Vitamins C and K3 sensitize human urothelial tumors to gemcitabine.
OBJECTIVE
We evaluated the antitumor effects of vitamins C and K3 for human urothelial carcinoma and the potential use of the combination of vitamins C plus K3 as a sensitizing agent for conventional chemotherapy for urothelial carcinoma.


METHODS
The antiproliferative and apoptotic effects of vitamin C alone, vitamin K3 alone, vitamins C plus K3, gemcitabine alone and gemcitabine plus vitamins C plus K3 were assessed in vitro by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay, propidium iodide staining and flow cytometry. For in vivo studies we implanted UMUC-14 tumorigenic urothelial carcinoma cells into the subcutis of nude mice. One week later we treated 10 mice each with saline (control), vitamins C plus K3, gemcitabine or gemcitabine plus vitamins C plus K3. Treatment was continued for 4 weeks, followed by necropsy. Tumor volume was measured and tumor kinetics were established. Apoptosis and proliferation were evaluated in tumor sections using immunohistochemistry and TUNEL assay.


RESULTS
Vitamins C plus K3 induced cytostasis and caused apoptosis to a greater degree than either vitamin alone (p < 0.05). Vitamins C plus K3 also substantially augmented the effects of gemcitabine in vitro. There were 32.3% apoptosis with gemcitabine plus vitamins C plus K3, 5.3% with gemcitabine alone and 15.8% with vitamins C plus K3 alone (p < 0.05). In vivo tumor growth was substantially inhibited by gemcitabine plus vitamins C plus K3 compared with that in the control or for either agent alone. Mean tumor weight and growth rate in the gemcitabine plus vitamins C plus K3 group (237 mg and 11.3 mm3 daily) were decreased compared with those in the control (530 mg and 34.3 mm3 daily), and those for vitamins C plus K3 alone (490 mg and 25.2 mm3 daily) and gemcitabine alone (400 mg and 21.3 mm3 daily) (p < 0.05).


CONCLUSIONS
Vitamins C and K3 have significant antiproliferative and apoptotic effects when used in combination. This combination enhances the efficacy of gemcitabine against bladder cancer in vivo.
Kassouf
Wassim
W
Department of Urology, University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Highshaw
Ralph
R
Nelkin
Gina M
GM
Dinney
Colin P
CP
Kamat
Ashish M
AM
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage; D017209:Apoptosis / Q000187:drug effects*; D001205:Ascorbic Acid / Q000008:administration & dosage*; D002277:Carcinoma / Q000188:drug therapy / Q000473:pathology*; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy / Q000473:pathology*; D019459:Urothelium; D024483:Vitamin K 3 / Q000008:administration & dosage*; D014815:Vitamins / Q000008:administration & dosage*; D000093542:Gemcitabine
D000964:Antimetabolites, Antineoplastic; D014815:Vitamins; D003841:Deoxycytidine; D024483:Vitamin K 3; D001205:Ascorbic Acid; D000093542:Gemcitabine