Analogs of vitamin e epitomized by α-tocopheryl succinate for pancreatic cancer treatment: In vitro results induce caution for in vivo applications

Objectives: 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 mu mol/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 mu mol/L in 1% FCS and 50 mu mol/L in 10% FCS). A 20-mu mol/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 anti-proliferative effects of alpha-TOS, any sensitivity appearing to be correlated with SMAD4/DPC4 homozygous deletion and Bax/Bak expression.