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This work compared the metabolic profile of a parental MDA-MB-231 cisplatin-sensitive triple negative breast cancer (TNBC) cell line with that of a derived cisplatin-resistant line, to characterize inherent metabolic adaptations to resistance, as a means for marker and new TNBC therapies discovery. Supported by cytotoxic, microscopic and biochemical characterization of both lines, Nuclear Magnetic Resonance (NMR) metabolomics was employed to characterize cell polar extracts for the two cell lines, as a function of time (0, 24 and 48 h), and identify statistically relevant differences both between sensitive and resistant cells and their time course behavior. Biochemical results revealed a slight increase in activation of the NF-κB pathway and a marked decrease of the ERK signaling pathway in resistant cells. This was accompanied by lower glycolytic and glutaminolytic activities, possibly linked to glutamine being required to increase stemness capacity and, hence, higher survival to cisplatin. The TCA cycle dynamics seemed to be time-dependent, with an apparent activation at 48 h preferentially supported by anaplerotic aromatic amino acids, leucine and lysine. A distinct behavior of leucine, compared to the other branched-chain-amino-acids, suggested the importance of the recognized relationship between leucine and in mTOR-mediated autophagy to increase resistance. Suggested markers of MDA-MB-231 TNBC cisplatin-resistance included higher phosphocreatine/creatine ratios, hypotaurine/taurine-mediated antioxidant protective mechanisms, a generalized marked depletion in nucleotides/nucleosides, and a distinctive pattern of choline compounds. Although the putative hypotheses generated here require biological demonstration, they pave the way to the use of metabolites as markers of cisplatin-resistance in TNBC and as guidance to develop therapies., (© 2023. The Author(s).)

Background: Percutaneous coronary intervention (PCI) is one of the most performed well-succeeded therapeutic procedures worldwide, reducing symptoms and improving quality of life. Neutrophil Gelatinase-associated Lipocalin (NGAL) is a biomarker of acute kidney injury (AKI) produced early after an ischemic renal insult. Osmotic diuresis and the vasoconstriction of the afferent arteriole promoted by Sodium-glucose Cotransporter-2 Inhibitors (SGLT2i) generate a concern regarding the possibility of dehydration and consequent AKI. There is no consensus on the maintenance or discontinuation of SGTL2i in patients who will undergo PCI. This study aimed to evaluate the safety of empagliflozin in diabetic patients submitted to elective PCI regarding kidney function., Methods: SAFE-PCI trial is a prospective, open-label, randomized (1:1), single-center pilot study and a follow-up of 30 days. The SGLT2i empagliflozin 25 mg daily was initiated at least 15 days before PCI in the intervention group and maintained until the end of the follow-up period. Serum NGAL was collected 6 h after PCI and creatinine before PCI, 24 h, and 48 h after the procedure. As per protocol, both groups received optimal medical treatment and standard protocol of nephroprotection., Results: A total of 42 patients were randomized (22 patients in the iSGLT-2 group and 20 patients in the control group). There was no difference between-group baseline data. The primary outcome (NGAL and creatinine values post PCI) did not differ in both groups: the mean NGAL value was 199 ng/dL in the empagliflozin group and 150 ng/dL in the control group (p = 0.249). Although there was an initial increase in creatinine in the SGLT-2i group compared to the control group between baseline creatinine and pre-PCI and 24 h post-PCI creatinine, no difference was detected in creatinine 48 h post-PCI (p = 0.065). The incidence of CI-AKI, determined by KDIGO criteria, in the iSGLT2-group was 13.6% and 10.0% in the control group without statistical difference., Conclusion: The present study showed that the use of empagliflozin is safe regarding kidney function during elective PCI in patients with T2D when compared with no use of SGLT2i. Trial registration Our clinical study is registered on ClinicalTrials.gov with the following number: NCT05037695., (© 2023. The Author(s).)