Inhibition of the thioredoxin system for radiosensitization therapy of cancer.

Radiotherapy (RT) stands as a cornerstone in the clinical armamentarium against various cancers due to its proven efficacy. However, the intrinsic radiation resistance exhibited by cancer cells, coupled with the adverse effects of RT on normal tissues, often compromises its therapeutic potential and leads to unwanted side effects. This comprehensive review aims to consolidate our understanding of how radiosensitizers inhibit the thioredoxin (Trx) system in cellular contexts. Notable radiosensitizers, including gold nanoparticles (GNPs), gold triethylphosphine cyanide ([Au(SCN) (PEt3)]), auranofin, ceria nanoparticles (CONPs), curcumin and its derivatives, piperlongamide, indolequinone derivatives, micheliolide, motexafin gadolinium, and ethane selenide selenidazole derivatives (SeDs), are meticulously elucidated in terms of their applications in radiotherapy. In this review, the sensitization mechanisms and the current research progress of these radiosensitizers are discussed in detail, with the overall aim of providing valuable insights for the judicious application of Trx system inhibitors in the field of cancer radiosensitization therapy.

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.

Evidence for the use of curcumin in radioprotection and radiosensitization.

Curcumin has antineoplastic properties and is considered a chemotherapeutic and chemopreventive agent. Curcumin may be associated with radiation therapy (RT) as a radiosensitizer for cancer cells and a radioprotector for normal cells. In principle, it may result in a reduction of RT dosage for the same therapeutic effect on cancer cells, and further reduced damage to normal cells. Though the overall level of evidence is modest, limited to in vivo and in vitro experiences and practically no clinical trials, as the risks of adverse effects are extremely low, it is reasonable to promote the general supplementation with curcumin during RT targeting the reduction of side effects through anti-inflammatory mechanisms.

Cell Death Induced by the Combination of Ephedra sinica Extract and Radiation in HNSCC is Positively Related to BAX and p-MLKL Expression.

BACKGROUND: Numerous studies have proven the efficacy and safety of natural products, and are widely used as attractive cancer treatments. The investigation of effective natural products for improving cancer treatment is a promising strategy. Combination treatment with radiosensitizers and radiotherapy (RT) is considered necessary for therapeutic improvement in head and neck squamous cell carcinoma(HNSCC). OBJECTIVE: This study aims to investigate whether Ephedra sinica (ES) extract could induce selective cell death in cancer cells and serve as a radiosensitizer for HNSCC. METHODS: HNSCC cells were pretreated with ES extract before radiation, and the radiosensitizing activity was assessed using a colony formation assay. Radiation-induced cell death was evaluated using an annexinV-FITC assay. Western blotting was performed to confirm cell death-related gene expression, including apoptosis and necrosis markers. RESULTS: ES extract significantly inhibited HNSCC cell viability (FaDu and SNU1076), while having minimal effect on normal HaCaT cells. When HNSCC cells were irradiated with 2, 4, or 8 Gy and cultured with ES extract (25 µg/mL), they exhibited increased radiation sensitivity compared to non-treated cells. The combination of ES extract and radiation resulted in increased cell death compared to non-treated, ES-treated, or irradiated cells. The apoptosis marker BAX and necrosis marker p-MLKL expression levels were also elevated following the combination treatment. CONCLUSION: ES extract demonstrated significant cytotoxic potential in HNSCC cells without affecting normal cells. It enhanced the radiosensitivity of HNSCC cells by upregulating BAX and p-MLKL expression, leading to increased cell death. These results suggest ES extract exhibits a potential radiosensitizing capacity in HNSCC.

Selenium promotes immunogenic radiotherapy against cervical cancer metastasis through evoking P53 activation.

Radiotherapy is still the recommended treatment for cervical cancer. However, radioresistance and radiation-induced side effects remain one of the biggest clinical problems. Selenium (Se) has been confirmed to exhibit radiation-enhancing effects for cancer treatment. However, Se species dominate the biological activities and which form of Se possesses better radiosensitizing properties and radiation safety remains elusive. Here, different Se species (the valence state of Se ranged from - 2, 0, +4 to + 6) synergy screen was carried out to identify the potential radiosensitizing effects and radiation safety of Se against cervical cancer. We found that the therapeutic effects varied with the changes in the Se valence state. Sodium selenite (+4) displayed strong cancer-killing effects but also possessed severe cytotoxicity. Sodium selenate (+6) neither enhanced the killing effects of X-ray nor possessed anticancer activity by its alone treatment. Although nano-selenium (0), especially Let-SeNPs, has better radiosensitizing activity, the - 2 organic Se, such as selenadiazole derivative SeD (-2) exhibited more potent anticancer effects and possessed a higher safe index. Overall, the selected Se drugs were able to synergize with X-ray to inhibit cell growth, clone formation, and cell migration by triggering G2/M phase arrest and apoptosis, and SeD (-2) was found to exhibit more potent enhancing capacity. Further mechanism studies showed that SeD mediated p53 pathway activation by inducing DNA damage through promoting ROS production. Additionally, SeD combined with X-ray therapy can induce an anti-tumor immune response in vivo. More importantly, SeD combined with X-ray significantly inhibited the liver metastasis of tumor cells and alleviated the side effects caused by radiation therapy in tumor-bearing mice. Taken together, this study demonstrates the radiosensitization and radiation safety effects of different Se species, which may shed light on the application of such Se-containing drugs serving as side effects-reducing agents for cervical cancer radiation treatment.

Noninvasive Red Laser Intervention before Radiotherapy of Triple-negative Breast Cancer in a Murine Model.

Radiotherapy is a well-established cancer treatment; it is estimated that approximately 52% of oncology patients will require this treatment modality at least once. However, some tumors, such as triple-negative breast cancer (TNBC), may present as radioresistant and thus require high doses of ionizing radiation and a prolonged period of treatment, which may result in more severe side effects. Moreover, such tumors show a high incidence of metastases and decreased survival expectancy of the patient. Thus, new strategies for radiosensitizing TNBC are urgently needed. Red light therapy, photobiomodulation, has been used in clinical practice to mitigate the adverse side effects usually associated with radiotherapy. However, no studies have explored its use as a radiosensitizer of TNBC. Here, we used TNBC-bearing mice as a radioresistant cancer model. Red light treatment was applied in three different protocols before a high dose of radiation (60 Gy split in 4 fractions) was administered. We evaluated tumor growth, mouse clinical signs, total blood cell counts, lung metastasis, survival, and levels of glutathione in the blood. Our data showed that the highest laser dose in combination with radiation arrested tumor progression, likely due to inhibition of GSH synthesis. In addition, red light treatment before each fraction of radiation, regardless of the light dose, improved the health status of the animals, prevented anemia, reduced metastases, and improved survival. Collectively, these results indicate that red light treatment in combination with radiation could prove useful in the treatment of TNBC.

X-ray sensitive selenium-containing Ru complexes sensitize nasopharyngeal carcinoma cells for radio/chemotherapy.

Radiotherapy has been extensively applied to cancer therapy in clinical trials. However, radiation resistance and dose limitation generally hamper the efficacy of radiotherapy. There is an urgent need for radiosensitizers with high efficiency and safety to enhance the anti-tumor effect of radiotherapy. In this paper, a selenium-containing (Se) ruthenium (Ru) complex (RuSe) was designed as a radiosensitizer to synergistically augment the killing effect of radiotherapy on nasopharyngeal carcinoma cells. In this system, the heavy atomic effect of Ru enhances the photoelectron production triggered by X-rays, thus inducing a burst of reactive oxygen species (ROS). In addition, Se atoms with a strong polarization property were introduced into the ligand of the metal complex to enhance the tumor chemo/radiotherapy effect. Consequently, RuC with a weak atomic polarization effect, as a comparison for RuSe, was also rationally explored to elucidate the role of Se atoms on chemo/radiotherapy sensitization. Indeed, compared with RuC, RuSe at a sub-toxic dose was able to potentiate the lethality of radiotherapy after preconditioning with cancer cells, by inducing ROS over-production, decreasing the mitochondrial membrane potential, and arresting the cell cycle at the sub-G1 phase. Furthermore, upon radiation, RuSe was superior to RuC, by inducing apoptotic cell death by activating caspase-3, -8, and -9. In summary, this study not only demonstrates an effective and safe strategy for the application of RuSe complexes to the cancer-targeted chemo/radiotherapy of human cancers, but also sheds light on the potential mechanisms of such Se-containing drugs as efficient radiotherapy sensitizers.

Hyperbaric oxygen enhanced the chemotherapy of mitochondrial targeting molecule IR-780 in bladder cancer.

BACKGROUND: Bladder cancer has a high rate of recurrence and drug resistance due to the lack of effective therapies. IR-780 iodide, a near-infrared (NIR) mitochondria-targeting fluorescent agent, has been demonstrated to achieve higher selectivity than other drugs in different tumor types and exhibited tumor-killing effects in some cancers. However, this therapeutic strategy is rarely studied in bladder cancer. MATERIAL AND METHODS: The accumulation of IR-780 in bladder cancer was measured by NIR imaging. Human bladder cell lines (T24, 5637, and TCCSUP) were treated with IR-780 or combined IR-780 and hyperbaric oxygen (HBO). Cell viability, cell apoptosis, cellular ATP production, mitochondrial reactive oxygen species (ROS), and plasma membrane potential were detected. Mitochondrial complex I protein NDUFS1 was measured by western blot. To confirm the anti-tumor efficacy of IR-780 + HBO, mouse bladder cell line (MB49) tumor-bearing mice were established and tumor size and weight were recorded. Besides, cell apoptosis and tumor size were assessed in drug-resistant bladder cancer cells (T24/DDP) and xenografts to evaluate the effect of IR-780 + HBO on drug-resistant bladder cancer. RESULTS: IR-780 selectively accumulated in bladder cancer (bladder cancer cells, transplanted tumors, and bladder cancer tissue from patients) and could induce cancer cell apoptosis by targeting the mitochondrial complex I protein NDUFS1. The combination with HBO could significantly enhance the anti-tumor effect of IR-780 in vitro by promoting cancer cell uptake and inducing excessive mitochondrial ROS production, while suppressing tumor growth and recurrence in animal models without causing apparent toxicity. Moreover, this combination antitumor strategy was also demonstrated in drug-resistant bladder cancer cells (T24/DDP) and xenografts. CONCLUSION: We identified for the first time a combination of IR-780 and HBO (IR-780 + HBO), which exhibits mitochondria-targeting and therapeutic capabilities, as a novel treatment paradigm for bladder cancer.

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.

Targeted Wolfram-Doped Polypyrrole for Photonic Hyperthermia-Synergized Radiotherapy.

Single ionizing radiation at a tolerable dose is ineffectual in eliminating malignancies but readily generates harmful effects on surrounding normal tissues. Herein, we intelligently fabricated novel wolfram-doped polypyrrole (WPPy) through a simple oxidative polymerization method with WCl6 as an oxidizing catalyst, which possessed good biocompatibility, high photothermal conversion, and intensive radiosensitivity capacities to concurrently serve as a photothermal reagent and a radiosensitizer for hyperthermia-synergized radiotherapy (RT) against a malignant tumor. In comparison with traditional polypyrrole without noble metal doping, the innovative introduction of WCl6 not only successfully launched the polymerization of a pyrrole monomer but also endowed WPPy with additional radiosensitization. More importantly, after further decoration with an active targeted component (SP94 polypeptide), the obtained WPPy@SP94 significantly increased tumor internalization and accumulation in vitro and in vivo and induced obvious DNA damage as well as robust ROS generation under X-ray irradiation, which meanwhile synergized with strong photonic hyperthermia to effectively inhibit tumor growth by single drug injection. Moreover, such biocompatible WPPy@SP94 showed negligible adverse effects on normal cells and tissues. WPPy@SP94 developed in this study not only expands the category of polypyrrole chemical syntheses but also sheds light on WPPy@SP94-based radiosensitizers for cancer RT.

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.

Poly (ADP-ribose) polymerase inhibitors sensitize cancer cells to hypofractionated radiotherapy through altered selection of DNA double-strand break repair pathways.

PURPOSE: Poly (ADP-ribose) polymerase inhibitors (PARPi) are known to induce radiosensitization. However, the exact mechanisms of radiosensitization remain unclear. We previously reported that PARPi may have a unique radiosensitizing effect to enhance ß-components of the linear-quadratic model. The aim of this study was to evaluate PARPi in combination with high-dose-per-fraction radiotherapy and to elucidate the underlying mechanisms of its radiosensitization. MATERIALS AND METHODS: Radiosensitizing effects of PARPi PJ34, olaparib, and veliparib were measured using a colony-forming assay in the human cancer cell lines, HCT116, NCI-H460, and HT29. Six different radiation dose fractionation schedules were examined by tumor regrowth assay using three-dimensional multicellular spheroids of HCT116, NCI-H460, SW620, and HCT15. The mechanisms of radiosensitization were analyzed by measuring DNA double-strand breaks (DSB), DNA damage responses, chromosomal translocations, cellular senescence, and cell cycle analysis. RESULTS: Olaparib and PJ34 were found to show radiosensitization preferentially at higher radiation doses per fraction. Similar results were obtained using a mouse model bearing human tumor xenografts. A kinetic analysis of DNA damage responses and repairs showed that olaparib and PJ34 reduced the homologous recombination activity. However, a neutral comet assay showed that PJ34 treatment did not affect the physical rejoining of DNA-DSBs induced by ionizing radiation. Cell cycle analysis revealed that olaparib and PJ34 strikingly increased G1 tetraploid cells following irradiation, leading to premature senescence. The C-banding analysis of metaphase spreads showed that olaparib and PJ34 significantly increased ionizing radiation-induced dicentric chromosomes. The data suggests that PARPi olaparib and PJ34 altered the choice of DNA-DSB repair pathways rather than reducing the total amount of DNA-DSB repair, which resulted in increased repair errors. Increased quadratic misrepair was one of the mechanisms of PARP-mediated radiosensitization, preferentially at the higher dose range compared to the lower dose range. CONCLUSION: PARPi may be a promising candidate to combine with stereotactic hypofractionated radiotherapy, aiming at high-dose region-directed radiosensitization.

Engineering Radiosensitizer-Based Metal-Phenolic Networks Potentiate STING Pathway Activation for Advanced Radiotherapy.

Radiotherapy, a mainstay of first-line cancer treatment, suffers from its high-dose radiation-induced systemic toxicity and radioresistance caused by the immunosuppressive tumor microenvironment. The synergy between radiosensitization and immunomodulation may overcome these obstacles for advanced radiotherapy. Here, the authors propose a radiosensitization cooperated with stimulator of interferon genes (STING) pathway activation strategy by fabricating a novel lanthanide-doped radiosensitizer-based metal-phenolic network, NaGdF4 :Nd@NaLuF4 @PEG-polyphenol/Mn (DSPM). The amphiphilic PEG-polyphenol successfully coordinates with NaGdF4 :Nd@NaLuF4 (radiosensitizer) and Mn2+ via robust metal-phenolic coordination. After cell internalization, the pH-responsive disassembly of DSPM triggers the release of their payloads, wherein radiosensitizer sensitizes cancer cells to X-ray and Mn2+ promote STING pathway activation. This radiosensitizer-based DSPM remarkably benefits dendritic cell maturation, anticancer therapeutics in primary tumors, accompanied by robust systemic immune therapeutic performance against metastatic tumors. Therefore, a powerful radiosensitization with STING pathway activation mediated immunostimulation strategy is highlighted here to optimize cancer radiotherapy.

Radiosensitizer Effect of ß-Apopicropodophyllin against Colorectal Cancer via Induction of Reactive Oxygen Species and Apoptosis.

ß-apopicropodophyllin (APP), a derivative of podophyllotoxin (PPT), has been identified as a potential anti-cancer drug. This study tested whether APP acts as an anti-cancer drug and can sensitize colorectal cancer (CRC) cells to radiation treatment. APP exerted an anti-cancer effect against the CRC cell lines HCT116, DLD-1, SW480, and COLO320DM, with IC50 values of 7.88 nM, 8.22 nM, 9.84 nM, and 7.757 nM, respectively, for the induction of DNA damage. Clonogenic and cell counting assays indicated that the combined treatment of APP and γ-ionizing radiation (IR) showed greater retardation of cell growth than either treatment alone, suggesting that APP sensitized CRC cells to IR. Annexin V-propidium iodide (PI) assays and immunoblot analysis showed that the combined treatment of APP and IR increased apoptosis in CRC cells compared with either APP or IR alone. Results obtained from the xenograft experiments also indicated that the combination of APP and IR enhanced apoptosis in the in vivo animal model. Apoptosis induction by the combined treatment of APP and IR resulted from reactive oxygen species (ROS). Inhibition of ROS by N-acetylcysteine (NAC) restored cell viability and decreased the induction of apoptosis by APP and IR in CRC cells. Taken together, these results indicate that a combined treatment of APP and IR might promote apoptosis by inducing ROS in CRC cells.

Harnessing the Power of Kiwifruit for Radiosensitization of Melanoma.

BACKGROUND: Melanoma is the deadliest variant of skin cancer and its incidence continues to increase. There are limited treatment options for advanced and metastatic cases of melanoma, despite advances in immunotherapy and chemotherapy. Melanoma is notorious as a radioresistant tumor. Previous studies found that phytochemicals, such as resveratrol and those found in green tea and blueberry, can sensitize various cancer cells, including melanoma, to radiotherapy. Our previous study also revealed that kiwifruit extract (KE) has antitumor activity to melanoma cells. This study was designed to expand upon our previous investigation and determine KE's potential as a radiosensitizer on CRL-11147 melanoma cancer cells and elucidate the possible mechanisms behind its potential. MATERIALS AND METHODS: Proliferation and apoptosis of CRL-11147 melanoma cells under radiation therapy (RT) plus KE versus RT alone were investigated using Proliferative cell nuclear antigen (PCNA) staining, quick cell proliferation assay, clonogenic assay, and caspase-3 activity assay. Reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry (IHC) were then used to investigate the mechanisms behind the observed results. RESULTS: The percentage of CRL-11147 colonies, PCNA staining intensity, and the optic density value of CRL-11147 cells decreased with RT/KE vs. RT alone. Relative caspase-3 activity was increased with RT/KE vs. RT alone. Increased expression of the anti-proliferative molecule p27 and pro-apoptotic molecule TRAILR1 correlated with the anti-tumor effect seen in the RT/KE group versus the RT alone group. CONCLUSION: KE augments radiosensitivity of CRL-11147 by up-regulating both p27 and TRAILR1 to inhibit proliferation and increase apoptosis, respectively.

Radiosensitizing Effect of Bromelain Using Tumor Mice Model via Ki-67 and PARP-1 Inhibition.

Recent reports have shown that bromelain (BL), a pineapple extract, acts as an adjuvant therapy in cancer treatment and prevention of carcinogenesis. The present study was designed to investigate the possible mechanisms by which BL could radiosensitize tumor cells in vitro and in a mouse tumor model. BL has shown a significant reduction in the viability of the radioresistant human breast carcinoma (MCF-7) cell line using cell proliferation assay. The in vivo study was designed using the Ehrlich model in female albino mice, treated with BL (6 mg/kg b. wt., intraperitoneal, once daily for 10 days) 1 hour before exposure to a fractionated dose of gamma radiation (5 Gy, 1 Gy for 5 subsequent days). The radiosensitizing effect of BL was evident in terms of a significant reduction in tumor volume, poly ADP ribose polymerase-1 (PARP-1), the proliferation marker Ki-67 and nuclear factor kappa activated B cells (NF-κB) with a significant elevation in the reactive oxygen species (ROS) content and lipid peroxidation (LPO) in tumor cells. The present findings offer a novel insight into the radiosensitizing effect of BL and its potential application in the radiotherapy course.

Curcumins antineoplastic, radiosensitizing and radioprotective properties.

BACKGROUND: Curcumin is an ingredient in the turmeric plant that gives yellow color to dishes and is used as a spice. It has been used locally/topically and systemically in the treatment of diseases in Far Eastern societies, especially in Indian and Chinese traditional medicine. Curcumin is a natural substance that does not show toxic properties in overdose. In addition to its anti-inflammatory, anti-oxidant, anti-neoplastic, anti-viral, anti-microbial, anti-angiogenic properties, platelet aggregation, apoptosis, and wound healing have been demonstrated in different studies. In recent years, it has been used as a radiosensitizing agent and a radioprotector in radiation therapy. Although curcumin has low bio-availability, it seems to be the ideal molecule due to its low molecular weight, high activity in inhibiting the growth of tumor cells and protecting normal tissues from the side effects of radiation. PURPOSE: Curcumin in combination with radiotherapy was discussed in the light of the literature.

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.

Gallotannin from Bouea macrophylla Seed Extract Suppresses Cancer Stem-like Cells and Radiosensitizes Head and Neck Cancer.

Cancer stem cells (CSCs) play a critical role in radiation resistance and recurrence. Thus, drugs targeting CSCs can be combined with radiotherapy to improve its antitumor efficacy. Here, we investigated whether a gallotannin extract from Bouea macrophylla seed (MPSE) and its main bioactive compound, pentagalloyl glucose (PGG), could suppress the stemness trait and further confer the radiosensitivity of head and neck squamous cell carcinoma (HNSCC) cell lines. In this study, we evaluate the effect of MPSE or PGG to suppress CSC-like phenotypes and radiosensitization of HNSCC cell lines using a series of in vitro experiments, tumorsphere formation assay, colony formation assay, apoptosis assay, and Western blotting analysis. We demonstrate that MPSE or PGG is able to suppress tumorsphere formation and decrease protein expression of cancer stem cell markers. MPSE or PGG also enhanced the radiosensitivity in HNSCC cells. Pretreatment of cells with MPSE or PGG increased IR-induced DNA damage (γ-H2Ax) and enhanced radiation-induced cell death. Notably, we observed that pretreatment with MPSE or PGG attenuated the IR-induced stemness-like properties characterized by tumorsphere formation and the CD44 CSC marker. Our findings describe a novel strategy for increasing therapeutic efficacy for head and neck cancer patients using the natural products MPSE and PGG.

Breast cancer suppression by curcumin-naringenin-magnetic-nano-particles: In vitro and in vivo studies.

BACKGROUND: The limitations of surgery, radiotherapy, and chemotherapy in cancer treatment and the increase in the application of nanomaterials in the field of biomedicine have promoted the use of nanomaterials in combination with radiotherapy for cancer treatment. OBJECTIVE: To improve the efficiency of cancer treatment, curcumin-naringenin loaded dextran-coated magnetic nanoparticles (CUR-NAR-D-MNPs) were used as chemotherapy and in combination with radiotherapy to verify their effectiveness in treating tumors. METHODS: CUR-NAR-D-MNPs were prepared and studied by several characterization methods. Median inhibitory concentration (IC50) and cellular toxicity were evaluated by 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide (MTT) assay. The cell death and radiosensitization were studied by acridine orange/ethidium bromide dual staining of MCF-7 human breast cancer cells. RESULTS: CUR-NAR-D-MNPs induce apoptosis and inhibited cell proliferation through reactive oxygen species (ROS) generation. CUR-NAR-D-MNPs used alone had a certain therapeutic effect on tumors. CUR-NAR-D-MNPs plus radiotherapy significantly reduced the tumor volume and led to cell cycle arrest and induction of apoptosis through modulation of P53high, P21high, TNF-αlow, CD44low, and ROShigh signalingCONCLUSIONS:CUR-NAR-D-MNPs are effective in the treatment of tumors when combined with radiotherapy, and show radiosensitization effects against cancer proliferation in vitro and in vivo.