Targeting mitochondrial translation by inhibiting DDX3: a novel radiosensitization strategy for cancer treatment.

DDX3 is a DEAD box RNA helicase with oncogenic properties. RK-33 is developed as a small-molecule inhibitor of DDX3 and showed potent radiosensitizing activity in preclinical tumor models. This study aimed to assess DDX3 as a target in breast cancer and to elucidate how RK-33 exerts its anti-neoplastic effects. High DDX3 expression was present in 35% of breast cancer patient samples and correlated with markers of aggressiveness and shorter survival. With a quantitative proteomics approach, we identified proteins involved in the mitochondrial translation and respiratory electron transport pathways to be significantly downregulated after RK-33 or DDX3 knockdown. DDX3 localized to the mitochondria and DDX3 inhibition with RK-33 reduced mitochondrial translation. As a consequence, oxygen consumption rates and intracellular ATP concentrations decreased and reactive oxygen species (ROS) increased. RK-33 antagonized the increase in oxygen consumption and ATP production observed after exposure to ionizing radiation and reduced DNA repair. Overall, we conclude that DDX3 inhibition with RK-33 causes radiosensitization in breast cancer through inhibition of mitochondrial translation, which results in reduced oxidative phosphorylation capacity and increased ROS levels, culminating in a bioenergetic catastrophe.

Nuclear molecular imaging with nanoparticles: radiochemistry, applications and translation.

Molecular imaging provides considerable insight into biological processes for greater understanding of health and disease. Numerous advances in medical physics, chemistry and biology have driven the growth of this field in the past two decades. With exquisite sensitivity, depth of detection and potential for theranostics, radioactive imaging approaches have played a major role in the emergence of molecular imaging. At the same time, developments in materials science, characterization and synthesis have led to explosive progress in the nanoparticle (NP) sciences. NPs are generally defined as particles with a diameter in the nanometre size range. Unique physical, chemical and biological properties arise at this scale, stimulating interest for applications as diverse as energy production and storage, chemical catalysis and electronics. In biomedicine, NPs have generated perhaps the greatest attention. These materials directly interface with life at the subcellular scale of nucleic acids, membranes and proteins. In this review, we will detail the advances made in combining radioactive imaging and NPs. First, we provide an overview of the NP platforms and their properties. This is followed by a look at methods for radiolabelling NPs with gamma-emitting radionuclides for use in single photon emission CT and planar scintigraphy. Next, utilization of positron-emitting radionuclides for positron emission tomography is considered. Finally, recent advances for multimodal nuclear imaging with NPs and efforts for clinical translation and ongoing trials are discussed.

Enzymatically activatable diagnostic probes.

Molecular imaging of disease development, progression and treatment is seen as key to further advancement in the understanding and triumph over illness. The role of enzymes is to catalyze the biochemical reactions that help regulate health, and when dysregulated in complex organisms lead to or indicate disease. The ability to image the action of these proteins for diagnostic purposes opens a window for the researcher and clinician to witness specifc molecular events in vitro and in vivo. Such probes have been developed and deployed for the optical, radionuclide and magnetic resonance modalities and offer significant benefits over conventional agents. The signal of enzymatically-activated probes is regulated by the specific activity of the desired enzyme. This allows for a higher signal to background ratio over non-specific and targeted agents. It also enables the modulation of contrast agent distribution (and even cellular accumulation) following enzymatic activity. This review summarizes the strategies and probes in development and use in this emergent field of molecular imaging, with a particular focus on the research and medical relevance of these advances.