Vitamins C and K3 Sensitize Human Urothelial Tumors to Gemcitabine
Received 24 September 2005
Purpose
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.
Materials and 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.
aDepartment of Urology, University of Texas M. D. Anderson Cancer Center, Houston, Texas
bDepartment of Cancer Biology, University of Texas M. D. Anderson Cancer Center, Houston, Texas
Correspondence and requests for reprints: Departments of Urology and Cancer Biology, Unit 1373, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, Texas 77030 (telephone: 713-792-3250; FAX: 713-794-4824)
Supported by SPORE Developmental Research Grant 5P50CA091846-03.
⁎ Financial interest and/or other relationship with AstraZeneca, GlaxoSmithKline, National Cancer Institute, Canji/Schering-Plough and Abbott/Vysis.
‡ Financial interest and/or other relationship with Healthgate, Pharmacia and Abbott.
ABSTRACT