title: Cellular and molecular effects of alpha-tocopheryloxybutyrate: lessons for the design of vitamin E analog for cancer prevention.
abstract: alpha-Tocopherol and its synthetic derivative, a-tocopheryl succinate (alpha-TS), are known to inhibit proliferation of cancer cells. alpha-TS is considered a more desirable anticancer agent because of the ability to induce apoptosis. It has been established previously that the whole intact alpha-TS molecule is necessary for its pro-apoptotic activity. For this reason, alpha-TS is not suitable for oral use because the ester bond linking succinate to tocopherol is subject to hydrolysis by intestinal esterases. One approach to overcome this problem is to replace the ester bond with an ether bond, since the latter is resistant to esterase-mediated hydrolysis. alpha-Tocopheryloxybutyrate (alpha-TOB) is the ether analog of alpha-TS. In this study, we compared the potency of alpha-TS and alpha-TOB using a panel of bioassays: cell growth, TUNEL labelling for apoptosis, PARP cleavage, caspase-3 and caspase-9 activation, as well as Akt and JNK phosphorylation. The experiments were carried out in two human prostate cancer cell lines: LNCaP and PC-3. Our results showed that alpha-TOB was capable of inhibiting cell growth and inducing apoptosis, although alpha-TOB was less active than alpha-TS on an equimolar basis. In general, it took twice as much alpha-TOB as alpha-TS to achieve the same response. Nonetheless, these two compounds shared the same mechanism of targeting the Akt and JNK signaling pathways, and activating the intrinsic cell death mediators of caspase-9 and caspase-3. Cellular analysis of alpha-TS and alpha-TOB showed that alpha-TOB was taken up as efficiently as alpha-TS (if not more so), suggesting that the lower activity of alpha-TOB is an inherent property of the molecule and not due to impaired uptake. Additional evidence is provided to show that beta-TS may act at the membrane level to interfere with Akt phosphorylation, although the exact nature of this disruption remains unclear. The future design of new anticancer tocopherol analogs should incorporate the ether linkage of the side chain for esterase resistance as well as other structural modifications for enhanced blocking of membrane signaling.
authors.affiliation: Department of Cancer Chemoprevention, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
authors.forename: Yue
authors.initials: Y
authors.lastname: Wu
authors.forename: Ke
authors.initials: K
authors.lastname: Zu
authors.forename: Jing
authors.initials: J
authors.lastname: Ni
authors.forename: Shuyuan
authors.initials: S
authors.lastname: Yeh
authors.forename: Dhanalakshmi
authors.initials: D
authors.lastname: Kasi
authors.forename: Nadine S
authors.initials: NS
authors.lastname: James
authors.forename: Sherry
authors.initials: S
authors.lastname: Chemler
authors.forename: Clement
authors.initials: C
authors.lastname: Ip
mesh_terms: D016588:Anticarcinogenic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D048670:MAP Kinase Kinase 4; D008297:Male; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D013347:Subcellular Fractions / Q000378:metabolism; D024505:Tocopherols; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D016588:Anticarcinogenic Agents; D011518:Proto-Oncogene Proteins; C113106:tocopheryloxybutyric acid; D014810:Vitamin E; D011065:Poly(ADP-ribose) Polymerases; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases; C505407:CASP3 protein, human; C506433:CASP9 protein, human; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases; D024505:Tocopherols