Search Results (39)

High-Z nanoparticles (NPs) have the potential to revolutionize cancer radiotherapy by radiosensitising tumours. This is particularly important for radioresistant cancers such as glioblastoma. A newer NP candidate in this area is thulium oxide nanoparticles (TmNPs). However, prior to clinical assessment, ideal NP characteristics, including biocompatibility, biosafety, and preferential uptake in cancer, should be assessed. This in vitro study compares the effects of TmNP treatment, without radiation, on 9L gliosarcoma (9LGS), a well-established glioblastoma cell model, with exposure to Madin Darby Canine Kidney (MDCK) cells, a widely used non-cancerous cell model. The findings demonstrated selective uptake of TmNPs in 9LGS over MDCK following treatment. A biological assessment of toxicity confirmed minimal long-term effects on MDCK, whilst TmNPs were observed to induce some notable cell death in 9LGS. Excessive TmNP uptake in 9LGS over time was observed to induce cell vacuolisation, which resulted in cell death via necrosis. It was concluded that this was the explanation for the underlying mechanisms of TmNP toxicity in cancer cells. This study was therefore able to demonstrate not only that TmNPs are a biocompatible, cancer-selective candidate for radiosensitiser usage, but further provided a theory to explain its mechanisms of cancer cell toxicity. Full article

Background/objectives: Brain cancer remains difficult to treat, with survival statistics stagnant for decades. The resistance of glioblastoma brain tumours can greatly challenge the effectiveness of conventional cancer radiotherapy. However, high dose rate radiotherapy has unique effects that allow for normal tissue sparing whilst maintaining tumour control. The addition of targeted radiosensitisers, such as the chemotherapeutic drug methotrexate (MTX) or the high-Z halogenated pyrimidine drug iododeoxyuridine (IUdR), can improve radiotherapy outcomes. Combining these radiosensitiser agents with ultra-high dose rate (UHDR) synchrotron X-rays can bear synergistic effects to enhance the efficacy of these multi-modal UHDR therapies, providing a means to overcome the radioresistance of brain cancer. Methods: Here, we use controlled in vitro assays following treatment, including a clonogenic assay to determine long-term cell survival and γH2AX immunofluorescent confocal microscopy to quantify double-strand DNA breaks (DSBs). Results: We find significant enhancement for highly synergistic combinations of IUdR+MTX with synchrotron X-rays. Cell survival results demonstrate 5.4 times increased 9L gliosarcoma cell killing when these agents are combined with UHDR synchrotron X-rays compared with conventional X-rays alone at the same 5 Gy dose. The underlying mechanisms are unveiled using γH2AX imaging and reveal significant increases in DSBs and dying cells following exposure to UHDR radiation. Conclusions: Our results demonstrate that highly synergistic combination treatments using UHDR synchrotron radiation can yield significantly improved brain cancer killing compared with conventional radiotherapy. We anticipate that these additive, multi-modal combination therapies will provide options for more targeted and effective use of radiotherapies for the future treatment of brain cancer. Full article

The emergence of nanotechnology in medicine, particularly using iron oxide nanoparticles (IONPs), may impact cancer treatment strategies. IONPs exhibit unique properties, such as superparamagnetism, biocompatibility, and ease of surface modification, making them ideal candidates for imaging, and therapeutic interventions. Their application in targeted drug delivery, especially with traditional chemotherapeutic agents like cisplatin, has shown potential in overcoming limitations such as low bioavailability and systemic toxicity of chemotherapies. Moreover, IONPs, by releasing iron ions, can induce ferroptosis, a form of iron-dependent cell death, which offers a promising pathway to reverse radio- and chemoresistance in cancer therapy. In particular, IONPs demonstrate significant potential as radiosensitisers, enhancing the effects of radiotherapy by promoting reactive oxygen species (ROS) generation, lipid peroxidation, and modulating the tumour microenvironment to stimulate antitumour immune responses. This review explores the multifunctional roles of IONPs in radiosensitisation through ferroptosis induction, highlighting their promise in advancing treatment for head and neck cancers. Additional research is crucial to fully addressing their potential in clinical settings, offering a novel approach to personalised cancer treatment. Full article

Global shortages, toxicities, and high levels of incomplete treatment with Bacillus Calmette Guerin (BCG) for non-muscle invasive bladder cancer has resulted in increasing interest in alternative treatments. Radiotherapy is not the standard of care for non-muscle invasive bladder cancer (NMIBC), despite being routinely used in muscle invasive bladder cancer. Modern techniques and advances in technology mean that radiotherapy can be delivered with increased precision in reducing normal tissue damage. Developing novel biomarker approaches, together with combination approaches with radiosensitisers and other systemic treatments, means that radiotherapy could offer greater benefits than current treatments with BCG or surgery. This review summarises the current landscape and future potential of radiotherapy for high-risk NMIBC. Full article

(1) Background/Objectives: Primary and secondary brain tumours often hold devastating prognoses and low survival rates despite the application of maximal neurosurgical resection, and state-of-the-art radiotherapy and chemotherapy. One limiting factor in their management is that several antineoplastic agents are unable to cross the blood–brain barrier (BBB) to reach the tumour microenvironment. Nanomedicine could hold the potential to become an effective means of drug delivery to overcome previous hurdles towards effective neuro-oncological treatments. (2) Methods: A scoping review following the PRISMA-ScR guidelines and checklist was conducted using key terms input into PubMed to find articles that reflect emerging trends in the utilisation of nanomedicine in drug delivery for primary and secondary brain tumours. (3) Results: The review highlights various strategies by which different nanoparticles can be exploited to bypass the BBB; we provide a synthesis of the literature on the ongoing contributions to therapeutic protocols based on chemotherapy, immunotherapy, focused ultrasound, radiotherapy/radiosurgery, and radio-immunotherapy. (4) Conclusions: The emerging trends summarised in this scoping review indicate encouraging advantageous properties of nanoparticles as potential effective drug delivery mechanisms; however, there are still nanotoxicity issues that largely remain to be addressed before the translation of these innovations from laboratory to clinical practice. Full article

Background/Objectives: Brain cancer is notoriously resistant to traditional treatments, including radiotherapy. Microbeam radiation therapy (MRT), arrays of ultra-fast synchrotron X-ray beams tens of micrometres wide (called peaks) and spaced hundreds of micrometres apart (valleys), is an effective alternative to conventional treatments. MRT’s advantage is that normal tissues can be spared from harm whilst maintaining tumour control. Combining MRT with targeted radiosensitisers, such as nanoparticles, chemotherapeutic drugs, and halogenated pyrimidine drugs, can further improve radiotherapy by enhancing radiation damage. However, the underlying mechanisms of MRT are still being understood, which is essential to ensuring the reliable and successful use of MRT. Methods: An in vitro study was performed using γH2AX imaging, and quantification was performed via confocal microscopy and a clonogenic cell survival assay. Results: We show that methotrexate chemotherapeutics and iododeoxyuridine enhance MRT cell-killing and thulium oxide nanoparticles (TmNPs) broaden MRT peaks, and using γH2AX immunofluorescent confocal microscopy to quantify DNA damage, we further our knowledge of MRT mechanisms. γH2AX images verify the biological responses of cells aligning with the physical collimation of MRT, and we can accurately measure MRT microbeam characteristics bio-dosimetrically. The peak-to-valley dose ratio (PVDR), the ratio of the peak dose to the valley dose that characterises an MRT field, was accurately measured biologically using γH2AX imaging, despite studies previously finding this challenging. Conclusions: The measurement of biological PVDR has been performed for the first time with high-Z radiosensitisers, including nanoparticles, and several novel radiosensitiser-enhanced MRT mechanisms were discovered. Our results deepen our understanding of MRT with radiosensitisers, and can contribute to its accurate and future successful use in treating cancer. Full article

Background/Objectives: The incidence of head and neck squamous cell carcinoma (HNSCC), currently ~800,000 cases per year worldwide, is rising. Radiotherapy remains a mainstay for the treatment of HNSCC, although inherent radioresistance, particularly in human papillomavirus (HPV)-negative disease subtypes, remains a significant barrier to effective treatment. Therefore, combinatorial strategies using drugs or inhibitors against specific cellular targets are necessary to enhance HNSCC radiosensitivity to lead to an improvement in patient outcomes. Given that radiotherapy acts through targeting and damaging DNA, a common strategy is to focus on enzymes within DNA-dependent cellular pathways, such as DNA damage repair. Methods: Here, we have employed a 3D spheroid model of HNSCC (FaDu) in combination with a targeted drug screen to identify novel radiosensitisers that suppress tumour growth. Results: We identified that histone deacetylases (HDACs) were prominent candidates, and subsequently identified that the HDAC inhibitors mocetinostat and pracinostat, as well as the combined HDAC–epidermal growth factor receptor inhibitor CUDC-101, were effective at radiosensitising cell models of HNSCC (FaDu, A253, UMSCC11b) through their impact on both spheroid growth and clonogenic survival assays. We also demonstrated that this combinatorial strategy leads to inhibition of the repair of DNA double-strand breaks through the neutral comet assay and γH2AX foci analysis using immunofluorescence microscopy, providing a mechanism of action through which HDAC inhibition functions in HNSCC radiosensitisation. Conclusions: We believe that this approach should be further investigated in preclinical models, in order to realise the full therapeutic potential of HDAC inhibition for the radiosensitisation of HNSCC, eventually leading to improved patient treatment efficacy and outcomes. Full article

Radiotherapy is one of the main cancer treatments being used for ~50% of all cancer patients. Conventional radiotherapy typically utilises X-rays (photons); however, there is increasing use of particle beam therapy (PBT), such as protons and carbon ions. This is because PBT elicits significant benefits through more precise dose delivery to the cancer than X-rays, but also due to the increases in linear energy transfer (LET) that lead to more enhanced biological effectiveness. Despite the radiotherapy type, the introduction of DNA damage ultimately drives the therapeutic response through stimulating cancer cell death. To combat this, cells harbour cell cycle checkpoints that enables time for efficient DNA damage repair. Interestingly, cancer cells frequently have mutations in key genes such as TP53 and ATM that drive the G₁/S checkpoint, whereas the G₂/M checkpoint driven through ATR, Chk1 and Wee1 remains intact. Therefore, targeting the G₂/M checkpoint through specific inhibitors is considered an important strategy for enhancing the efficacy of radiotherapy. In this review, we focus on inhibitors of Chk1 and Wee1 kinases and present the current biological evidence supporting their utility as radiosensitisers with different radiotherapy modalities, as well as clinical trials that have and are investigating their potential for cancer patient benefit. Full article

Titanium dioxide nanoparticles (TiO₂ NPs) have been investigated as one of the potential dose enhancement agents for radiation therapy. The role of TiO₂ NPs as a photodynamic sensitiser has been well documented, but its sensitisation with X-rays is not highlighted. Unlike other metal NPs, such as gold NPs, the main challenge for TiO₂ NPs as radiosensitisers is their low atomic number, resulting in a small cross-section for X-rays. This review summarises the results of current research in this area to explore the dose enhancement inflicted by TiO₂ NPs, which could potentially be of great value in improving radiation therapy efficiency. Full article

Histone deacetylases inhibitors (HDACis) have shown promising therapeutic outcomes in haematological malignancies such as leukaemia, multiple myeloma, and lymphoma, with disappointing results in solid tumours when used as monotherapy. As a result, combination therapies either with radiation or other deoxyribonucleic acid (DNA) damaging agents have been suggested as ideal strategy to improve their efficacy in solid tumours. Numerous in vitro and in vivo studies have demonstrated that HDACis can sensitise malignant cells to both electromagnetic and particle types of radiation by inhibiting DNA damage repair. Although the radiosensitising ability of HDACis has been reported as early as the 1990s, the mechanisms of radiosensitisation are yet to be fully understood. This review brings forth the various protocols used to sequence the administration of radiation and HDACi treatments in the different studies. The possible contribution of these various protocols to the ambiguity that surrounds the mechanisms of radiosensitisation is also highlighted. Full article

Nanoparticles are being increasingly studied to enhance radiation effects. Among them, nanodiamonds (NDs) are taken into great consideration due to their low toxicity, inertness, chemical stability, and the possibility of surface functionalization. The objective of this study is to explore the influence of the chemical/physical properties of NDs on cellular radiosensitivity to combined treatments with radiation beams of different energies. DAOY, a human radioresistant medulloblastoma cell line was treated with NDs—differing for surface modifications [hydrogenated (H-NDs) and oxidized (OX-NDs)], size, and concentration—and analysed for (i) ND internalization and intracellular localization, (ii) clonogenic survival after combined treatment with different radiation beam energies and (iii) DNA damage and apoptosis, to explore the nature of ND–radiation biological interactions. Results show that chemical/physical characteristics of NDs are crucial in determining cell toxicity, with hydrogenated NDs (H-NDs) decreasing either cellular viability when administered alone, or cell survival when combined with radiation, depending on ND size and concentration, while OX-NDs do not. Also, irradiation at high energy (γ-rays at 1.25 MeV), in combination with H-NDs, is more efficient in eliciting radiosensitisation when compared to irradiation at lower energy (X-rays at 250 kVp). Finally, the molecular mechanisms of ND radiosensitisation was addressed, demonstrating that cell killing is mediated by the induction of Caspase-3-dependent apoptosis that is independent to DNA damage. Identifying the optimal combination of ND characteristics and radiation energy has the potential to offer a promising therapeutic strategy for tackling radioresistant cancers using H-NDs in conjunction with high-energy radiation. Full article

The role of hypoxic tumour cells in resistance to radiotherapy, and in suppression of immune response, continues to endorse tumour hypoxia as a bona fide, yet largely untapped, drug target. Radiotherapy innovations such as stereotactic body radiotherapy herald new opportunities for classical oxygen-mimetic radiosensitisers. Only nimorazole is used clinically as a radiosensitiser, and there is a dearth of new radiosensitisers in development. In this report, we augment previous work to present new nitroimidazole alkylsulfonamides and we document their cytotoxicity and ability to radiosensitise anoxic tumour cells in vitro. We compare radiosensitisation with etanidazole and earlier nitroimidazole sulfonamide analogues and we identify 2-nitroimidazole and 5-nitroimidazole analogues with marked tumour radiosensitisation in ex vivo assays of surviving clonogens and with in vivo tumour growth inhibition. Full article

Resistance to cancer therapies remains a clinical challenge and an unsolved problem. In a previous study, we characterized a new colon cancer cell line, namely HT500, derived from human HT29 cells and resistant to clinically relevant levels of ionizing radiation (IR). Here, we explored the effects of two natural flavonoids, quercetin (Q) and fisetin (F), well-known senolytic agents that inhibit genotoxic stress by selectively removing senescent cells. We hypothesized that the biochemical mechanisms responsible for the radiosensitising effects of these natural senolytics could intercept multiple biochemical pathways of signal transduction correlated to cell death resistance. Radioresistant HT500 cells modulate autophagic flux differently than HT29 cells and secrete pro-inflammatory cytokines (IL-8), commonly associated with senescence-related secretory phenotypes (SASP). Q and F inhibit PI₃K/AKT and ERK pathways, which promote p16^INK4 stability and resistance to apoptosis, but they also activate AMPK and ULK kinases in response to autophagic stress at an early stage. In summary, the combination of natural senolytics and IR activates two forms of cell death: apoptosis correlated to the inhibition of ERKs and lethal autophagy dependent on AMPK kinase. Our study confirms that senescence and autophagy partially overlap, share common modulatory pathways, and reveal how senolytic flavonoids can play an important role in these processes. Full article

The addition of platinum chemotherapy to primary radiotherapy (chemoradiation) improves survival outcomes for patients with head and neck squamous cell carcinoma (HNSCC), but it carries a high incidence of acute and long-term treatment-related complications, resulting in a poor quality of life. In addition, patients with significant co-morbidities, or older patients, cannot tolerate or do not benefit from concurrent chemoradiation. These patients are often treated with radiotherapy alone resulting in poor locoregional control and worse survival outcomes. Thus, there is an urgent need to assess other less toxic treatment modalities, which could become an alternative to chemoradiation in HNSCC. Currently, there are several promising anti-cancer drugs available, but there has been very limited success so far in replacing concurrent chemoradiation due to their low efficacy or increased toxicities. However, there is new hope that a treatment strategy that incorporates agents that act as radiosensitisers to improve the efficacy of conventional radiotherapy could be an alternative to more toxic chemotherapeutic agents. Recently, imidazole-based or quinone-based anti-malarial compounds have drawn considerable attention as potential radiosensitisers in several cancers. Here, we will discuss the possibility of using these compounds as radiosensitisers, which could be assessed as safe and effective alternatives to chemotherapy, particularly for patients with HNSCC that are not suitable for concurrent chemotherapy due to their age or co-morbidities or in metastatic settings. In addition, these agents could also be tested to assess their efficacy in combination with immunotherapy in recurrent and metastatic settings or in combination with radiotherapy and immunotherapy in curative settings. Full article

Cisplatin-based chemo-radiotherapy (CRT) is the standard treatment for advanced cervical cancer (CC) but the response rate is poor (46–72%) and cisplatin is nephrotoxic. Therefore, better treatment of CC is urgently needed. We have directly compared, for the first time, the cytotoxicity of four DDR inhibitors (rucaparib/PARPi, VE-821/ATRi, PF-477736/CHK1i and MK-1775/WEE1i) as single agents, and in combination with cisplatin and radiotherapy (RT) in a panel of CC cells. All inhibitors alone caused concentration-dependent cytotoxicity. Low ATM and DNA-PKcs levels were associated with greater VE-821 cytotoxicity. Cisplatin induced ATR, CHK1 and WEE1 activity in all of the cell lines. Cisplatin only activated PARP in S-phase cells, but RT activated PARP in the entire population. Rucaparib was the most potent radiosensitiser and VE-821 was the most potent chemosensitiser. VE-821, PF-47736 and MK-1775 attenuated cisplatin-induced S-phase arrest but tended to increase G2 phase accumulation. In mice, cisplatin-induced acute kidney injury was associated with oxidative stress and PARP activation and was prevented by rucaparib. Therefore, while all inhibitors investigated may increase the efficacy of CRT, the greatest clinical potential of rucaparib may be in limiting kidney damage, which is dose-limiting. Full article