A gamma-tocopherol-rich mixture of tocopherols inhibits chemically induced lung tumorigenesis in A/J mice and xenograft tumor growth.
The present study investigated the effects of a preparation of a gamma-tocopherol-rich mixture of tocopherols (gamma-TmT) on chemically induced lung tumorigenesis in female A/J mice and the growth of H1299 human lung cancer cell xenograft tumors. In the A/J mouse model, the lung tumors were induced by either 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK; intraperitoneal injections with 100 and 75 mg/kg on Week 1 and 2, respectively) or NNK plus benzo[a]pyrene (B[a]P) (8 weekly gavages of 2 mumole each from Week 1 to 8). The NNK plus B[a]P treatment induced 21 tumors per lung on Week 19; dietary 0.3% gamma-TmT treatment during the entire experimental period significantly lowered tumor multiplicity, tumor volume and tumor burden (by 30, 50 and 55%, respectively; P < 0.05). For three groups of mice treated with NNK alone, the gamma-TmT diet was given during the initiation stage (Week 0 to 3), post-initiation stage (Week 3 to 19) or the entire experimental period, and the tumor multiplicity was reduced by 17.8, 19.7 or 29.3%, respectively (P < 0.05). gamma-TmT treatment during the tumor initiation stage or throughout the entire period of the experiment also significantly reduced tumor burden (by 36 or 43%, respectively). In the xenograft tumor model of human lung cancer H1299 cells in NCr-nu/nu mice, 0.3% dietary gamma-TmT treatment significantly reduced tumor volume and tumor weight by 56 and 47%, respectively (P < 0.05). In both the carcinogenesis and tumor growth models, the inhibitory action of gamma-TmT was associated with enhanced apoptosis and lowered levels of 8-hydroxydeoxyguanine, gamma-H2AX and nitrotyrosine in the tumors of the gamma-TmT-treated mice. In cell culture, the growth of H1299 cells was inhibited by tocopherols with their effectiveness following the order of delta-T > gamma-TmT > gamma-T, whereas alpha-T was not effective. These results demonstrate the inhibitory effect of gamma-TmT against lung tumorigenesis and the growth of xenograft tumors of human lung cancer cells. The inhibitory activity may be due mainly to the actions of delta-T and gamma-T.
Lu
Gang
G
Susan Lehman Cullman Laboratory for Cancer Research, Department of Chemical Biology, Center for Cancer Prevention Research, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 164 Frelinghuysen Road, Piscataway, NJ 08854, USA.
Xiao
Hang
H
Li
Guang-Xun
GX
Picinich
Sonia C
SC
Chen
Yu-Kuo
YK
Liu
Anna
A
Lee
Mao-Jung
MJ
Loy
Shea
S
Yang
Chung S
CS
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001564:Benzo(a)pyrene; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000032:analysis; D015232:Dinoprostone / Q000097:blood; D005260:Female; D006657:Histones / Q000032:analysis; D007975:Leukotriene B4 / Q000097:blood; D008175:Lung Neoplasms / Q000098:blood supply / Q000139:chemically induced / Q000517:prevention & control*; D051379:Mice; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D009602:Nitrosamines; D014443:Tyrosine / Q000031:analogs & derivatives / Q000032:analysis; D023041:Xenograft Model Antitumor Assays; D024504:gamma-Tocopherol / Q000494:pharmacology*
D000975:Antioxidants; C468783:H2AX protein, human; D006657:Histones; D009602:Nitrosamines; D007975:Leukotriene B4; D001564:Benzo(a)pyrene; C002744:3-nitrotyrosine; D014443:Tyrosine; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; D000080242:8-Hydroxy-2'-Deoxyguanosine; D024504:gamma-Tocopherol; D003849:Deoxyguanosine; D015232:Dinoprostone