RETRA induces necroptosis in cervical cancer cells through RIPK1, RIPK3, MLKL and increased ROS production.

Cervical cancer is the fourth most prevalent cancer in women worldwide, predominantly infected with human papillomavirus (HPV). The current chemo and radiotherapies are mostly futile due to acquired resistance to apoptosis and warrant new therapeutic approaches targeting potent non-apoptotic cell death pathways to eliminate cervical cancer cells. Induction of necroptosis by pharmaceutical interventions is emerging as a promising tool in multiple apoptotic resistant cancer cells. RETRA (REactivation of Transcriptional Reporter Activity) is a small molecule known to induce expression of p53 regulated genes in mutant (mt) p53 cells but, detailed mechanisms of its anticancer effects are poorly known. The present study investigated the potentials of RETRA as an anticancer agent and found that it induces necroptosis selectively in cervical cancer cells irrespective of p53 status through the phosphorylation of receptor-interacting protein kinase 1,3 (RIPK1, RIPK3) and mixed lineage kinase domain-like protein (MLKL) with no cytotoxic effects in normal human peripheral blood mononuclear cells (PBMCs). RETRA-treated cells also displayed necroptotic morphology of disintegrated plasma membranes with intact nuclei and also showed cell cycle arrest at the S phase with the upregulation of p21 and downregulation of cyclin-D3. Intriguingly, the combinatorial approach of using RETRA with Necrostain-1, a known inhibitor of necroptosis, reversed the effect of RETRA and rescued cell death. Moreover, induction of necroptosis by RETRA is associated with mitochondrial hyperpolarization and elevated ROS production. Collectively, these findings suggest that RETRA induces cell death via necroptosis with increased production of ROS, accentuating the therapeutic implication of RETRA in cervical cancer cells.

Emerging neuroprotective interventions in periventricular leukomalacia - A systematic review of preclinical studies.

INTRODUCTION: Periventricular leukomalacia (PVL) is a result of various antenatal, intrapartum, or postnatal insults to the developing brain and is an important harbinger of cerebral palsy in preterm neonates. There is no proven therapy for PVL. This calls for appraisal of targeted therapies that have been investigated in animal models to evaluate their relevance in a clinical research context. AREAS COVERED: This systematic review identifies interventions that were evaluated in preclinical studies for neuroprotective efficacy against PVL. We identified 142 studies evaluating various interventions in PVL animal models (search method is detailed in section 2). EXPERT OPINION: Interventions that have yielded significant results in preclinical research, and that have been evaluated in a limited number of clinical trials include stem cells, erythropoietin, and melatonin. Many other therapeutic modalities evaluated in preclinical studies have been identified, but more data on their neuroprotective potential in PVL must be garnered before they can be considered for clinical trials. Because most of the tested interventions had only a partial efficacy, a combination of interventions that could be synergistic should be investigated in future preclinical studies. Furthermore, since the nature and pattern of perinatal insults to preterm brain predisposing it to PVL are substantially variable, individualized approaches for the choice of appropriate neuroprotective interventions tailored to different subgroups of preterm neonates should be explored.