Inhibition of DMBA-induced mammary cancer by the monoterpene d-limonene

Elegbede, J. Abiodun; Elson, Charles E.; Qureshi, Asaf A.; Tanner, Martin A.; Gould, Michael N.

doi:10.1093/carcin/5.5.661

Cited by 161 publications

(69 citation statements)

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“…29 Limonene, the simplest monoterpene ( Figure 1) is able to both prevent and treat rat mammary tumors, and to treat advanced stomach, lung and liver cancers in rats. [30][31][32][33][34][35] The monohydroxylated derivative of limonene, perillyl alcohol (POH) (Figure 1) is 5-10 times more effective than limonene at treating advanced carcinomas. 36 In tumor-bearing animals fed monoterpenes, tumor regression is associated with an increase in apoptotic cells and a decrease in cell proliferation within the tumor parenchyma.…”

Section: Introductionmentioning

confidence: 99%

Perillyl alcohol selectively induces G0/G1 arrest and apoptosis in Bcr/Abl-transformed myeloid cell lines

et al. 1999

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The Bcr/Abl tyrosine kinase that is expressed from the Philadelphia chromosome protects leukemia cells from apoptosis caused by removal of growth factors or by cytotoxic agents and ionizing irradiation. This resistance to apoptosis is associated with a Bcr/Abl-mediated G2/M delay. Therefore, inhibiting Bcr/Abl signaling pathways should block the ability of the Bcr/Abl kinase to protect cells from apoptosis. The monoterpenes, limonene and perillyl alcohol (POH) are new anticancer agents that selectively induce apoptosis in neoplastic cells of a variety of rodent carcinoma models. Since the potential antitumor activities of monoterpenes overlap with signaling pathways affected by the Bcr/Abl kinase, POH and limonene were tested for antileukemia activity. POH, but not limonene selectively induced G0/G1 arrest followed by apoptosis in Bcr/Abl-transformed, but not nontransformed FDC.P1 and 32D myeloid cell lines. In contrast to their greater sensitivity to POH, Bcr/Abl-transformed cells were more resistant than nontransformed cells to several chemotherapy agents and ionizing irradiation. Since in Bcr/Abl-transformed cells, POH induces apoptosis associated with G0/G1 arrest, POH must activate an apoptotic pathway that is not protected by the Bcr/Abl-induced G2/M delay. Monoterpenes may represent novel agents for treating Ph ؉ leukemias.

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Section: Introductionmentioning

confidence: 99%

Perillyl alcohol selectively induces G0/G1 arrest and apoptosis in Bcr/Abl-transformed myeloid cell lines

et al. 1999

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“…Limonene has significant chemopreventive and chemotherapeutic activity without toxicity in rodents (Elegbede et al, 1984(Elegbede et al, , 1986Elson et al, 1988;Maltzman et al, 1989;Wattenberg et al, 1989Wattenberg et al, , 1991. Most studies have been directed at the use of limonene in the prevention of carcinogen-induced cancer (Wattenberg et al, 1983;Elegbede et al, 1984). It has been shown that limonene inhibits rat mammary carcinomas induced by both the indirectly acting carcinogen DMBA (Elegbede et al, 1984) and the directly acting carcinogen NMU (Maltzman et al, 1989).…”

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confidence: 99%

“…Most studies have been directed at the use of limonene in the prevention of carcinogen-induced cancer (Wattenberg et al, 1983;Elegbede et al, 1984). It has been shown that limonene inhibits rat mammary carcinomas induced by both the indirectly acting carcinogen DMBA (Elegbede et al, 1984) and the directly acting carcinogen NMU (Maltzman et al, 1989). The inhibitory effect of limonene was observed at both the initiation and promotion/progression stages for DMBA-induced cancers (Elson et al, 1988), but only at the promotion/progression stage for NMU-induced mammary cancer (Maltzman et al, 1989).…”

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Effectiveness of combined limonene and 4-hydroxyandrostenedione in the treatment of NMU-induced rat mammary tumours

Chander¹,

Lansdown²,

Luqmani³

et al. 1994

Br J Cancer

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Summary Limonene, a monocyclic monoterpene, occurs naturally in orange peel oil. It has been shown to exhibit both chemopreventive and chemotherapeutic activity without toxicity in rodent models. In this study we examined the effect of limonene both at maximally optimal and suboptimal doses and in combination with suboptimal doses of 4-hydroxyandrostrenedione on nitrosmethylurea-induced rat mammary tumours. A 10% limonene dose mixed in the diet caused tumour regression in all animals. A 5% limonene dose was only able to cause regression in 50% of the rats (P <0.05). A suboptimal dose of 4-hydroxyandrostrenedione (12.5mgkg 1) resulted in tumour re ression in 75% of rats. A combination of 5% limonene with 4-hydroxyandrostrenedione (12.5mgkg-) resulted in a greater tumour regression (83.3%) than either agent given individually (P <0.001 and 0.006 for limonene/4-hydroxyandrostrenedione vs limonene alone and 4-hydroxyandrostrenedione alone respectively).

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“…5 In established rat mammary carcinomas, limonene produces complete regression in > 80% of the tumors. 6,7 Perillyl alcohol is five-fold more potent than limonene in producing regression in both early 8 and advanced mammary tumors, 9 and also has activity in vivo against cancers of the pancreas, 10 melanoma 11 and liver 12 and in vitro against neuroblastoma 13 and colon carcinoma. 14 The exact mechanism for the anticancer activity of monoterpenes has not been fully established.…”

Section: Introductionmentioning

confidence: 99%

Phase I Study of Perillyl Alcohol in Patients with Refractory Malignancies

Murren¹,

Pizzorno²,

DiStasio³

et al. 2002

Cancer Biology & Therapy

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We treated 21 patients in a dose-finding and pharmacokinetic study of the monoterpene perillyl alcohol with the drug given orally in 3 divided doses on a chronic basis. The average number of days that patients remained on study was 48 (range 11-172). Fatigue and low-grade nausea were dose limiting. Using this schedule, a starting dose of 1.6 g/m2 with escalation to 2.1 g/m2 as tolerated is recommended. Two major metabolites were detectable and the mean peak plasma concentrations were 383 µM for perillic acid and 27 µM for dihydroperillic acid. The peak plasma concentration and the metabolite half-life were 2h and 1h post ingestion for perillic acid, and 4 h and 2.4 h for dihydroperillic acid, respectively. Stabilization of disease was observed in one of the 16 patients evaluable for response. Many of the gastrointestinal side effects that were poorly tolerated on a chronic basis may be partly related to the soybean oil base used in the current formulation. Further development of perillyl alcohol on this schedule would be facilitated by reformulation of the capsule.

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Inhibition of DMBA-induced mammary cancer by the monoterpene d-limonene

Cited by 161 publications

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Perillyl alcohol selectively induces G0/G1 arrest and apoptosis in Bcr/Abl-transformed myeloid cell lines

Perillyl alcohol selectively induces G0/G1 arrest and apoptosis in Bcr/Abl-transformed myeloid cell lines

Effectiveness of combined limonene and 4-hydroxyandrostenedione in the treatment of NMU-induced rat mammary tumours

Phase I Study of Perillyl Alcohol in Patients with Refractory Malignancies

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