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

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 POHmediated 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. Leukemia (2002) 16, 213-222.

Perillyl Alcohol Is an Angiogenesis Inhibitor

“…other important molecules involved in neovessel formation, like Ang1, do not directly stimulate endothelial cell growth but rather stabilize vascular networks by promoting endothelial cell survival (Papapetropoulos et al, 1999(Papapetropoulos et al, , 2000. POH has well-established cytostatic and apoptotic activities in a variety of mammalian cancer cells (Crowell, 1999;Burke et al, 2002;Clark et al, 2002). We also observed the induction of programmed cell death in the cancer cell lines used in our study.…”

“…Data from rodents have shown that tumor regression occurs when plasma levels of perillic acid and dihydroperillic acid reach 390 to 480 M and 110 to 230 M, respectively (Belanger, 1998;Crowell, 1999). Additionally, POH has a cytostatic and cytotoxic effect against a variety of cancer cell lines (Crowell, 1999;Burke et al, 2002;Clark et al, 2002). Treatment of pancreatic tumor cells with POH for 2 days results in a concentration-dependent decrease in cell proliferation, with IC 50 values of 290 and 480 M for the human and hamster cell lines, respectively.…”

Cell Cycle Arrest by the Isoprenoids Perillyl Alcohol, Geraniol, and Farnesol Is Mediated by p21Cip1and p27Kip1in Human Pancreatic Adenocarcinoma Cells

“…In addition to early findings that isoprenoids may inhibit posttranslational protein prenylation (Crowell et al, 1991;Ren et al, 1997), reported effects include induction of G 0 /G 1 cell cycle arrest (Yu et al, 1995;Miquel et al, 1998;Clark et al, 2002;Elegbede et al, 2003), increased apoptosis (Haug et al, 1994;Mills et al, 1995;Reddy et al, 1997;Stayrook et al, 1997;Ariazi et al, 1999;Rioja et al, 2000;Burke et al, 2002;Clark et al, 2002;Elegbede et al, 2003;Xu et al, 2004), transient G 2 /M phase arrest (Shi and Gould, 2002;Rajesh and Howard, 2003), inhibition of cholesterol biosynthesis (Ren and Gould, 1994;Peffley and Gayen, 2003), inhibition of angiogenesis (Loutrari et al, 2004), and increased sensitization to radiation and anticancer drugs (Samaila et al, 2004).…”

Development and Validation of a Stability-Indicating Method for Perillyl Alcohol Incorporated in Poly(lactide-co-glycolide) Nanoparticles and Stress Degradation Studies

“…1,2 Medical interest in this compound has been generated by several researches showing that POH has been able to demonstrate activity against a variety of tumor models, such as adenocarcinoma, brain, breast, colon, gliomas, leukemic cells, liver, lung, pancreas, prostate and skin. [2][3][4][5][6][7] However, the results of phase I and II clinical trials showed nausea, vomiting and loose stools identified as common toxicities with rare leukocytosis, thrombocytosis, lethargy, renal tubular degeneration with elevated serum creatinine and gastritis. [8][9][10] Chemotherapeutic agents harm healthy tissues, leading to systemic toxicity and adverse effects that greatly limit the maximum tolerated dose of anti-cancer drugs and thus restrict their therapeutic efficacy.…”