Abstract
Exponentially growing cultures of human bladder tumor cells (RT4 and T24) were treated with Vitamin C (VC) alone, Vitamin K3 (VK3) alone, or with a VC:VK3 combination continuously for 5 days or treated with vitamins for 1 h, washed with PBS and then incubated in culture medium for 5 days. Co-administration of the vitamins enhanced the antitumor activity 12- to 24-fold for the RT-4 cells and 6- to 41-fold for the T24 cells. Flow cytometry of RT4 cells exposed to the vitamins revealed a growth arrested population and a population undergoing cell death. Growth arrested cells were blocked near the G0/G1-S-phase interface, while cell death was due to autoschizis. Catalase treatment abrogated both cell cycle arrest and cell death which implicated hydrogen peroxide (H2O2) in these processes. The H2O2 production resulted in a moderate increase in lipid peroxidation and depletion of cell thiol levels. Analysis of cellular ATP levels revealed a transient increase in ATP production for VC and the VC:VK3 combination, but decreased ATP levels following VK3 treatment. Lipid peroxidation, thiol depletion and ATP modulation occurred at a 17-fold lower concentration in the vitamin combination than with either vitamin alone. These results suggested that the increased cytotoxicity of the vitamin combination was due to redox cycling and increased oxidative stress.
Highlights
Bladder cancer is the second most common urological malignancy in the United States of America with an estimated 72,570 new cases and 15,210 deaths in 2013 [1]
T24 cells treated continuous for 5 days with Vitamin C (VC):Vitamin K3 (VK3) resulted in a 41 fold decrease in VC (1,490 μM to 13.1 μM) and a 6-fold decrease in VK3 (212 μM to 2.13 μM) with an fractional inhibitory concentration index (FIC) value of 0.158 demonstrating a significant synergism after only 1hr of VC:VK3 treatment
A 1 h VC:VK3 treatment of the RT-4 cells resulted in an 18-fold decrease in the CD50 value of VC (4740 μM reduced to 267 μM) and a 22-fold decrease in VK3 CD50 values (60.7 μM reduced to 2.68 μM) with a FIC value of 0.100
Summary
Bladder cancer is the second most common urological malignancy in the United States of America with an estimated 72,570 new cases and 15,210 deaths in 2013 [1]. Because of the lifelong need for monitoring for recurrence, the typical cost incurred by a bladder tumor patient from diagnosis to death has been reported to be the highest among all cancers [4,10]. Taken together, these facts demonstrate the need for the development of agents that are more effective, less toxic, and more cost effective agents that are more effective, less toxic and affordable [7]
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