Hepatocellular carcinoma (HCC) is one of the most threatening tumours in the world today. Pharmacological treatments for HCC mainly rely on protein kinase inhibitors, such as sorafenib and ...regorafenib. Even so, these approaches exhibit side effects and acquired drug resistance, which is an obstacle to HCC treatment. We have previously shown that selective lysophosphatidic acid receptor 6 (LPAR6) chemical antagonists inhibit HCC growth. Here, we investigated whether LPAR6 mediates resistance to sorafenib by affecting energy metabolism in HCC. To uncover the role of LPAR6 in drug resistance and cancer energy metabolism, we used a gain-of-function and loss-of-function approach in 2D tissue and 3D spheroids. LPAR6 was ectopically expressed in HLE cells (HLE-LPAR6) and knocked down in HepG2 (HepG2 LPAR6-shRNA). Measurements of oxygen consumption and lactate and pyruvate production were performed to assess the energy metabolism response of HCC cells to sorafenib treatment. We found that LPAR6 mediates the resistance of HCC cells to sorafenib by promoting lactic acid fermentation at the expense of oxidative phosphorylation (OXPHOS) and that the selective LPAR6 antagonist 9-xanthenyl acetate (XAA) can effectively overcome this resistance. Our study shows for the first time that an LPAR6-mediated metabolic mechanism supports sorafenib resistance in HCC and proposes a pharmacological approach to overcome it.
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•Hepatocellular carcinoma (HCC) is one of the most threatening tumours worldwide.•Acquired resistance to sorafenib is an important issue in the treatment of HCC.•Selective lysophosphatidic acid receptor 6 (LPAR6) antagonists inhibit HCC growth.•LPAR6 mediates sorafenib resistance by modulating the bioenergetic phenotype of HCC cells.•A selective LPAR6 chemical antagonist effectively overcomes sorafenib resistance.
Medicinal plants belonging to the genus Berberis may be considered an interesting source of drugs to counteract the problem of antimicrobial multiresistance. The important properties associated with ...this genus are mainly due to the presence of berberine, an alkaloid with a benzyltetrahydroisoquinoline structure. Berberine is active against both Gram-negative and Gram-positive bacteria, influencing DNA duplication, RNA transcription, protein synthesis, and the integrity of the cell surface structure. Countless studies have shown the enhancement of these beneficial effects following the synthesis of different berberine analogues. Recently, a possible interaction between berberine derivatives and the FtsZ protein was predicted through molecular docking simulations. FtsZ is a highly conserved protein essential for the first step of cell division in bacteria. The importance of FtsZ for the growth of numerous bacterial species and its high conservation make it a perfect candidate for the development of broad-spectrum inhibitors. In this work, we investigate the inhibition mechanisms of the recombinant FtsZ of Escherichia coli by different N-arylmethyl benzodioxolethylamines as berberine simplified analogues appropriately designed to evaluate the effect of structural changes on the interaction with the enzyme. All the compounds determine the inhibition of FtsZ GTPase activity by different mechanisms. The tertiary amine 1c proved to be the best competitive inhibitor, as it causes a remarkable increase in FtsZ Ksub.m (at 40 μM) and a drastic reduction in its assembly capabilities. Moreover, a fluorescence spectroscopic analysis carried out on 1c demonstrated its strong interaction with FtsZ (Ksub.d = 26.6 nM). The in vitro results were in agreement with docking simulation studies.
Besides their nutritional value, whey protein (WP) peptides are food components retaining important pharmacological properties for controlling hypertension. We herein report how the use of ...complementary experimental and theoretical investigations allowed the identification of novel angiotensin converting enzyme inhibitory (ACEI) peptides obtained from a WP hydrolysate and addressed the rational design of even shorter sequences based on molecular pruning. Thus, after bromelain digestion followed by a 5 kDa cutoff ultrafiltration, WP hydrolysate with ACEI activity was fractioned by RP-HPLC; 2 out of 23 collected fractions retained ACEI activity and were analyzed by liquid chromatography–tandem mass spectrometry (LC–MS/MS). In the face of 128 identified peptides, molecular docking was carried out to prioritize peptides and to rationally guide the design of novel shorter and bioactive sequences. Therefore, 11 peptides, consisting of 3–6 amino acids and with molecular weights in the range from 399 to 674 Da, were rationally designed and then purchased to determine the IC50 value. This approach allowed the identification of two novel peptides: MHI and IAEK with IC50 ACEI values equal to 11.59 and 25.08 μM, respectively. Interestingly, we also confirmed the well-known ACEI IPAVF with an IC50 equal to 9.09 μM. In light of these results, this integrated approach could pave the way for high-throughput screening and identification of new peptides in dairy products. In addition, the herein proposed ACEI peptides could be exploited for novel applications both for food production and pharmaceuticals.
Thalidomide was first used for relief of morning sickness in pregnant women and then withdrawn from the market because of its dramatic effects on normal fetal development. Over the last decades, it ...has been used successfully for the treatment of several pathologies, including cancer. Many analogues with improved activity have been synthesized and tested. Herein we report some effects on the growth and progression of MCF-7 and MDA-MB-231 breast cancer cells by a small series of thalidomide-correlated compounds, which are very effective at inducing cancer cell death by triggering TNFα-mediated apoptosis. The most active compounds are able to drastically reduce the migration of breast cancer cells by regulation of the two major proteins involved in epithelial-mesenchymal transition (EMT): vimentin and E-cadherin. Moreover, these compounds diminish the intracellular biosynthesis of vascular endothelial growth factor (VEGF), which is primarily involved in the promotion of angiogenesis, sustaining tumor progression. The multiple features of these compounds that act on various key points of the tumorigenesis process make them good candidates for preclinical studies.
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