Autoschizis: A mode of cell death of cancer cells induced by a prooxidant treatment in vitro and in vivo

A pro‐oxidant treatment encompassing a combined administration of ascorbate (VC) and menadione (VK3) on a series of carcinoma cell lines and xenotransplants resulted in specific cytotoxic activities that allowed us to describe a new mode of cell death named autoschizis. Observed in human prostate, bladder, and ovarian carcinoma cells as well as in a transgenic murine prostate cancer model, as well as in vivo, this mode of cell death process differs from apoptosis or necrosis according to the morphological and biochemical investigations collected, using morphological and biochemical techniques. Comparing the untreated tumor cells with injured ones it was found that, in vitro, this autoschizis cell death is initiated by pro‐oxidant stress in which tumor cells deteriorate through irreversible cell damages caused by reactivation of nucleases. The initial damages consist in superficial and deep cytoplasmic changes involving membranes and the cytoskeleton resulting in dramatic cell size reduction through auto‐ or self‐excisions. Followed by a series of sequential injuries caused by hydrogen peroxide and reactive oxidative species on endomembranes,mitochondria and lysosomes and other organelle's injuries contribute to autophagic activities that also involve sequential nucleus defects. These injuries include karyolysis with nucleollus degradation ruled by reactivated nucleases and cathepsins K and L leaking from lysosomes verified by immunocytochemistry, DNA gel electrophoretic smear pattern, similar to Necrosis. Additionally, flow cytometry disclosed cell cycle blocks in G1/S and G2/M phases in all the treated tumor cells. Biochemical data from in vitro and in vivo tests showed that this mode of cell death is independent from caspase‐3 activation, while inhibiting the repair mechanisms of the cell through depletion of ATP, thiols, impeding protein, nucleic acid synthesis or repairs while starving energetically the tumor cells, i.e. trying to survive through autophagocytosis of reserves. Based on some data from biochemistry, this new mode of cell death verified by morphology and described in 1998 would encompass necroptosis, pathanos, pyroptosis and oxytosis. In xenotransplanted carcinomas, this pro‐oxidant treatment induces major cell demise by autoschizis with significant reduction of the tumors' size and high survival rate of the host animals. Because this mode of killing specifically targets cancer cells and, based on preliminary clinical data, it has been suggested that this treatment would be a useful, safe and inexpensive strategy to be implemented synergistically with radiation and/or chemotherapy as an adjuvant or treatments in oncology.