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Pancreatic cancer has a high mortality rate due to its aggressive nature and high metastatic rate. When coupled to the difficulties in detecting this type of tumor early and the lack of effective treatments, this cancer is currently one of the most important clinical challenges in the field of oncology. Melitherapy is an innovative therapeutic approach that is based on modifying the composition and structure of cell membranes to treat different diseases, including cancers. In this context, 2-hydroxycervonic acid (HCA) is a melitherapeutic agent developed to combat pancreatic cancer cells, provoking the programmed cell death by apoptosis of these cells by inducing ER stress and triggering the production of ROS species. The efficacy of HCA was demonstrated in vivo, alone and in combination with gemcitabine, using a MIA PaCa-2 cell xenograft model of pancreatic cancer in which no apparent toxicity was evident. HCA is metabolized by α-oxidation to C21:5n-3 (heneicosapentaenoic acid), which in turn also showed anti-proliferative effect in these cells. Given the unmet clinical needs associated with pancreatic cancer, the data presented here suggest that the use of HCA merits further study as a potential therapy for this condition.

Background Alzheimer’s disease (AD) is a neurodegenerative disease with as yet no efficient therapies. Many drugs and therapies have been designed and developed against this neurodegenerative disease, although none has successfully terminated a phase‐III clinical trial in humans. To shift the perspective for the design of new AD therapies, membrane lipid therapy has been tested, which assumes that brain lipid alterations lie upstream in the pathophysiology of AD. A hydroxylated derivative of docosahexaenoic acid was used, 2‐hydroxy‐docosahexaenoic acid (DHA‐H), which has shown efficacy against hallmarks of AD pathology in a transgenic mouse model of AD (5xFAD). Method Lipid samples were obtained from cultured cells and blood plasma and brain from WT and 5xFAD mice. Both, cell cultures and animals were treated with DHA‐H and DHA under different conditions. Mice were subjected to the Radial Arm Maze test during the last month of treatment just before sacrifice. Fatty acid analysis was performed by GC‐FID and GC‐MS (Gas Chromatography‐Flame Ionization Detector and ‐Mass Spectrometry) and the lipidomic analysis carried out by ESI‐MS (Electrospray ionization‐Mass Spectrometry). Result Here, for the first time, DHA‐H is shown to undergo α‐oxidation to generate the heneicosapentaenoic acid (HPA, C21:5, n‐3) metabolite, an odd‐chain omega‐3 polyunsaturated fatty acid that accumulates in cell cultures, mouse blood plasma and brain tissue upon DHA‐H treatment. Interestingly, DHA‐H does not share metabolic routes with its natural analog DHA (C22:6, n‐3) but rather, DHA‐H and DHA accumulate distinctly, both having different effects on cell fatty acid composition. This is partly explained because DHA‐H α‐hydroxyl group provokes steric hindrance on fatty acid carbon 1, which in turn leads to diminished uptake by cultured cells and accumulation as free fatty acid in cell membranes. Finally, DHA‐H administration to mice elevated the brain HPA levels which in turn were directly and positively correlated with cognitive spatial scores in AD mice. This effect appeared in the apparent absence of DHA‐H and without any significant change DHA levels in brain. Conclusion The evidence presented in this work suggest that the metabolic conversion of DHA‐H into HPA could represent a key event in the therapeutic effects of DHA‐H against AD.

Background DHA‐H (Hydroxy‐docosahexaenoic acid) is a molecule in development for Alzheimer’s disease (AD) treatment based on the concept of membrane lipid therapy (melitherapy). Once entered the cell, DHA‐H is metabolized via α‐oxidation to the fatty acid HPA (Heneicosapentaenoic acid). DHA‐H has been shown to reduce the amyloidogenic processing of Amyloid Precursor Protein (APP), as well as having a neuroprotective effect in cellular models. Although the mechanism of action of DHA‐H is not yet fully understood, results obtained in excitotoxicity models and lipid profile analysis suggest that HPA could be a DHA‐H effector. Methods : APP processing was assessed in cell cultures of HEK293 and N2a neuroblastoma cell lines and analyzed by western blot. Neuroprotective effect of DHA‐H and HPA was tested in neuron cells differentiated from SH‐SY5Y neuroblastoma cells that were stimulated with NMDA (N‐Methyl‐D‐Aspartate)/Ca to induce excitotoxicity. Lipid samples for lipid profile analysis were obtained from the same cultured cells by addition of chloroform/methanol. Fatty acids were transformed into methyl esters and analyzed by GC‐FID (Gas Chromatography‐Flame ionization detector). Results : DHA‐H administration decreases the levels of derivatives from the APP amyloidogenic processing. DHA‐H and HPA showed a neuroprotective effect in a neuronal model of NMDA‐induced excitotoxicity. DHA‐H administration does not significantly alter the main fatty acids but clearly increases HPA levels in the cells. Conclusion All these results together demonstrate that DHA‐H exerts neuroprotection and prevents amyloidogenic processing possibly through its metabolic intermediate HPA. Therefore, HPA appears as a new promising molecule for Alzheimer’s therapy.

Background DHA‐H (2‐hydroxy‐docosahexaenoic acid) is a promising therapeutic approach for Alzheimer’s Disease (AD). DHA‐H gives rise to dose‐dependent increased levels of HPA (Heneicosapentaenoic acid) in blood plasma and brain whereas DHA‐H remains virtually absent from the brain of DHA‐H‐treated mice. Oral administration of DHA‐H to a transgenic model of AD (5xFAD mice) induces a significative cognitive recovery. However, the molecular mechanism underlying this neuroprotective effect remains largely unresolved. Method Screening of potential receptors for DHA‐H and HPA was performed using computational tools. PPARG (Peroxisome Proliferator‐Activated Receptor γ) activity was determined by cell‐based assays. Levels of proteins involved in amyloid production as well as synaptic markers were determined by WB and/or ELISA. β‐ and γ‐secretase activities were measured in cell‐free assays. Neuronal density was determined by immunohistochemistry. Brain levels of DHA‐H and HPA were determined by Electrospray Ionization – Mass Spectrometry (ESI‐MS). Result Both DHA‐H and HPA are activators of PPARG. We have analyzed the effect of DHA‐H treatment on the amyloidogenic route in the 5xFAD mice and this effect was related with PPARG activity. We observed a modulation of protein levels and enzymatic activities involved in β‐amyloid production as well as a prevention of synaptic and neuron degeneration in DHA‐H‐treated mice as compared with untreated controls. These changes were related with improved cognitive scores in these mice. Conclusion All these results together indicate that DHA‐H administration must prevent neuronal degeneration and cognitive decline in AD mice through its immediate metabolite HPA and without apparent involvement of PPARG.