Cell damage and death by autoschizis in human bladder (RT4) carcinoma cells resulting from treatment with ascorbate and menadione

Ultrastruct Pathol. 2010 May;34(3):140-60. doi: 10.3109/01913121003662304.


A human bladder carcinoma cell line RT4 was sham-treated with buffer or treated with ascorbate (VC) alone, menadione alone (VK(3)), or a combination of ascorbate:menadione (VC+VK(3)) for 1, 2, and 4 h. Cytotoxic damage was found to be treatment-dependent in this sequence: VC+VK(3)>VC>VK(3)>sham. The combined treatment induced the greatest oxidative stress, with early tumor cell injury affecting the cytoskeletal architecture and contributing to the self-excisions of pieces of cytoplasm freed from organelles. Additional damage, including a reduction in cell size, organelle alterations, nuclear damage, and nucleic acid degradation as well as compromised lysosome integrity, is caused by reactivation of DNases and the redox cycling of VC or VC+VK(3). In addition, cell death caused by VC+VK(3) treatment as well as by prolonged VC treatment is consistent with cell demise by autoschizis, not apoptosis. This report confirms and complements previous observations about this new mode of tumor cell death. It supports the contention that a combination of VC+VK(3), also named Apatone, could be co-administered as a nontoxic adjuvant with radiation and/or chemotherapies to kill bladder tumor cells and other cancer cells without any supplementary risk or side effects for patients.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Ascorbic Acid / pharmacology*
  • Cell Death / drug effects*
  • Cell Line, Tumor
  • Cell Nucleus / drug effects
  • Cell Nucleus / ultrastructure
  • Cell Survival / drug effects
  • DNA Damage
  • Drug Screening Assays, Antitumor
  • Drug Therapy, Combination
  • Humans
  • Male
  • Microscopy, Electron, Transmission
  • Organelles / drug effects
  • Organelles / ultrastructure
  • Oxidative Stress / drug effects
  • Urinary Bladder Neoplasms / drug therapy*
  • Urinary Bladder Neoplasms / metabolism
  • Urinary Bladder Neoplasms / pathology
  • Vitamin K 3 / pharmacology*


  • Antineoplastic Agents
  • Vitamin K 3
  • Ascorbic Acid