Studies on the effect of PSC 833, a potent inhibitor of P-glycoprotein function on the development of cancer /cby Janarthanan Kankesan.
Published: 2006
Language: eng
Number of pages: 165
ISBN-13: 9780494160152
Description: P-glycoprotein (Pgp, product of MDR1 gene) is portrayed as the hallmark of multidrug resistance (MDR) in cancer. However, high expression of Pgp is seen in several untreated human as well as experimental cancers. In recent years, we and others have implicated a role for Pgp in promoting tumor cell proliferation while resisting cell death and differentiation and in tumor versus host immune responses. Based on these observations, we hypothesized that over-expression of Pgp is intimately associated with the development of cancer and inhibition of Pgp should inhibit the carcinogenic process. To test this hypothesis, we examined the effect of PSC 833 (PSC, Novartis), a potent inhibitor of Pgp function, on the growth of several human cancer cell lines in vitro as well as development of experimental cancers in vivo. Using several human cancer cell lines including liver, breast, colorectal, melanoma and astrocytoma, we demonstrate that PSC inhibits the growth by activation of cell cycle arrest and/or apoptosis. Extending these studies to in vivo experimental rat model systems, we show that PSC inhibits the growth and progression of chemically induced liver, colorectal and mammary carcinogenesis. To determine the mechanism of PSC action, we examined alterations in ceramide and p21 signaling in a human hepatocellular carcinoma cell line (HepG2) and in two human breast cancer cell lines (MDA-MB-231 and MCF-7). The results indicate that PSC induced intracellular ceramide levels by several fold, and reversal of this induction partially rescued the cells from apoptosis. Changes in PSC-induced p21 levels were directly correlated to activation of cell cycle arrest and inversely correlated to apoptosis. Based on these results, we tentatively conclude that PSC inhibits the development of cancer by selectively targeting tumor cells to undergo cell cycle arrest and/or apoptosis mediated via Pgp, ceramide and p21 signaling.
Notes: Source: Dissertation Abstracts International, Volume: 67-07, Section: B, page: 3720.

Thesis (Ph.D.)--University of Toronto, 2006.

Includes bibliographic references.

Electronic version licensed for access by U. of T. users.