Recipients of organ transplants are susceptible to Kaposi's sarcoma as a result of treatment with immunosuppressive drugs. Sirolimus (rapamycin), an immunosuppressive drug, may also have antitumor effects.

The PI3K/AKT pathway is one of the most frequently over-activated intracellular pathways in several human cancers. This pathway, acting on different downstream target proteins, contributes to the carcinogenesis, proliferation, invasion, and metastasis of tumour cells. A multi-level impairment, involving mutation and genetic alteration, aberrant regulation of miRNAs sequences, and abnormal phosphorylation of cascade factors, has been found in multiple cancer types. The deregulation of this pathway counteracts common therapeutic strategies and contributes to multidrug resistance. In this review, we underline the involvement of this pathway in patho-physiological cell survival mechanisms, emphasizing its key role in the development of drug resistance. We also provide an overview of the potential inhibition strategies currently available.

Sirolimus (SRL) is a mammalian target of rapamycin inhibitor that, in contrast to cyclosporine (CsA), has been shown to inhibit rather than promote cancers in experimental models. At 3 mo ± 2 wk after renal transplantation, 430 of 525 enrolled patients were randomly assigned to remain on SRL-CsA-steroids (ST) or to have CsA withdrawn and SRL troughs increased two-fold (SRL-ST). Median times to first skin and nonskin malignancies were compared between treatments using a survival analysis. Mean annualized rates of skin malignancy were calculated, and the relative risk was determined using a Poisson model. Malignancy-free survival rates for nonskin malignancies were compared using Kaplan-Meier estimates and the log-rank test. At 5 yr, the median time to a first skin carcinoma was delayed (491 versus 1126 d; log-rank test, P = 0.007), and the risk for an event was significantly lower with SRL-ST therapy (relative risk SRL-ST to SRL-CsA-ST 0.346; 95% confidence interval 0.227 to 0.526; P < 0.001, intention-to-treat analysis). The relative risks for both basal and squamous cell carcinomas were significantly reduced. Kaplan-Meier estimates of nonskin cancer were 9.6 versus 4.0% (SRL-CsA-ST versus SRL-ST; P = 0.032, intention-to-treat analysis). Nonskin cancers included those of the lung, larynx, oropharynx, kidney, gastrointestinal tract, prostate, breast, thyroid, and cervix as well as glioma, liposarcoma, astrocytoma, leukemia, lymphoma, and Kaposi’s sarcoma. Patients who received SRL-based, calcineurin inhibitor–free therapy after CsA withdrawal at month 3 had a reduced incidence of both skin and nonskin malignancies at 5 yr after renal transplantation compared with those who received SRL therapy combined with CsA. Longer follow-up and additional trials are needed to confirm these promising results.

We report the 48‐month results of a trial testing whether withdrawal of cyclosporine (CsA) from a sirolimus (SRL)‐CsA‐steroid (ST) regimen would impact renal allograft survival. Eligible patients receiving SRL‐CsA‐ST from transplantation were randomly assigned at 3 months to remain on triple therapy (SRL‐CsA‐ST, n = 215) or to have CsA withdrawn and SRL trough concentrations increased (SRL‐ST, n = 215). SRL‐ST therapy resulted in significantly better graft survival, either when including death with a functioning graft as an event (84.2% vs. 91.5%, P = 0.024) or when censoring it (90.6% vs. 96.1%, P = 0.026). Calculated glomerular filtration rate (43.8 vs. 58.3 ml/min, P < 0.001) and mean arterial blood pressure (101.3 vs. 97.1 mmHg, P = 0.047) were also improved with SRL‐ST. Differences in the incidences of biopsy‐proven acute rejection after randomization (6.5% vs. 10.2%, SRL‐CsA‐ST versus SRL‐ST, respectively) and mortality (7.9% vs. 4.7%) were not significant. SRL‐CsA‐ST‐treated patients had significantly higher incidences of adverse events generally associated with CsA, whereas those in the SRL‐ST group experienced greater frequencies of events commonly related to higher trough levels of SRL. In conclusion, early withdrawal of CsA from a SRL‐CsA‐ST regimen rapidly improves renal function and ultimately results in better graft survival.

Although there has been technical and pharmacological progress in kidney transplant medicine, some patients may experience acute post-transplant complications. Among the mechanisms involved in these conditions, ischemia/reperfusion (I/R) injury may have a primary pathophysiological role since it is one of the leading causes of delayed graft function (DGF), a slow recovery of the renal function with the need for dialysis (generally during the first week after transplantation). DGF has a significant social and economic impact as it is associated with prolonged hospitalization and the development of severe complications (including acute rejection). During I/R injury, oxidative stress plays a major role activating several pathways including ferroptosis, an iron-driven cell death characterized by iron accumulation and excessive lipid peroxidation, and mitophagy, a selective degradation of damaged mitochondria by autophagy. Ferroptosis may contribute to the renal damage, while mitophagy can have a protective role by reducing the release of reactive oxygen species from dysfunctional mitochondria. Deep comprehension of both pathways may offer the possibility of identifying new early diagnostic noninvasive biomarkers of DGF and introducing new clinically employable pharmacological strategies. In this review we summarize all relevant knowledge in this field and discuss current antioxidant pharmacological strategies that could represent, in the next future, potential treatments for I/R injury.