Analogs of vitamin E epitomized by alpha-tocopheryl succinate for pancreatic cancer treatment: in vitro results induce caution for in vivo applications.
OBJECTIVE
alpha-Tocopheryl succinate (alpha-TOS) is thought to be toxic only for cancer cells. We ascertained in vitro alpha-TOS effects on pancreatic cancer (PC) and normal cell growth and verified whether the combination of nontoxic alpha-TOS and 5-fluorouracil (5-FU) doses causes cancer cell death and whether alpha-TOS effects are mediated by the proapoptotic proteins Bax/Bak and/or SMAD4/DPC4 status.


METHODS
Five PC cell lines, myoblasts, normal monocytes, wild-type (WT) and Bax/Bak double knockout mouse embryonic fibroblast (MEF) cells, and permanently SMAD4/DPC4-transfected PSN1 cells were cultured in 1% and 10% fetal calf serums (FCSs), without or with alpha-TOS (5-500 micromol/L). Nontoxic 5-FU (0.0001 mmol/L) and alpha-TOS alone or in combination were also evaluated.


RESULTS
Only PSN1 PC cell line, which had SMAD4/DPC4 homozygous deletion, was sensitive to nontoxic alpha-TOS doses (5 micromol/L in 1% FCS and 50 micromol/L in 10% FCS). A 20-micromol/L alpha-TOS inhibited MEF-WT, not MEF-double knockout growth. Only PSN1 cells were sensitive to nontoxic 5-FU and alpha-TOS combination. SMAD4/DPC4 transfection restored PSN1 resistance to the effects of combined 5-FU and alpha-TOS effects.


CONCLUSIONS
Only a minority of PC cells are sensitive to the antiproliferative effects of alpha-TOS, any sensitivity appearing to be correlated with SMAD4/DPC4 homozygous deletion and Bax/Bak expression.
Greco
Eliana
E
Department of Laboratory Medicine, University of Padova, Padova, Italy.
Basso
Daniela
D
Fadi
Elisa
E
Padoan
Andrea
A
Fogar
Paola
P
Zambon
Carlo-Federico
CF
Navaglia
Filippo
F
Bozzato
Dania
D
Moz
Stefania
S
Pedrazzoli
Sergio
S
Plebani
Mario
M
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D005347:Fibroblasts / Q000187:drug effects; D005472:Fluorouracil / Q000494:pharmacology; D006801:Humans; D051379:Mice; D009000:Monocytes / Q000187:drug effects; D032446:Myoblasts / Q000187:drug effects; D010190:Pancreatic Neoplasms / Q000188:drug therapy*; D051901:Smad4 Protein / Q000032:analysis; D014810:Vitamin E / Q000031:analogs & derivatives*; D024502:alpha-Tocopherol / Q000494:pharmacology* / Q000627:therapeutic use; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000032:analysis; D051028:bcl-2-Associated X Protein / Q000032:analysis
D000970:Antineoplastic Agents; D051901:Smad4 Protein; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D014810:Vitamin E; D024502:alpha-Tocopherol; D005472:Fluorouracil