In vitro and in vivo anticancer effects of the novel vitamin E ether analogue RRR-alpha-tocopheryloxybutyl sulfonic acid in prostate cancer.
OBJECTIVE
Among derivatives of alpha-vitamin E, alpha-vitamin E succinate (VES), has attracted much attention due to its potent anti-prostate cancer activity in vitro and in vivo. However, the in vivo antitumor activity of VES might be compromised if administrated orally due to the VES hydrolysis by esterases in the gastrointestinal tract.


METHODS
New nonhydrolyzable VES ether analogues were synthesized and their growth inhibition was screened by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide growth assay. Among them, RRR-alpha-tocopheryloxybutyl sulfonic acid (VEBSA) was further characterized by terminal deoxyribonucleotidyl transferase-mediated dUTP nick end labeling apoptosis assay, soft agar assay, and in vivo tumor formation.


RESULTS
VEBSA has potent antitumor ability, albeit to a lesser extent than VES, in in vitro cultured prostate cancer LNCaP and PC3 cells. Like VES, VEBSA induced apoptosis, repressed androgen receptor protein expression, and enhanced vitamin D receptor expression, suggesting that VEBSA can go through mechanisms similar to those used by VES to inhibit the growth of prostate cancer cells in vitro. However, 6 weeks of oral consumption of VEBSA, but not of VES, reduced the tumor burden in the xenografted prostate tumors in nude mice. Furthermore, oral intake of VEBSA for 20 weeks inhibited prostate tumor growth and progression more efficiently compared with VES in the prostate cancer tumor model of TRAMP mice.


CONCLUSIONS
Oral consumption of VEBSA allows a greater anticancer activity compared with VES. Chemoprevention prefers the oral consumption of agents; the advantage of VEBSA over VES to be administrated orally will allow VEBSA to serve as an agent for both preventive and therapeutic purposes for prostate cancer.
Ni
Jing
J
Department of Urology, University of Rochester Medical Center, Rochester, New York, USA.
Mai
Tiejun
T
Pang
See-Tong
ST
Haque
Imranul
I
Huang
Kaohsing
K
DiMaggio
Matthew A
MA
Xie
Shaozhen
S
James
Nadine S
NS
Kasi
Dhanalakshmi
D
Chemler
Sherry R
SR
Yeh
Shuyuan
S
D000284:Administration, Oral; D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism; D018167:Receptors, Calcitriol / Q000378:metabolism; D013451:Sulfonic Acids / Q000138:chemical synthesis / Q000627:therapeutic use; D014810:Vitamin E / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays; D024502:alpha-Tocopherol / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000627:therapeutic use
C541975:RRR-alpha-tocopheryloxybutyl sulfonic acid; C519038:RRR-alpha-tocopheryloxybutyrate; D011944:Receptors, Androgen; D018167:Receptors, Calcitriol; D013451:Sulfonic Acids; D014810:Vitamin E; D024502:alpha-Tocopherol