Kidney transplantation is the most successful treatment option for patients with end‐stage renal disease, and chronic antibody‐mediated rejection is the principal cause of allograft loss. Predictive factors for chronic rejection include high levels of HLA alloantibodies (particularly HLA class II) and activation of graft endothelial cells (ECs). The mechanistic basis for this association is unresolved. We used an experimental model of HLA‐DR antibody stimulation of microvascular ECs to examine the mechanisms underlying the association between HLA class II antibodies, EC activation and allograft damage. Activation of ECs with the F(Ab′)₂ fragment of HLA‐DR antibody led to phosphorylation of Akt, ERK and MEK and increased IL‐6 production by ECs cocultured with allogeneic peripheral blood mononuclear cells (PBMCs) in an Akt‐dependent manner. We previously showed that HLA‐DR–expressing ECs induce polarization of Th17 and FoxP3^bright regulatory T cell (Treg) subsets. Preactivation of ECs with anti‐HLA‐DR antibody redirected EC allogenicity toward a proinflammatory response by decreasing amplification of functional Treg and by further increasing IL‐6–dependent Th17 expansion. Alloimmunized patient serum containing relevant HLA‐DR alloantibodies selectively bound and increased EC secretion of IL‐6 in cocultures with PBMCs. These data contribute to understanding of potential mechanisms of antibody‐mediated endothelial damage independent of complement activation and FcR‐expressing effector cells.

Despite chemotherapy intensification, a subgroup of high-risk paediatric T-cell acute lymphoblastic leukemia (T-ALL) patients still experience treatment failure. In this context, we hypothesised that therapy resistance in T-ALL might involve aldo-keto reductase 1C (AKR1C) enzymes as previously reported for solid tumors. Expression of NRF2-AKR1C signaling components has been analysed in paediatric T-ALL samples endowed with different treatment outcomes as well as in patient-derived xenografts of T-ALL. The effects of AKR1C enzyme modulation has been investigated in T-ALL cell lines and primary cultures by combining AKR1C inhibition, overexpression, and gene silencing approaches. We show that T-ALL cells overexpress AKR1C1-3 enzymes in therapy-resistant patients. We report that AKR1C1-3 enzymes play a role in the response to vincristine (VCR) treatment, also ex vivo in patient-derived xenografts. Moreover, we demonstrate that the modulation of AKR1C1-3 levels is sufficient to sensitise T-ALL cells to VCR. Finally, we show that T-ALL chemotherapeutics induce overactivation of AKR1C enzymes independent of therapy resistance, thus establishing a potential resistance loop during T-ALL combination treatment. Here, we demonstrate that expression and activity of AKR1C enzymes correlate with response to chemotherapeutics in T-ALL, posing AKR1C1-3 as potential targets for combination treatments during T-ALL therapy.

We synthesized eight new bipyridine and bipyrimidine gold (III) dithiocarbamate-containing complexes (C1–C8) and tested them in a panel of human cancer cell lines. We used osteosarcoma (MG-63), lung (A549), prostate (PC3 and DU145), breast (MCF-7), ovarian (A2780 and A2780cis, cisplatin- and doxorubicin-resistant), and cervical (ME-180 and R-ME-180, cisplatin resistant) cancer cell lines. We found that C2, C3, C6, and C7 were more cytotoxic than cisplatin in all cell lines tested and overcame cisplatin and doxorubicin resistance in A2780cis and R-ME-180 cells. In the PC3 prostate cancer cell line, the gold (III) complex C6 ([Au₂(BPM)(DMDTC)₂]Cl₄) induced apoptosis and double-stranded DNA breaks, modified cell cycle phases, increased Reactive Oxigen Species (ROS) generation, and reduced thioredoxin reductase and proteasome activities. It inhibited PC3 cell migration and was more cytotoxic against PC3 cells than normal human adipose-derived stromal cells. In mice bearing PC3 tumor xenografts, C6 reduced tumor growth by more than 70% without causing weight loss. Altogether, our results demonstrate the anticancer activity of these new gold (III) complexes and support the potential of C6 as a new agent for prostate cancer treatment.