Isothiocyanates (ITCs) and their conjugates are effective inhibitors against lung tumorigenesis in animal models. The chemopreventive effects of ITCs have previously been attributed to inhibition of cytochrome-P450s and induction of phase II enzymes. Studies in cell culture showed a new mechanism of tumor inhibition by ITCs, involving induction of apoptosis and cell cycle arrest, in fact, our recent study show ITCs induce apoptosis at G2/M phase in lung cells. These studies suggested that ITCs may inhibit tumorigenesis when administered during post-initiation phases. Indeed, we have demonstrated that the N-acetylcysteine conjugates of phenethyl and benzyl ITCs given in the diet after benzo[a]pyrene treatment significantly inhibit lung tumor formation in A/J mice. We recently generated BubR1-knockout mice and demonstrated its susceptibility to carcinogen-induced lung cancer. BubR1 has been shown as an essential component of the mitotic checkpoints in mammalian cells. The presence of BubR1 at kinetochores greatly facilitates the binding of Bub3, Mad1, Mad2 and CENP-E, so BubR1 may integrate the signals for spindle check point regulation. Previous studies of ITCs chemopreventive effect on animal assay mostly using A/J mice or 344 rats, these animal are susceptibility to carcinogen-induced lung cancer, but the genomic mechanism for their susceptibility was not clear. Since it is known that in BubR1-knockout mice lung cancer induction is due to deficiency of mitotic checkpoint regulation, it provides a novel animal model which is excellent for detection our hypothesis that ITCs induce apoptosis at G2/M phase, which compliments the deficiency of mitotic checkpoint regulation, resulting in prevention of genomic instability and tumor development. In this project, our primary goal is to examine the chemopreventive effects of ITCs in mitotic checkpoint deficient mice as well as the effects of ITCs on mitotic checkpoint regulation.
| Rao, Chinthalapally V; Yang, Yang-Ming; Swamy, Malisetty V et al. (2005) Colonic tumorigenesis in BubR1+/-ApcMin/+ compound mutant mice is linked to premature separation of sister chromatids and enhanced genomic instability. Proc Natl Acad Sci U S A 102:4365-70 |
| Yang, Yang-Ming; Jhanwar-Uniyal, Meena; Schwartz, Joel et al. (2005) N-acetylcysteine conjugate of phenethyl isothiocyanate enhances apoptosis in growth-stimulated human lung cells. Cancer Res 65:8538-47 |
