancer cells was observed using CCK-8 and cell cloning experiments. The apoptotic effect of ononin combined with radiation on lung cancer cells was assessed using Hochester staining, flow cytometry, and WB assay. Additionally, WB and immunofluorescence analysis were conducted to investigate the influence of ononin on HIF-1α/VEGF pathway. Furthermore, Molecular Dynamics Simulation was employed to validate the targeted binding ability of ononin and HIF-1α. A lung cancer cell line was established to investigate the effects of knockdown and overexpression of HIF-1α. Subsequently, the experiment was repeated using tumor bearing nude mice and C57BL/6 mouse models in an in vivo study. Tumor volume was measured using a vernier caliper, while HE, immunohistochemistry, and immunofluorescence techniques were employed to observe the effects of ononin combined with radiation on tumor morphology, proliferation, and apoptosis. Additionally, Immunofluorescence was employed to examine the impact of ononin on HIF-1α/VEGF pathway in vivo, and its effect on liver function in mice was assessed through biochemistry analysis. RESULTS: At a concentration of 25 µM, ononin did not affect the proliferation of lung epithelial cells but inhibited the survival of lung cancer cells. In vitro experiments demonstrated that the combination of ononin and radiation could effectively inhibit the growth of lung cancer cells, induce apoptosis, and suppress the excessive activation of the Hypoxia inducible factor 1 alpha/Vascular endothelial growth factor pathway. In vivo experiments showed that the combination of ononin and radiation reduced the size and proliferation of lung cancer tumors, promoted cancer cell apoptosis, mitigated abnormal activation of the Hypoxia inducible factor 1 alpha pathway, and protected against liver function damage. CONCLUSION: This study provides evidence that the combination of AM and its small molecule ononin can enhance the sensitivity of lung cancer to radiation. Additionally, it has been observed that this combination can specifically target HIF-1α and exert its effects. Notably, ononin exhibits the unique ability to protect liver function from damage while simultaneously enhancing the tumor-killing effects of radiation, thereby demonstrating a synergistic and detoxifying role in tumor radiotherapy. These findings contribute to the establishment of a solid basis for the development of novel radiation sensitizers derived from traditional Chinese medicine.

YY1 modulates the radiosensitivity of esophageal squamous cell carcinoma through KIF3B-mediated Hippo signaling pathway.

Radiotherapy is an important strategy in the comprehensive treatment of esophageal squamous cell carcinoma (ESCC). However, effectiveness of radiotherapy is still restricted by radioresistance. Herein, we aimed to understand the mechanisms underlying ESCC radioresistance, for which we looked into the potential role of YY1. YY1 was upregulated in radioresistant tissues and correlated with poor prognosis of patients with ESCC. YY1 depletion enhanced the radiosensitivity of ESCC in vitro and in vivo. Multi-group sequencing showed that downregulation of YY1 inhibited the transcriptional activity of Kinesin Family Member 3B (KIF3B), which further activated the Hippo signaling pathway by interacting with Integrin-beta1 (ITGB1). Once the Hippo pathway was activated, its main effector, Yes-associated protein 1 (YAP1), was phosphorylated in the cytoplasm and its expression reduced in the nucleus, thus enhancing the radiosensitivity by regulating its targeted genes. Our study provides new insights into the mechanisms underlying ESCC radioresistance and highlights the potential role of YY1 as a therapeutic target for ESCC.

RASSF1A promotes radiosensitivity in nasopharyngeal carcinoma by promoting FoxO3a and inhibiting the Nrf2/TXNRD1 signaling pathway.

Radiotherapy is widely used as the first-line treatment for nasopharyngeal carcinoma (NPC). However, the resistance of some patients to treatment lowers its clinical effectiveness. Compared to typical epithelial cells, NPC markedly lowers the Ras-association domain family 1A (RASSF1A) protein expression. RASSF1A overexpression sensitizes NPC cells to radiotherapy. Mechanistically, RASSF1A promotes the expression of Forkhead box O3a (FoxO3a) in the nucleus and inhibits the Nuclear factor E2-related factor 2 (Nrf2) signaling pathway via binding to the Kelch-like ECH-associated protein 1 (Keap1) promoter. Through elevating intracellular ROS levels, RASSF1A overexpression inhibits the expression of thioredoxin reductase 1 (TXNRD1), a crucial Nrf2 target gene, and increases NPC sensitivity to radiation. Immunohistochemical staining of NPC tissue sections revealed that the expression of RASSF1A is negatively correlated with that of TXNRD1. The traditional Chinese medicine component andrographolide (AGP), which induces RASSF1A expression, increased the sensitivity of NPC cells to radiotherapy in vitro and in vivo. Our findings implied that RASSF1A increases the sensitivity of NPC to radiation by increasing FoxO3a expression in the nucleus, inhibiting the Nrf2/TXNRD1 signaling pathway, and elevating intracellular ROS levels. AGP targets RASSF1A and may be a promising adjuvant sensitizer for enhancing radiosensitivity in NPC.

High-fat diet alters the radiation tolerance of female mice and the modulatory effect of melatonin.

High-fat diet (HFD) increases the risk of developing malignant tumors. Ionizing radiation (IR) is used as an adjuvant treatment in oncology. In this study, we investigated the effects of an 8-week 35% fat HFD on the tolerance to IR and the modulatory effect of melatonin (MLT). The results of lethal dose irradiation survival experiments revealed that the 8-week HFD altered the radiation tolerance of female mice and increased their radiosensitivity, whereas it had no comparable effects on males. Pre-treatment with MLT was, however, found to attenuate the radiation-induced hematopoietic damage in mice, promote intestinal structural repair after whole abdominal irradiation (WAI), and enhance the regeneration of Lgr5+ intestinal stem cells. 16S rRNA high-throughput sequencing and untargeted metabolome analyses revealed that HFD consumption and WAI sex-specifically altered the composition of intestinal microbiota and fecal metabolites and that MLT supplementation differentially modulated the composition of the intestinal microflora in mice. However, in both males and females, different bacteria were associated with the modulation of the metabolite 5-methoxytryptamine. Collectively, the findings indicate that MLT ameliorates the radiation-induced damage and sex-specifically shapes the composition of the gut microbiota and metabolites, protecting mice from the adverse side effects associated with HFD and IR.

A Cross-Talk about Radioresistance in Lung Cancer-How to Improve Radiosensitivity According to Chinese Medicine and Medicaments That Commonly Occur in Pharmacies.

Lung cancer is one of the most common cancers in the population and is characterized by non-specific symptoms that delay the diagnosis and reduce the effectiveness of oncological treatment. Due to the difficult placement of the tumor, one of the main methods of lung cancer treatment is radiotherapy, which damages the DNA of cancer cells, inducing their apoptosis. However, resistance to ionizing radiation may develop during radiotherapy cycles, leading to an increase in the number of DNA points of control that protect cells from apoptosis. Cancer stem cells are essential for radioresistance, and due to their ability to undergo epithelial-mesenchymal transition, they modify the phenotype, bypassing the genotoxic effect of radiotherapy. It is therefore necessary to search for new methods that could improve the cytotoxic effect of cells through new mechanisms of action. Chinese medicine, with several thousand years of tradition, offers a wide range of possibilities in the search for compounds that could be used in conventional medicine. This review introduces the potential candidates that may present a radiosensitizing effect on lung cancer cells, breaking their radioresistance. Additionally, it includes candidates taken from conventional medicine-drugs commonly available in pharmacies, which may also be significant candidates.

Calreticulin Expression Controls Cellular Redox, Stemness, and Radiosensitivity to Function as a Novel Adjuvant for Radiotherapy in Neuroblastoma.

Radiotherapy (RT) is currently only used in children with high-risk neuroblastoma (NB) due to concerns of long-term side effects as well as lack of effective adjuvant. Calreticulin (CALR) has served distinct physiological roles in cancer malignancies; nonetheless, impact of radiation on chaperones and molecular roles they play remains largely unknown. In present study, we systemically analyzed correlation between CALR and NB cells of different malignancies to investigate potential role of CALR in mediating radioresistance of NB. Our data revealed that more malignant NB cells are correlated to lower CALR expression, greater radioresistance, and elevated stemness as indicated by colony- and neurospheroid-forming abilities and vice versa. Of note, manipulating CALR expression in NB cells of varying endogenous CALR expression manifested changes in not only stemness but also radioresistant properties of those NB cells. Further, CALR overexpression resulted in greatly enhanced ROS and led to increased secretion of proinflammatory cytokines. Importantly, growth of NB tumors was significantly hampered by CALR overexpression and was synergistically ablated when RT was also administered. Collectively, our current study unraveled a new notion of utilizing CALR expression in malignant NB to diminish cancer stemness and mitigate radioresistance to achieve favorable therapeutic outcome for NB.

Using Hyperbaric Oxygen to Improve the Radiosensitivity of Human U251 Glioma Cells.

The aim of this study was to explore the use of hyperbaric oxygen to enhance the radiosensitivity of human glioma cells. Sub-cultured U251 human glioma cells were randomly divided into four groups: an untreated control group, cells treated with hyperbaric oxygen (HBO) only, cells treated with X-ray irradiation (X-ray) only, and cells treated with both HBO and X-ray. Cell morphology, cell proliferation activity, cell cycle distribution, and apoptosis were observed in these groups to evaluate the role of HBO in improving the radiosensitivity of glioma cells. With the increase in X-ray doses (0 Gy, 2 Gy, 4 Gy, 6 Gy, 8 Gy), the survival fraction (SF) of glioma cells gradually decreased. Significantly lower SF was observed for the cells treated with the HBO and X-ray together than in the X-ray group for each dose (all P < 0.05). The proliferation inhibition was significantly higher in the HBO combined with X-ray group than in the X-ray group for each dose (all P < 0.05) for the U251 cell line. The percentage of G2/M phase cells was significantly higher in the HBO combined with X-ray (2 Gy) group (26.70% ± 2.46%) and the HBO group (22.36% ± 0.91%) than in the control group (11.56% ± 2.01%) and X-ray (2 Gy) group (10.35% ± 2.69%) (all P < 0.05). U251 cell apoptosis was significantly higher in the HBO combined with X-ray (2 Gy) group than in the HBO group, the X-ray (2 Gy) group, and the control group (all P < 0.05). We conclude that HBO can enhance the proliferation inhibition and apoptosis of glioma U251 cells by blocking glioma cells in the G2/M phase and improve the radiosensitivity of U251 glioma cells.

Natural Radiosensitizers in Radiotherapy: Cancer Treatment by Combining Ionizing Radiation with Resveratrol.

Conventional cancer treatment is mainly based on the surgical removal of the tumor followed by radiotherapy and/or chemotherapy. When surgical removal is not possible, radiotherapy and, less often, chemotherapy is the only way to treat patients. However, despite significant progress in understanding the molecular mechanisms of carcinogenesis and developments in modern radiotherapy techniques, radiotherapy (alone or in combination) does not always guarantee treatment success. One of the main causes is the radioresistance of cancer cells. Increasing the radiosensitivity of cancer cells improves the processes leading to their elimination during radiotherapy and prolonging the survival of cancer patients. In order to enhance the effect of radiotherapy in the treatment of radioresistant neoplasms, radiosensitizers are used. In clinical practice, synthetic radiosensitizers are commonly applied, but scientists have recently focused on using natural products (phytocompounds) as adjuvants in radiotherapy. In this review article, we only discuss naturally occurring radiosensitizers currently in clinical trials (paclitaxel, curcumin, genistein, and papaverine) and those whose radiation sensitizing effects, such as resveratrol, have been repeatedly confirmed by many independent studies.

Tailoring bismuth-based nanoparticles for enhanced radiosensitivity in cancer therapy.

Achieving a complete response to cancer treatment is a severe challenge, and has puzzled humans for a long time. Fortunately, radiotherapy (RT) gives rise to a common clinical treatment method, during which the usage of radiosensitizers is essential. Among preclinical radiosensitizers, bismuth-based nanoparticles (Bi-based NPs) are widely explored in cancer diagnosis and treatment, because they share favourable properties, such as low toxicity, strong X-ray absorption and facile preparation. However, pure Bi alone cannot achieve both efficient and safe RT outcomes, mainly due to poor targeting of tumor sites, long retention-induced systemic toxicity and immune resistance. This work provides an overview of recent advances and developments in Bi-based NPs that are tailored to enhance radiosensitivity. For the fabrication process, surface modification of Bi-based NPs is essential to achieve tumor-targeted delivery and penetration. Moreover, the incorporation of other elements, such as Fe ions, can increase diagnostic accuracy with optimal theranostic efficacy. Meanwhile, the structure-activity relationship can also be manipulated to maximize the chemotherapeutic drug loading capability of Bi-based NPs, to enhance X-ray attenuation by means of a large surface area or to achieve safer metabolic routes with rapid clearance from the human body. In addition, Bi-based NPs exhibit synergistic antitumor potential when combined with diverse therapies, such as photothermal therapy (PTT) and high-intensity focused ultrasound (HIFU). To summarize, the latest research on Bi-based NPs as radiosensitizers is described in the review, including both their advantages and disadvantages for improving treatment, thus providing a useful guide for future clinical application.

The RelB-BLNK Axis Determines Cellular Response to a Novel Redox-Active Agent Betamethasone during Radiation Therapy in Prostate Cancer.

Aberrant levels of reactive oxygen species (ROS) are potential mechanisms that contribute to both cancer therapy efficacy and the side effects of cancer treatment. Upregulation of the non-canonical redox-sensitive NF-kB family member, RelB, confers radioresistance in prostate cancer (PCa). We screened FDA-approved compounds and identified betamethasone (BET) as a drug that increases hydrogen peroxide levels in vitro and protects non-PCa tissues/cells while also enhancing radiation killing of PCa tissues/cells, both in vitro and in vivo. Significantly, BET increases ROS levels and exerts different effects on RelB expression in normal cells and PCa cells. BET induces protein expression of RelB and RelB target genes, including the primary antioxidant enzyme, manganese superoxide dismutase (MnSOD), in normal cells, while it suppresses protein expression of RelB and MnSOD in LNCaP cells and PC3 cells. RNA sequencing analysis identifies B-cell linker protein (BLNK) as a novel RelB complementary partner that BET differentially regulates in normal cells and PCa cells. RelB and BLNK are upregulated and correlate with the aggressiveness of PCa in human samples. The RelB-BLNK axis translocates to the nuclear compartment to activate MnSOD protein expression. BET promotes the RelB-BLNK axis in normal cells but suppresses the RelB-BLNK axis in PCa cells. Targeted disruptions of RelB-BLNK expressions mitigate the radioprotective effect of BET on normal cells and the radiosensitizing effect of BET on PCa cells. Our study identified a novel RelB complementary partner and reveals a complex redox-mediated mechanism showing that the RelB-BLNK axis, at least in part, triggers differential responses to the redox-active agent BET by stimulating adaptive responses in normal cells but pushing PCa cells into oxidative stress overload.

Black Phosphorus Quantum Dots Enhance the Radiosensitivity of Human Renal Cell Carcinoma Cells through Inhibition of DNA-PKcs Kinase.

Renal cell carcinoma (RCC) is one of the most aggressive urological malignancies and has a poor prognosis, especially in patients with metastasis. Although RCC is traditionally considered to be radioresistant, radiotherapy (RT) is still a common treatment for palliative management of metastatic RCC. Novel approaches are urgently needed to overcome radioresistance of RCC. Black phosphorus quantum dots (BPQDs) have recently received great attention due to their unique physicochemical properties and good biocompatibility. In the present study, we found that BPQDs enhance ionizing radiation (IR)-induced apoptotic cell death of RCC cells. BPQDs treatment significantly increases IR-induced DNA double-strand breaks (DSBs), as indicated by the neutral comet assay and the DSBs biomarkers γH2AX and 53BP1. Mechanistically, BPQDs can interact with purified DNA-protein kinase catalytic subunit (DNA-PKcs) and promote its kinase activity in vitro. BPQDs impair the autophosphorylation of DNA-PKcs at S2056, and this site phosphorylation is essential for efficient DNA DSBs repair and the release of DNA-PKcs from the damage sites. Consistent with this, BPQDs suppress nonhomologous end-joining (NHEJ) repair and lead to sustained high levels of autophosphorylated DNA-PKcs on the damaged sites. Moreover, animal experiments indicate that the combined approach with both BPQDs and IR displays better efficacy than monotreatment. These findings demonstrate that BPQDs have potential applications in radiosensitizing RCC cells.

Interaction of curcumin with glioblastoma cells via high and low linear energy transfer radiation therapy inducing radiosensitization effects.

Glioblastoma is a deadly cancer tumor in the brain and has a survival rate of about 15 months. Despite the high mortality rate, temozolomide has proven to increase the survival rate of patients when combined with radiotherapy. However, its effects may be limited because some patients develop therapeutic resistance. Curcumin has proven to be a cancer treatment due to its broad anticancer spectrum, high efficiency and low toxic level. Additionally, curcumin significantly enhanced radiation efficacy under high and low Linear Energy Transfer (LET) radiation conditions in vitro. In combination with radiation, curcumin increased the cell population in the sub-G1 phase and the reactive oxygen species (ROS) level, ultimately increasing GBM cellular apoptosis. The radiosensitizing effects of curcumin are much higher in neutron (high LET)-irradiated cell lines than in γ (low LET)-irradiated cell lines. Curcumin plus neutron combination significantly inhibited cell invasion compared with that of single treatment or curcumin combined γ-ray treatment. Curcumin enhances the radiosensitivity of Glioblastoma (GBM), suggesting it may have clinical utility in combination cancer treatment with neutron high-LET radiation.

Verbascoside enhances radiosensitivity of hepatocellular carcinoma cells through regulating miR-101-3p/Wee1 axis.

Verbascoside is a kind of phenylpropanoid glycoside derived from multiple medicinal plants, exerting anti-tumor effects in diverse human malignancies. However, the function of Verbascoside on the radiosensitivity of hepatocellular carcinoma (HCC) cells remains unknown. Human Huh7 and HepG2 cell lines were treated with Verbascosideis, and cell viability was detected with cell counting kit-8 (CCK-8) assay. Quantitative real-time polymerase chain reaction (qRT-PCR) was applied to detect miR-101-3p expression, and Western blot was used to quantify the expression of WEE1 G2 checkpoint kinase (WEE1). Then, CCK-8 and flow cytometry assays were used to detect the proliferation and apoptosis of HCC cells after Verbascoside and X-ray combined treatment, and the expressions of WEE1 and apoptosis-related proteins Bax and Bcl-2 were detected by Western blot. Verbascoside could improve the radiosensitivity of HCC cells in a dose-dependent manner. Verbascoside increased the expression of miR-101-3p but reduced WEE1 expression in HCC cells. Additionally, WEE1 was identified as a target of miR-101-3p. MiR-101-3p inhibition or WEE1 overexpression could reverse the effect of Verbascoside on the viability and apoptosis of HCC cells. Verbascoside increases the radiosensitivity of hepatocellular carcinoma cells via modulating miR-101-3p/WEE1 axis.

Flavonoids Synergistically Enhance the Anti-Glioblastoma Effects of Chemotherapeutic Drugs.

Flavonoids are polyphenolic plant secondary metabolites with pleiotropic biological properties, including anti-cancer activities. These natural compounds have potential utility in glioblastoma (GBM), a malignant central nervous system tumor derived from astrocytes. Conventional GBM treatment modalities such as chemotherapy, radiation therapy, and surgical tumor resection are beneficial but limited by extensive tumor invasion and drug/radiation resistance. Therefore, dietary flavonoids-with demonstrated anti-GBM properties in preclinical research-are potential alternative therapies. This review explores the synergistic enhancement of the anti-GBM effects of conventional chemotherapeutic drugs by flavonoids. Primary studies published between 2011 and 2021 on flavonoid-chemotherapeutic synergy in GBM were obtained from PubMed. These studies demonstrate that flavonoids such as chrysin, epigallocatechin-3-gallate (EGCG), formononetin, hispidulin, icariin, quercetin, rutin, and silibinin synergistically enhance the effects of canonical chemotherapeutics. These beneficial effects are mediated by the modulation of intracellular signaling mechanisms related to apoptosis, proliferation, autophagy, motility, and chemoresistance. In this light, flavonoids hold promise in improving current therapeutic strategies and ultimately overcoming GBM drug resistance. However, despite positive preclinical results, further investigations are necessary before the commencement of clinical trials. Key considerations include the bioavailability, blood-brain barrier (BBB) permeability, and safety of flavonoids; optimal dosages of flavonoids and chemotherapeutics; drug delivery platforms; and the potential for adverse interactions.

Early senescence and production of senescence-associated cytokines are major determinants of radioresistance in head-and-neck squamous cell carcinoma.

Resistance against radio(chemo)therapy-induced cell death is a major determinant of oncological treatment failure and remains a perpetual clinical challenge. The underlying mechanisms are manifold and demand for comprehensive, cancer entity- and subtype-specific examination. In the present study, resistance against radiotherapy was systematically assessed in a panel of human head-and-neck squamous cell carcinoma (HNSCC) cell lines and xenotransplants derived thereof with the overarching aim to extract master regulators and potential candidates for mechanism-based pharmacological targeting. Clonogenic survival data were integrated with molecular and functional data on DNA damage repair and different cell fate decisions. A positive correlation between radioresistance and early induction of HNSCC cell senescence accompanied by NF-κB-dependent production of distinct senescence-associated cytokines, particularly ligands of the CXCR2 chemokine receptor, was identified. Time-lapse microscopy and medium transfer experiments disclosed the non-cell autonomous, paracrine nature of these mechanisms, and pharmacological interference with senescence-associated cytokine production by the NF-κB inhibitor metformin significantly improved radiotherapeutic performance in vitro and in vivo. With regard to clinical relevance, retrospective analyses of TCGA HNSCC data and an in-house HNSCC cohort revealed that elevated expression of CXCR2 and/or its ligands are associated with impaired treatment outcome. Collectively, our study identifies radiation-induced tumor cell senescence and the NF-κB-dependent production of distinct senescence-associated cytokines as critical drivers of radioresistance in HNSCC whose therapeutic targeting in the context of multi-modality treatment approaches should be further examined and may be of particular interest for the subgroup of patients with elevated expression of the CXCR2/ligand axis.

LINC02532 Contributes to Radiosensitivity in Clear Cell Renal Cell Carcinoma through the miR-654-5p/YY1 Axis.

BACKGROUND: Studies have shown that long non-coding RNAs (lncRNAs) play essential roles in tumor progression and can affect the response to radiotherapy, including in clear cell renal cell carcinoma (ccRCC). LINC02532 has been found to be upregulated in ccRCC. However, not much is known about this lncRNA. Hence, this study aimed to investigate the role of LINC02532 in ccRCC, especially in terms of radioresistance. METHODS: Quantitative real-time PCR was used to detect the expression of LINC02532, miR-654-5p, and YY1 in ccRCC cells. Protein levels of YY1, cleaved PARP, and cleaved-Caspase-3 were detected by Western blotting. Cell survival fractions, viability, and apoptosis were determined by clonogenic survival assays, CCK-8 assays, and flow cytometry, respectively. The interplay among LINC02532, miR-654-5p, and YY1 was detected by chromatin immunoprecipitation and dual-luciferase reporter assays. In addition, in vivo xenograft models were established to investigate the effect of LINC02532 on ccRCC radioresistance in 10 nude mice. RESULTS: LINC02532 was highly expressed in ccRCC cells and was upregulated in the cells after irradiation. Moreover, LINC02532 knockdown enhanced cell radiosensitivity both in vitro and in vivo. Furthermore, YY1 activated LINC02532 in ccRCC cells, and LINC02532 acted as a competing endogenous RNA that sponged miR-654-5p to regulate YY1 expression. Rescue experiments indicated that miR-654-5p overexpression or YY1 inhibition recovered ccRCC cell functions that had been previously impaired by LINC02532 overexpression. CONCLUSIONS: Our results revealed a positive feedback loop of LINC02532/miR-654-5p/YY1 in regulating the radiosensitivity of ccRCC, suggesting that LINC02532 might be a potential target for ccRCC radiotherapy. This study could serve as a foundation for further research on the role of LINC02532 in ccRCC and other cancers.

Utilization of Pharmacological Ascorbate to Enhance Hydrogen Peroxide-Mediated Radiosensitivity in Cancer Therapy.

Interest in the use of pharmacological ascorbate as a treatment for cancer has increased considerably since it was introduced by Cameron and Pauling in the 1970s. Recently, pharmacological ascorbate has been used in preclinical and early-phase clinical trials as a selective radiation sensitizer in cancer. The results of these studies are promising. This review summarizes data on pharmacological ascorbate (1) as a safe and efficacious adjuvant to cancer therapy; (2) as a selective radiosensitizer of cancer via a mechanism involving hydrogen peroxide; and (3) as a radioprotector in normal tissues. Additionally, we present new data demonstrating the ability of pharmacological ascorbate to enhance radiation-induced DNA damage in glioblastoma cells, facilitating cancer cell death. We propose that pharmacological ascorbate may be a general radiosensitizer in cancer therapy and simultaneously a radioprotector of normal tissue.

Immunogenic Cell Death Induction by Ionizing Radiation.

Immunogenic cell death (ICD) is a form of regulated cell death (RCD) induced by various stresses and produces antitumor immunity via damage-associated molecular patterns (DAMPs) release or exposure, mainly including high mobility group box 1 (HMGB1), calreticulin (CRT), adenosine triphosphate (ATP), and heat shock proteins (HSPs). Emerging evidence has suggested that ionizing radiation (IR) can induce ICD, and the dose, type, and fractionation of irradiation influence the induction of ICD. At present, IR-induced ICD is mainly verified in vitro in mice and there is few clinical evidence about it. To boost the induction of ICD by IR, some strategies have shown synergy with IR to enhance antitumor immune response, such as hyperthermia, nanoparticles, and chemotherapy. In this review, we focus on the molecular mechanisms of ICD, ICD-promoting factors associated with irradiation, the clinical evidence of ICD, and immunogenic forms of cell death. Finally, we summarize various methods of improving ICD induced by IR.

Moving Forward in the Next Decade: Radiation Oncology Sciences for Patient-Centered Cancer Care.

In a time of rapid advances in science and technology, the opportunities for radiation oncology are undergoing transformational change. The linkage between and understanding of the physical dose and induced biological perturbations are opening entirely new areas of application. The ability to define anatomic extent of disease and the elucidation of the biology of metastases has brought a key role for radiation oncology for treating metastatic disease. That radiation can stimulate and suppress subpopulations of the immune response makes radiation a key participant in cancer immunotherapy. Targeted radiopharmaceutical therapy delivers radiation systemically with radionuclides and carrier molecules selected for their physical, chemical, and biochemical properties. Radiation oncology usage of "big data" and machine learning and artificial intelligence adds the opportunity to markedly change the workflow for clinical practice while physically targeting and adapting radiation fields in real time. Future precision targeting requires multidimensional understanding of the imaging, underlying biology, and anatomical relationship among tissues for radiation as spatial and temporal "focused biology." Other means of energy delivery are available as are agents that can be activated by radiation with increasing ability to target treatments. With broad applicability of radiation in cancer treatment, radiation therapy is a necessity for effective cancer care, opening a career path for global health serving the medically underserved in geographically isolated populations as a substantial societal contribution addressing health disparities. Understanding risk and mitigation of radiation injury make it an important discipline for and beyond cancer care including energy policy, space exploration, national security, and global partnerships.

Imaging application and radiosensitivity enhancement of pectin decorated multifunctional magnetic nanoparticles in cancer therapy.

In this contribution, we report the fabrication of multifunctional nanoparticles with gold shell over an iron oxide nanoparticles (INPs) core. The fabricated system combines the magnetic property of INPs and the surface plasmon resonance of gold. The developed nanoparticles are coated with thiolated pectin (TPGINs), which provides stability to the nanoparticles dispersion and allows the loading of hydrophobic anticancer drugs. Curcumin (Cur) is used as the model drug and an encapsulation efficiency of approximately 80% in TPGINs is observed. Cytotoxicity study with HeLa cells shows that Cur-loaded TPGINs have better viability percent (~30%) than Cur alone (~40%) at a dose of 30 µg of TPGINs. Further, annexin V-PI assay demonstrated the enhanced anticancer activity of Cur-loaded TPGINs via induction of apoptosis. The use of TPGINs leads to a significant enhancement in generating reactive oxygen species (ROS) in HeLa cells through improved radiosensitization by gamma irradiation (0.5 Gy). TPGINs are further evaluated for imparting contrast in magnetic resonance imaging (MRI) with the r2 relaxivity in the range of 11.06-13.94 s-1 µg-1 mL when measured at 7 Tesla. These experimental results indicate the potential of TPGINs for drug delivery and MR imaging.