Emerging evidence suggests that metformin, a widely used anti-diabetic drug, may be useful in the prevention and treatment of different cancers. In the present study, we demonstrate that metformin directly inhibits the enzymatic function of hexokinase (HK) I and II in a cell line of triple-negative breast cancer (MDA-MB-231). The inhibition is selective for these isoforms, as documented by experiments with purified HK I and II as well as with cell lysates. Measurements of 18F-fluoro-deoxyglycose uptake document that it is dose- and time-dependent and powerful enough to virtually abolish glucose consumption despite unchanged availability of membrane glucose transporters. The profound energetic imbalance activates phosphorylation and is subsequently followed by cell death. More importantly, the “in vivo” relevance of this effect is confirmed by studies of orthotopic xenografts of MDA-MB-231 cells in athymic (nu/nu) mice. Administration of high drug doses after tumor development caused an evident tumor necrosis in a time as short as 48 h. On the other hand, 1 mo metformin treatment markedly reduced cancer glucose consumption and growth. Taken together, our results strongly suggest that HK inhibition contributes to metformin therapeutic and preventive potential in breast cancer.
Several studies have highlighted the role of vascular 18 F-NaF uptake as a marker of ongoing calcium deposition. However, accumulation of 18 F-NaF is often inconsistent with localization of arterial plaque. Calcification activity and thus 18 F-NaF uptake might prevail in the earlier plaque stages. To test this hypothesis, we evaluated 18 F-NaF uptake in plaque of 3 different densities, using density as a marker of calcification progression. We also tested whether attenuationweighted image reconstruction affects 18 F-NaF uptake in the different plaque stages. Methods: Sixty-four oncologic patients (14 men and 50 women; mean age, 65.3 ± 8.2 y; range, 26-81 y) underwent 18 F-NaF PET/CT. A volume of interest was drawn on each plaque within the infrarenal aorta to assess mean standardized uptake value and attenuation (in Hounsfield units [HU]). Plaque was then categorized as light (,210 HU), medium (211-510 HU), or heavy (.510 HU). Standardized uptake value was normalized for blood 18 F-NaF activity to obtain the plaque target-to-background ratio (TBR). During this process, several focal, noncalcified areas of 18 F-NaF were identified (hot spots). The TBR of the hot spots was computed after isocontour thresholding. The TBR of a noncalcified control region was also calculated. In 35 patients, the TBR of nonattenuation-corrected images was calculated. Results: The average TBR was highest in light plaque (2.21 ± 0.88), significantly lower in medium plaque (1.59 ± 0.63, P , 0.001), and lower still in heavy plaque (1.14 ± 0.37, P , 0.0001 with respect to both light and medium plaque). The TBR of the control region was not significantly different from that of heavy plaque but was significantly lower than that of light and medium plaque (P , 0.01). Hot spots had the highest absolute TBR (3.89 ± 1.87, P , 0.0001 vs. light plaque). TBRs originating from non-attenuation-corrected images did not significantly differ from those originating from attenuation-corrected images. Conclusion: Our results support the concept that 18 FNaF is a feasible option in imaging molecular calcium deposition in the early stages of plaque formation, when active uptake mechanisms are the main determinants of calcium presence, but that retention of 18 F-NaF progressively decreases with increasing calcium deposition in the arterial wall. Our data suggest that nonattenuation-corrected reconstruction does not significantly affect evaluation of plaque of any thickness.
Background:: The rising incidence rate of prostate cancer (PCa) has promoted the development of new diagnostic and therapeutic radiopharmaceuticals during the last decades. Promising improvements have been achieved in clinical practice using prostate specific membrane antigen (PSMA) labeled agents, including specific antibodies and small molecular weight inhibitors. Focusing on molecular docking studies, this review aims to highlight the progress in the design of PSMA targeted agents for a potential use in nuclear medicine. Results:: Although the first development of radiopharmaceuticals able to specifically recognize PSMA was exclusively oriented to macromolecule protein structure such as radiolabeled monoclonal antibodies and derivatives, the isolation of the crystal structure of PSMA served as the trigger for the synthesis and the further evaluation of a variety of low molecular weight inhibitors. Among the nuclear imaging probes and radiotherapeutics that have been developed and tested till today, labeled Glutamate-ureido inhibitors are the most prevalent PSMA-targeting agents for nuclear medicine applications. Conclusion:: PSMA represents for researchers the most attractive target for the detection and treatment of patients affected by PCa using nuclear medicine modalities. [99mTc]MIP-1404 is considered the tracer of choice for SPECT imaging and [68Ga]PSMA-11 is the leading diagnostic for PET imaging by general consensus. [18F]DCFPyL and [18F]PSMA-1007 are clearly the emerging PET PSMA candidates for their great potential for a widespread commercial distribution. After paving the way with new imaging tools, academic and industrial R&Ds are now focusing on the development of PSMA inhibitors labeled with alpha or beta minus emitters for a theragnostic application.
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