AACR: OSW-1, a Novel Anticancer Agent with Novel Method of Action

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AACR Abstract Number: 2254

OSW-1: A novel anticancer agent with potent anticancer activity and

unique mechanism of action

Yan Zhou, Celia -Prieto, Li Feng, Helene Pelicano, Zhendong

Jin, J. Keating, Peng Huang. UT MD Cancer Center,

Houston, TX and The University of Iowa, Iowa City, IA.

Background: OSW-1 is a naturally occurring compound found in the

bulbs of Ornithogalum saudersiae. Previous in vitro study showed that

OSW-1 has a potent cytotoxic activity against cancer cells, but the

mechanism of the drug action remains unknown. Our present study

tested the anticancer activity of OSW-1 against a variety of human

cancer cell lines and primary leukemia cells from patients, and

investigated the mechanisms responsible for its anticancer activity.

Methods: The cytotoxic activity of OSW-1 was tested using MTT assay

and apoptosis analyses including annexin-V reactivity, loss of

mitochondrial transmembrane potential, caspase activation, and loss

of DNA integrity. DNA microarray analysis was used to assess changes

in gene expression after cancer cells were incubated with OSW-1.

Special sub-clones of leukemia cells with mitochondrial DNA

alterations and respiration deficiency cells were used to evaluate

the role of mitochondrial respiration in OSW-1 action. Electronic

microscopy was used to reveal the morphological changes in

mitochondria after drug treatment.

Results: The IC50 of OSW-1 in several leukemia cell lines, ovarian

and pancreatic cancer cells were between 0.03- 0.3 nM. The median

IC50 in primary leukemia cells isolated from 35 patients with chronic

lymphocytic leukemia (CLL) is 0.24 nM. Normal lymphocytes and normal

ovarian epithelial cells were less sensitive to the cytotoxic action

of OSW-1 in comparison with leukemia and ovarian cancer cells,

respectively.

Microarray assay revealed that OWS-1 induced significant alterations

in expression of genes involved in mitochondrial respiration. Cells

with respiration deficiency were relatively resistant to OSW-1.

Morphological analysis by electronic microscopy revealed that OSW-1

induced significant mitochondrial swelling, flatting of cristae, and

decreased matrix density.

Conclusions: OSW-1 exhibits potent anticancer activity against a wide

spectrum of cancer cells and is relatively less toxic to normal

cells. Its mechanism of action seems to involve mitochondrial

respiration.

Presenter: Yan Zhou

Affiliation: UT MD anderson Cancer center, Houston, TX; E-mail:

zhouyan01@...

Copyright © 2004 American Association for Cancer Research. All rights

reserved. Citation information: Proceedings of the AACR, Volume 45,

March 2004.