Inhibition of IKK-NFκB pathway sensitizes lung cancer cell lines to radiation

Objective:Cancer cell radioresistance is a stumbling block in radiation therapy.The activity in the nuclear factor kappa B(NFκB)pathway correlates with anti-apoptotic mechanisms and increased radioresistance.The IKK complex plays a major role in NFκB activation upon numerous signals.In this study,we examined the interaction between ionizing radiation(IR)and different members of the IKK-NFκB pathway,as well as upstream activators,RAF1,ERK,and AKT1.Methods:The effect of 4 Gy of IR on the expression of the RAF1-ERK-IKK-NFκB pathway was examined in A549 and H1299 lung cancer cell lines using Western blot analysis and confocal microscopy.We examined changes in radiation sensitivity using gene silencing or pharmacological inhibitors of ERK and IKKβ.Results:IKKα,IKKγ,and IκBαincreased upon exposure to IR,thereby affecting nuclear levels of NFκB(phospho-p65).ERK inhibition or si RNA-mediated down-regulation of RAF1 suppressed the post-irradiation survival of the examined lung cancer cell lines.A similar effect was detected on survival upon silencing IKKα/IKKγor inhibiting IKKβ.Conclusions:Exposure of lung cancer cells to IR results in NFκB activation via IKK.The genetic or pharmacological blockage of the RAF1-ERK-IKK-NFκB pathway sensitizes cells to therapeutic doses of radiation.Therefore,the IKK pathway is a promising target for therapeutic intervention in combination with radiotherapy.

Effect of Low Gamma Irradiation on the Germination and Morphological Characteristics of Broad Beans (Vicia faba L.), Mung Beans (Vigna radiata L.), and Peas (Pisum sativum L.) Seedlings

Understanding the effects of ionising radiation (IR) on plants has been a major focus of research. Acute high-dose effects are well-documented and understood (mainly through laboratory testing). Lower doses, on the other hand, are less understood, as low dosage research is controversial, and there are only a few studies that use low and ecologically relevant IR levels, particularly those conducted under controlled conditions. The effect of low gamma radiation was investigated in this study using Vicia faba L., Vigna radiata L., and Pisum sativum L. Healthy and viable seeds of these plants were irradiated with varying doses of gamma radiation (Cs−137 source) and sown under controlled environmental conditions. The doses/dose rates used were within the scope of the International Commission on Radiological Protection’s Derived Consideration Reference Level (DCRL) for these groups of plants (1 - 10 mGy∙d−1), so this study tested this DCRL. Observations were made on certain germination parameters and growth traits like germination percentage and rate, shoot and root length, seed weight, number of leaves, wet and dry biomass, plant height, leaf chlorophyll content, and leaf area. In the germination phase, the doses employed in this experiment did not affect the seeds’ weight, germination percentage, and rate, but there were some interesting effects on the root and shoot length;as all irradiated groups performed better than the control group (particularly the 16.2 mGy and 48.5 mGy dose in V. radiata and P. sativum, while the 1070 mGy dose had the highest value in V. faba). However, the plants were able to compensate for the effects observed in the germination phase and by the end of the experiment, there were no statistically significant effects (at 0.05 p level) in all the morphometric parameters studied;the visible organs appeared normal, and growth rate was normal. This study, therefore, concludes that the DCRL used to protect these groups of plants from the effects of IR (1 - 10 mGy∙d−1) is appropriate and present regulation appears to be suitable.

Alpha-2-macroglobulin as a radioprotective agent: a review

Radiation is an important modality in cancer treatment, and eighty percent of cancer patients need radiotherapy at some point during their clinical management. However, radiation-induced damage to normal tissues restricts the therapeutic doses of radiation that can be delivered to tumours and thereby limits the effectiveness of the treatment. The use of radioprotectors represents an obvious strategy to obtain better tumour control using a higher dose in radiotherapy. However, most of the synthetic radioprotective compounds studied have shown inadequate clinical efficacy owing to their inherent toxicity and high cost. Hence, the development of radioprotective agents with lower toxicity and an extended window of protection has attracted a great deal of attention, and the identification of alternative agents that are less toxic and highly effective is an absolute necessity. Recent studies have shown that alpha-2-macroglobulin（α2M） possesses radioprotective effects. α2M is a tetrameric, disulfide-rich plasma glycoprotein that functions as a nonselective inhibitor of different types of non-specific proteases and as a carrier of cytokines, growth factors, and hormones. α2M induces protein factors whose interplay underlies radioprotection, which supports the idea that α2M is the central effector of natural radioprotection in the rat. Pretreatment with α2M has also induced a significant reduction of irradiation-induced DNA damage and the complete restoration of liver and body weight. Mihailovi？ et al. concluded that the radioprotection provided by α2M was in part mediated through cytoprotection of new blood cells produced in the bone marrow; these authors also indicated that an important aspect of the radioprotective effect of amifostine was the result of the induction of the endogenous cytoprotective capability of α2M. The radioprotective effects of α2M are possibly due to antioxidant, antifibrosis, and anti-inflammatory functions, as well as the maintenance of homeostasis, and enhancement of the DNA repair and cell recovery processes. This review is the first to summarise the observations and elucidate the possible mechanisms responsible for the beneficial effects of α2M. The lacunae in the existing knowledge and directions for future research are also addressed.

Radiotherapy and the cellular DNA damage response: current and future perspectives on head and neck cancer treatment

Incidences of head and neck squamous cell carcinoma(HNSCC)have been on the rise in the last few decades,with a significant risk factor being human papillomavirus(HPV)type-16/18 infection,particularly in the development of oropharyngeal cancers.Radiotherapy(RT)is an important treatment modality for HNSCC,where it promotes extensive cellular DNA damage leading to the therapeutic effect.It has been well-established that HPV-positive HNSCC display better response rates and improved survival following RT compared to HPV-negative HNSCC.The differential radiosensitivity has been largely associated with altered cellular DNA damage response mechanisms in HPV-positive HNSCC,and particularly with the signaling and repair of DNA double strand breaks.However,other factors,particularly hypoxia present within the solid cancer,have a major impact on relative radioresistance.Consequently,recent approaches aimed at enhancing the radiosensitivity of HNSCC have largely centered on targeting key proteins involved in DNA repair,DNA damage checkpoint activation,and hypoxia signaling.These studies have utilised in vitro and in vivo models of HPV-positive and HPV-negative HNSCC and examined the impact of specific inhibitors against the targets in combination with radiation in suppressing HNSCC cell growth and survival.Here,accumulating evidence has shown that targeting enzymes including poly(ADP-ribose)polymerase,ataxia telangiectasia and Rad-3 related,DNA-dependent protein kinase catalytic subunit,and checkpoint kinase 1 can radiosensitise HNSCC cells which should be taken forward in further preclinical studies,with the goal of optimizing the future effective RT treatment of HNSCC.