Abstract
Introduction: Vitamin C (VC), Vitamin K3 (VK3) and the combination (VC:VK3) were evaluated against human bladder cancer cell lines RT-4 and T24 to evaluate their synergistic anticancer activity. Methods/Results: An MTT assay compared a 1hr pulsed versus a 5hr continuous exposure. VC:VK3 was synergistic, increasing the antitumor activity 12- to 24 fold for RT-4 cells. VC:VK3 pulsed versus continuous exposure produced comparable CD50 values, indicating a triggered response involving a catalase reversible redox mechanism generating hydrogen peroxide. Hydrogen peroxide production caused lipid peroxidation and depletion of cellular thiols. ATP levels were measured over 5hrs to determine metabolic effects where VC:VK3 caused a unique spike in ATP levels. Though the cause of the ATP spike is unknown a possible mechanism is a shunt formed around a defective region of complex III of the ETC from coenzyme Q to cytochrome c, producing a shift from glycolytic to oxidative metabolism and a diminution of lactic acidosis. Analysis of mitochondrial and extra mitochondrial calcium levels revealed a unique calcium pattern for RT4 cells treated with CD90 doses of VC, VK3 or VC:VK3. Conclusion: VC:VK3 was able to cause autoschizic cell death through oxidative stress, thiol depletion, lipid peroxidation, modification of ATP levels and calcium regulation. Because of these results, VC:VK3 was granted orphan drug status for the treatment of metastatic or locally advanced, inoperable transitional cell carcinoma of the urothelium (stage III and IV bladder cancer). Efforts are underway to conduct a phase II clinical trial for this indication.
Highlights
Vitamin C (VC), Vitamin K3 (VK3) and the combination (VC:VK3) were evaluated against human bladder cancer cell lines RT-4 and T24 to evaluate their synergistic anticancer activity
While the increase in lipid peroxidation values for cells were significantly higher than control levels after 1hr of vitamin exposure, significant levels of lipid peroxidation and damage to the cell membrane occur only after 2–3 hr vitamin exposure and suggest that wholesale, indiscriminate lipid peroxidation was a late event in the cell death process
While VC traditionally is perceived as an antioxidant, it may act as a pro-oxidant, increase DNA damage and induce cell death [75]
Summary
Vitamin C (VC), Vitamin K3 (VK3) and the combination (VC:VK3) were evaluated against human bladder cancer cell lines RT-4 and T24 to evaluate their synergistic anticancer activity. Bladder cancer is one of the most expensive cancers to treat since the course of therapy requires extensive patient surveillance to monitor for recurrence as well as repeated procedures to remove new tumors or cryptic tumor foci overlooked during the initial transurethral resection [1,2,3,4]. These urothelial carcinomas are primarily of epithelial origin (>90%) with multiple genetic pathways leading to disease progression [5]. Even with the latest pharmacologic strategies, the relative survival rate for bladder cancer is 5 years, while the median survival for patients with inoperable metastatic bladder cancer is 7 to 20 months [5,8,9]
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