Recently we reported that rapid determination of enthalpy of binding can be achieved for a large number of congeneric agents or in combinatorial libraries fairly efficiently. We show that using a thermodynamic Craig plot can be very useful in dissecting the enthalpy and entropy contribution of different substituents on a common scaffold, in order to design potent, selective, or pan-active compounds. In our implementation, the approach identified a critical Lys residue in the BIR3 domain of XIAP. We report for the first time that it is possible to target such residue covalently to attain potent and selective agents. Preliminary cellular studies in various models of leukemia, multiple myeloma, and pancreatic cancers suggest that the derived agents possess a potentially intriguing pattern of activity, especially for cell lines that are resistant to the pan-IAP antagonist and clinical candidate LCL161.
Daratumumab (Dara), a multiple myeloma (MM) therapy, is an antibody against the surface receptor CD38, which is expressed not only on plasma cells but also on NK cells and monocytes. Correlative data have highlighted the immune-modulatory role of Dara, despite the paradoxical Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:
Background: Resistance to endocrine treatments is a major clinical challenge in the management of estrogen receptor positive breast cancers. Although multiple mechanisms leading to endocrine resistance have been proposed, the poor outcome of this subgroup of patients demands additional studies. Methods: FoxO3a involvement in the acquisition and reversion of tamoxifen resistance was assessed in vitro in three parental ER+ breast cancer cells, MCF-7, T47D and ZR-75-1, in the deriving Tamoxifen resistant models (TamR) and in Tet-inducible TamR/FoxO3a stable cell lines, by growth curves, PLA, siRNA, RT-PCR, Western blot, Immunofluorescence, Transmission Electron Microscopy, TUNEL, cell cycle, proteomics analyses and animal models. FoxO3a clinical relevance was validated in silico by Kaplan–Meier survival curves. Results: Here, we show that tamoxifen resistant breast cancer cells (TamR) express low FoxO3a levels. The hyperactive growth factors signaling, characterizing these cells, leads to FoxO3a hyper-phosphorylation and subsequent proteasomal degradation. FoxO3a re-expression by using TamR tetracycline inducible cells or by treating TamR with the anticonvulsant lamotrigine (LTG), restored the sensitivity to the antiestrogen and strongly reduced tumor mass in TamR-derived mouse xenografts. Proteomics data unveiled novel potential mediators of FoxO3a anti-proliferative and pro-apoptotic activity, while the Kaplan–Meier analysis showed that FoxO3a is predictive of a positive response to tamoxifen therapy in Luminal A breast cancer patients. Conclusions: Altogether, our data indicate that FoxO3a is a key target to be exploited in endocrine-resistant tumors. In this context, LTG, being able to induce FoxO3a, might represent a valid candidate in combination therapy to prevent resistance to tamoxifen in patients at risk.
Alterations in cellular metabolism are among the most consistent hallmarks of cancer. Herein, after a comprehensive metabolic phenotype characterization of MCF7 and ZR75 breast cancer cells, we investigated the activity of bergapten (Bg), a plant-derived compound, against breast cancer. The study of different biochemical pathways involved in cell metabolism revealed that the two cell lines have different bioenergetic phenotypes: MCF7 cells express a glycolytic phenotype only partially oxidative, while ZR75 cells mainly have an oxidative phenotype. In both cell lines, Bg blocked glycolysis and significantly decreased glucose-6-phosphate dehydrogenase (G6PDH) activity promoting glucose accumulation; modulated bioenergetic requirements altering the expression of oxidative phosphorylation (OXPHOS) complexes and ATP production; and induced a lipid-lowering effect since an increased lipase activity concomitantly to a reduction in triglyceride levels was observed. Quantitative data of different metabolites and enzymatic activities were presented. Treatment with Bg resulted in an alteration in different metabolic pathways inducing death in the cells. We report a novel action of the natural product Bg on breast cancer, since it induced metabolic reprogramming by disrupting the interconnected network of different metabolic mechanisms. Bg can be used in combination with other forms of targeted chemotherapy to improve cancer treatment outcomes.
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