Wow -- waddya make of this?

[Guest guest]

http://www.aacrmeetingabstracts.org/cgi/content/abstract/2005/1/148-c

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Experimental and Molecular Therapeutics 5: Novel Agents 1

Abstract #629

Sanguinarine causes cell cycle arrest and apoptosis of human

pancreatic cancinoma AsPC-1 and BxPC-3 cells

Haseeb Ahsan, R. Reagan-Shaw, Jorien G. Breur and Nihal Ahmad

University of Wisconsin, Madison, WI

Pancreatic cancer is one of the most lethal cancers and it is

estimated that in the USA alone, 31,860 new cases for pancreatic

cancer will be diagnosed and 31,270 deaths will occur during 2004.

Pancreatic cancer is clinically very silent and difficult to

diagnose. It is associated with low responsiveness to conventional

chemotherapies and surgery is not very useful, except in early

stages. This warrants the development of novel mechanism-based

approaches for the management of pancreatic cancer. In the recent

past, naturally occurring agents such as plant-derived alkaloids have

remarkable anti-cancer effects. Sanguinarine, derived from the roots

of Sanguinaria canadensis and other poppy fumaria species, possesses

strong antimicrobial, anti-inflammatory and antioxidant properties.

Sanguinarine has also shown anti-proliferative effects in cell

culture studies. In this study, we determined the anti-proliferative

effects of sanguinarine against human pancreatic carcinoma (AsPC-1

and BxPC-3) cells. Our data demonstrated that sanguinarine (at low

concentrations of 0.1-10 µM; for 24 h) treatment to AsPC-1 and BxPC-3

cells resulted in a dose dependent i) inhibition of cell growth (up

to 62% in AsPC-1 and 47.3% in BxPC-3 cells at 10 µM), ii) inhibition

of cell viability (up to 97.3% in AsPC-1 and 95.6% in BxPC-3 cells at

10 µM), iii) arrest of cells in G0-G1 phase of the cell cycle (up to

64.7% in AsPC-1 and 74.1% in BxPC-3 cells at 10 µM), and iii)

induction of apoptosis (97.9% in AsPC-1 and 96.5% in BxPC-3 cells at

10 µM). Sanguinarine treatment also resulted in a significant dose-

dependent inhibition in the colony forming ability of both the cell

lines. Since, mitochondrial pathway is critical for the regulation of

apoptosis, and sanguinarine has been shown to induce apoptosis via

mitochondrial pathway, we studied the involvement and regulation of

mitochondrial events in sanguinarine-mediated apoptosis of AsPC-1 and

BxPC-3 cells. Our data demonstrated that sanguinarine-treatment to

AsPC-1 and BxPC-3 cells resulted in a dose dependent i) increase in

pro-apoptotic Bax protein, ii) decrease in ani-apoptotic Bcl-2

protein, and iii) increase in Bax/Bcl-2 protein ratio. Sanguinarine

treatment also resulted in a dose dependent increase in Bak and Bid,

the pro-apoptotic members of Bcl-2 family proteins in AsPC-1 cells.

Based on our data and the available literature, we suggest that

sanguinarine imparts strong anti-proliferative effects against

pancreatic cancer cells via i) induction of apoptosis that is

mediated by modulations in Bcl-2 family proteins, and ii) cell cycle

blockade at G1 phase. These results suggest that sanguinarine may be

developed as an agent for the management of pancreatic cancer.