Synergistic antitumor activity of vitamins C and K3 on human urologic tumor cell lines

Morphology and DNA degeneration during autoschizic cell death in bladder carcinoma T24 cells induced by ascorbate and menadione treatment

“…VC:VK 3 treatment of a second cell line (T24 bladder carcinoma) produced identical cytoplasmic and nuclear changes with specific DNA degradation (Ervin et al, 1998;Gilloteaux et al, 1998aGilloteaux et al, , 1998bGilloteaux et al, , 1999aGilloteaux et al, , 2001aGilloteaux et al, , 2001bGilloteaux et al, , 2001cJamison et al, 2004). After these changes were observed in other bladder cancer cell lines (J82, SCaBER, TCCSUP, RT4) (Jamison et al, 1996;Venugopal et al, 1996b), we believed that we had discovered a new form of cell death. This new form of cell death was named autoschizis (from the Greek autos, self, and skhizein, to split) by Gilloteaux et al (1998aGilloteaux et al ( , 1998bGilloteaux et al ( , 1999aGilloteaux et al ( , 1999bGilloteaux et al ( , 2001aGilloteaux et al ( , 2001bGilloteaux et al ( , 2001c because this cell death is initiated by membrane defects that triggered self-excisions of the cytoplasm characterized by self-morsellations (from Latin morsus, bite).…”

“…In addition to the metabolic changes associated with membrane damage, the depletion of cellular thiol levels by VC (Venugopal et al, 1996a(Venugopal et al, , 1996b alters the membrane attachment sites of actin, which in turn would affect cytoplasmic-to-nuclear transport (Schindler and Jiang, 1986) as well as the bundling of actin filaments in the superficial cytoplasm (Higgs and Pollard, 2001;Kovar and Pollard, 2004;Watanabe and Higashida, 2004). The alterations seen in Figure 4 are similar to the increase in F-actin levels following H 2 O 2 -induced cell damage (Hinshaw et al, 1986) and are associated with more DNA damage (Yamafuji et al, 1971;Morgan et al, 1976;Lupulescu, 1991Lupulescu, , 1992Maramag et al, 1997) because DNase II is reactivated by the peroxides that originated from VC metabolism.…”

“…VK 3 has also been shown to be cytotoxic to a variety of urological tumors (Venugopal et al, 1996a(Venugopal et al, , 1996bErvin et al, 1998;Gilloteaux et al, 1998aGilloteaux et al, , 1998bGilloteaux et al, , 1999aGilloteaux et al, , 2001aGilloteaux et al, , 2001bGilloteaux et al, , 2001cGilloteaux et al, , 2005Jamison et al, 2004Jamison et al, , 2005. Furthermore, VK 3 has been shown to be equally potent against human multiple drug-resistant and drug-sensitive cells, as well as against human tumor explants derived from patients who are refractory to other types of chemotherapy .…”

“…The single-electron reduction of the quinone produces the semiquinone that reduces oxygen to the superoxide radical and regenerates the quinone. As a result, redox cycling can ensue and produce large amounts of superoxide, which can dismutate to form H 2 O 2 or form more toxic ROS via intracellular metal-catalyzed reactions (O'Brien, 1991;Venugopal et al, 1996aVenugopal et al, , 1996bJamison et al, 2001Jamison et al, , 2002Jamison et al, , 2004. This redox cycling generates oxidative stress (Bellomo et al, 1982;Cohen and Slubberfield, 1990) and results in a number of deleterious effects on T24 cells, including depletion of NADPH (Akman et al, 1985) and reduced glutathione (Carbonera and Azzone, 1988;Bellomo et al, 1990;Cohen and Stubberfield, 1990;Fawthrop et al, 1991) with the oxidation of sulfhydryl groups in proteins, especially microtubules and other cytoskeletal proteins, such as the cytokeratins (Bellomo et al, 1990;Malorni et al, 1991;Wu et al, 1993aWu et al, , 1993bJarabak and Jarabak, 1995).…”

“…These studies have led to the detailed description and characterization of two types of cell death: necrosis/oncosis (Majno and Joris, 1995), and apoptosis (Kerr, 1971;Kerr et al, 1972;Wyllie, 1981;Wyllie et al, 1984). However, during the course of studies designed to evaluate the antitumor activity of sodium ascorbate (VC) and menadione bisulfite (VK 3 ) combinations against the DU145 human prostate carcinoma cell line, it was observed that cancer cells underwent cell death by using a mechanism different than necrosis or apoptosis (Gilloteaux et al, 1995(Gilloteaux et al, , 1998aJamison et al, 1996;Venugopal et al, 1996b). VC:VK 3 treatment of a second cell line (T24 bladder carcinoma) produced identical cytoplasmic and nuclear changes with specific DNA degradation (Ervin et al, 1998;Gilloteaux et al, 1998aGilloteaux et al, , 1998bGilloteaux et al, , 1999aGilloteaux et al, , 2001aGilloteaux et al, , 2001bGilloteaux et al, , 2001cJamison et al, 2004).…”