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Antileukemia activity of perillyl alcohol (POH): uncoupling apoptosis from G0/G1 arrest suggests that the primary effect of POH on Bcr/Abl-transformed cells is to induce growth arrest

Leukemia volume 16, pages 213–222 (2002)Cite this article

Abstract

In hematopoietic cells, the Bcr/Abl tyrosine kinase that is encoded by the Philadelphia chromosome translocation both stimulates proliferation and activates an anti-apoptotic program that is associated with a G2/M delay upon exposure to various apoptotic stimuli. We recently reported that the monocyclic monoterpene, perillyl alcohol (POH) selectively induces in Bcr/Abl transformed cells, G0/G1 arrest and apoptosis. Therefore, POH activates anti-proliferative and apoptotic pathways against which the Bcr/Abl kinase does not protect. In this report, we show that in Bcr/Abl-transformed cells, POH induces cytoplasmic acidification, redistribution of phosphatidylserine in the plasma membrane along with DNA fragmentation, all of which can be prevented by the phorbol ester, TPA. The ability of TPA to protect against POH-induced cytotoxicity was blocked by inhibitors of protein kinase C (PKC) and the Na+/H+ antiport. In contrast, TPA does not protect the cells from POH-mediated G0/G1 arrest. While POH inhibits a distal step in the mevalonate biosynthesis pathway, lovastatin, also a potential anticancer agent, inhibits the initial step in this pathway. Not surprisingly, lovastatin also induces G0/G1 arrest and apoptosis in Bcr/Abl-transformed cells, however, TPA protects cells from both apoptosis and G0/G1 arrest caused by lovastatin. Thus, in Bcr/Abl-transformed cells, POH and lovastatin cause growth arrest by different mechanisms. Together, these observations demonstrate that POH-mediated cell cycle arrest precedes apoptosis and raises the possibility that that the primary effect of POH is to induce G0/G1 arrest with apoptosis being a consequence of the growth arrest.

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Acknowledgements

This work was supported by NIH grants CA81307, CA38128, CA14520 (Core) and CA09471 (Training), American Institute for Cancer Research grant No. 98A103, a Florence Carter Fellowship from the American Medical Association to MS. JAE was supported by an ACS International Cancer Research Fellowship from the International Union Against Cancer (UICC). The expert technical assistance of Li Zhong and Aren Andreoli are gratefully acknowledged.

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  1. JA Elegbede

    Present address: Chemistry Department, University of Nevada Las Vegas, Las Vegas, NV 89154-4003, USA

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  1. Department of Human Oncology, Oncology and the UW Comprehensive Cancer Center, University of Wisconsin, Madison, WI, USA

    SS Clark, SM Perman, GJ Jenkins & JA Elegbede

  2. Department of Medicine, Oncology and the UW Comprehensive Cancer Center, University of Wisconsin, Madison, WI, USA

    MB Sahin

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Clark, S., Perman, S., Sahin, M. et al. Antileukemia activity of perillyl alcohol (POH): uncoupling apoptosis from G0/G1 arrest suggests that the primary effect of POH on Bcr/Abl-transformed cells is to induce growth arrest. Leukemia 16, 213–222 (2002). https://doi.org/10.1038/sj.leu.2402369

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