TY - JOUR
T1 - Vitamin C and K3 Combination Causes Enhanced Anticancer Activity against RT-4 Bladder Cancer Cells
AU - McGuire, Karen
AU - Jamison, James
AU - Gilloteaux, Jacques
AU - Summers, Jack
PY - 2013
Y1 - 2013
N2 - 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.
AB - 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.
U2 - 10.4172/1948-5956.1000223
DO - 10.4172/1948-5956.1000223
M3 - Article
SN - 1948-5956
VL - 05
SP - 325
EP - 333
JO - Journal of Cancer Science & Therapy
JF - Journal of Cancer Science & Therapy
IS - 10
ER -
