This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Berchtold, C. M. Articles by Gould, M. N. Search for Related Content PubMed PubMed Citation Articles by Berchtold, C. M. Articles by Gould, M. N. Related Collections Preclinical Intervention Preclinical Intervention: In Vitro: Drugs, Mechanisms

Perillyl Alcohol Inhibits a Calcium-Dependent Constitutive Nuclear Factor-B Pathway

Departments of ¹ Oncology and ² Pharmacology; ³ McArdle Laboratory for Cancer Research; and ⁴ 301 SMI, University of Wisconsin-Madison, Madison, Wisconsin

Requests for reprints: Michael N. Gould, McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, 1400 University Avenue, Room 506, Madison, WI 53706. Phone: 608-263-6615; E-mail: gould{at}oncology.wisc.edu.

The cell death induced by the monoterpene anticancer agent perillyl alcohol correlates to the increased expression of certain proapoptotic genes known to influence cell survival. Whereas sequence-specific DNA-binding factors dictate the expression patterns of genes through transcriptional regulation, those transcriptional factors influencing constitutive cell survival with perillyl alcohol treatment are not well studied. Here, we investigated whether the monoterpenes can regulate the activity of nuclear factor-B (NF-B), a calcium-dependent transcription factor necessary for survival in the WEHI-231 B-lymphoma cells. Unique among the monoterpenes, perillyl alcohol short-term treatment induced a persistent decrease of calcium levels, whereas other various monoterpenes caused transient reductions in calcium levels. Perillyl alcohol treatment also rapidly elicited reductions of NF-B DNA-binding activity and target gene induction, which was associated with an increase in apoptosis in these B-lymphoma cells. This apoptosis was directly due to NF-B because its prior activation abolished the cell killing effects of perillyl alcohol treatment. Our findings suggest that perillyl alcohol can inhibit NF-B function to modulate gene expression patterns and cell survival of certain B-lymphoma cells. The effects of perillyl alcohol were not limited to these B-lymphoma cells but were also observed in MDA-MB 468 cells, an estrogen receptor–negative breast cancer cell line. These results identify a calcium-dependent NF-B pathway as a molecular target of perillyl alcohol activity in different cancer cell types.

This article has been cited by other articles:

				I. V. Lebedeva, Z.-z. Su, N. Vozhilla, L. Chatman, D. Sarkar, P. Dent, M. Athar, and P. B. Fisher Mechanism of In vitro Pancreatic Cancer Cell Growth Inhibition by Melanoma Differentiation-Associated Gene-7/Interleukin-24 and Perillyl Alcohol Cancer Res., September 15, 2008; 68(18): 7439 - 7447. [Abstract] [Full Text] [PDF]

				S. Markovina, N. S. Callander, S. L. O'Connor, J. Kim, J. E. Werndli, M. Raschko, C. P. Leith, B. S. Kahl, K. Kim, and S. Miyamoto Bortezomib-Resistant Nuclear Factor-{kappa}B Activity in Multiple Myeloma Cells Mol. Cancer Res., August 1, 2008; 6(8): 1356 - 1364. [Abstract] [Full Text] [PDF]

				I. V. Lebedeva, Z.-z. Su, N. Vozhilla, L. Chatman, D. Sarkar, P. Dent, M. Athar, and P. B. Fisher Chemoprevention by perillyl alcohol coupled with viral gene therapy reduces pancreatic cancer pathogenesis Mol. Cancer Ther., July 1, 2008; 7(7): 2042 - 2050. [Abstract] [Full Text] [PDF]

				C.M. Payne, C. Weber, C. Crowley-Skillicorn, K. Dvorak, H. Bernstein, C. Bernstein, H. Holubec, B. Dvorakova, and H. Garewal Deoxycholate induces mitochondrial oxidative stress and activates NF-{kappa}B through multiple mechanisms in HCT-116 colon epithelial cells Carcinogenesis, January 1, 2007; 28(1): 215 - 222. [Abstract] [Full Text] [PDF]