Cytotoxicity and Biotransformation of the Anticancer Drug Perillyl Alcohol in PC12 Cells and in the Rat

Boon, P. J. M.; Boon, D. Van Der; Mulder, G. J.

doi:10.1006/taap.2000.8988

Cited by 44 publications

(25 citation statements)

References 20 publications

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“…Thus, dietary administration of the monoterpenes, limonene or perillyl alcohol (POH) can cure advanced mammary, stomach, lung, skin and liver cancers in rats, mice or hamsters [42][43][44][45][46][47][48][49][50][51] and they do not cause significant toxicity in rats, dogs or humans. [42][43][44][45][52][53][54][55][56] The anticancer activities of these monoter-penes are associated with a selective induction of apoptosis in the neoplastic tissue but not in adjacent normal tissues. 43,50 Although the specific anticancer mechanisms are poorly understood, the broad anticancer activity of monoterpenes, coupled with their negligible toxicity prompted us to test limonene and its hydroxylated derivative, POH, against Bcr/Abltransformed and nontransformed cell lines.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2002

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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.

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Section: Introductionmentioning

confidence: 99%

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

et al. 2002

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“…inhibited, indicate that perillaldehyde is a major intermediary metabolite of perillyl alcohol in the rat in vivo and in rat hepatocytes in vitro (Boon et al, 2000).…”

Section: D235 Perillyl Alcohol and Perillaldehydementioning

confidence: 87%

Scientific Opinion on Flavouring Group Evaluation 12, Revision 4 (FGE.12Rev4): primary saturated or unsaturated alicyclic alcohols, aldehydes, acids and esters from chemical groups 1 and 7

Publication¹

2013

EFS2

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The Panel on Food Contact Materials, Enzymes, Flavourings and Processing Aids of the European Food Safety Authority was requested to evaluate 12 flavouring substances in Flavouring Group Evaluation 12, Revision 4 (FGE.12Rev4), including two additional substances, using the Procedure in Commission Regulation (EC) No 1565/2000. The present revision includes two additional flavouring substances: 12-beta-santalen-14-ol [FLno: 02.216] and 12-alpha-santalen-14-ol ]. None of the substances was considered to have genotoxic potential. The substances were evaluated through a stepwise approach (the Procedure) that integrates information on structure-activity relationships, intake from current uses and the toxicological threshold of concern and available data on metabolism and toxicity. The Panel concluded that none of the 12 substances [FLnos: 02.134, 02.186, 02.216, 02.217, 05.157, 05.182, 05.183, 05.198, 08.135, 09.342, 09.670 and 09.829] gives rise to safety concerns at their levels of dietary intake, estimated on the basis of the maximised survey-derived daily intake approach. Besides the safety assessment of these flavouring substances, the specifications for the materials of commerce have also been considered. Specifications including complete purity criteria and identity for the materials of commerce have been provided for all 12 candidate substances.

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“…From perillic acid only the acyl glucuronide was generated, whereas perillyl alcohol and perillaldehyde formed both acyl and ether glucuronides. The results, together with those of studies in which alcohol dehydrogenase or aldehyde dehydrogenase were inhibited, indicate that perillaldehyde is a major intermediary metabolite of perillyl alcohol in the rat in vivo and in rat hepatocytes in vitro (Boon et al, 2000). To six male rabbits p-mentha-1, 8-dien-7-al (perillaldehyde) was administered orally at a dose level of 2000 mg per animal.…”

Section: Perillyl Alcohol and Perillaldehydementioning

confidence: 91%

Scientific Opinion on Flavouring Group Evaluation 12, Revision 2 (FGE.12Rev2): Primary saturated or unsaturated alicyclic alcohol, aldehyde, acid, and esters from chemical group 7

Flavourings¹

2011

EFS2

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Cytotoxicity and Biotransformation of the Anticancer Drug Perillyl Alcohol in PC12 Cells and in the Rat

Cited by 44 publications

References 20 publications

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

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

Scientific Opinion on Flavouring Group Evaluation 12, Revision 4 (FGE.12Rev4): primary saturated or unsaturated alicyclic alcohols, aldehydes, acids and esters from chemical groups 1 and 7

Scientific Opinion on Flavouring Group Evaluation 12, Revision 2 (FGE.12Rev2): Primary saturated or unsaturated alicyclic alcohol, aldehyde, acid, and esters from chemical group 7

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