Inhibition of protein prenylation by metabolites of limonene

Hardcastle, IanR; Rowlands, MartinG; Barber, Amy; Grimshaw, RachelM; Mohan, MukeshK; Nutley, BernardP; Jarman, Michael

doi:10.1016/s0006-2952(98)00349-9

Cited by 78 publications

(65 citation statements)

References 27 publications

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“…46 and 47). As well, it has been described as a farnesyl-transferase inhibitor that results in the blockage of ras oncoprotein activity (48,49), although this has been challenged (50,51). Importantly, in all these cases relatively high concentrations of POH (well above 100 mmol/L) are required to achieve 50% inhibition of target activity (see also Fig.…”

Section: Discussionmentioning

confidence: 99%

A Novel Temozolomide–Perillyl Alcohol Conjugate Exhibits Superior Activity against Breast Cancer Cells In Vitro and Intracranial Triple-Negative Tumor Growth In Vivo

Chen

Cho

Wang

et al. 2014

Molecular Cancer Therapeutics

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There is no effective therapy for breast cancer that has spread to the brain. A major roadblock is the bloodbrain barrier (BBB), which prevents the usual breast cancer drugs from effectively reaching intracranial metastases. The alkylating agent temozolomide (TMZ) is able to penetrate the BBB and has become the gold standard for chemotherapeutic treatment of glioblastoma. However, when it was tested in clinical trials for activity against brain metastases of breast cancer, the results were mixed and ranged from "encouraging activity" to "no objective responses." In an effort to generate an agent with greater activity against intracranial breast metastases, we synthesized a TMZ analog where the natural product perillyl alcohol (POH) was covalently linked to TMZ's amide functionality. The resulting novel compound, called TMZ-POH (T-P), displayed greatly increased anticancer activity in a variety of breast cancer cell lines, inclusive of TMZ-resistant ones. It caused DNA damage and cell death much more efficiently than its parental compound TMZ, because linkage with POH increased its biologic half-life and thus provided greater opportunity for placement of cytotoxic DNA lesions. In an intracranial mouse tumor model with triple-negative breast cancer, T-P revealed considerably greater therapeutic efficacy than TMZ, where a single cycle of treatment extended median survival benefit from 6 days (in the case of TMZ) to 28 days. At the same time, T-P seemed to be well tolerated by the animals. Thus, T-P may have potential as a novel therapy for brain-targeted breast cancer metastases.

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Section: Discussionmentioning

confidence: 99%

A Novel Temozolomide–Perillyl Alcohol Conjugate Exhibits Superior Activity against Breast Cancer Cells In Vitro and Intracranial Triple-Negative Tumor Growth In Vivo

Chen

Cho

Wang

et al. 2014

Molecular Cancer Therapeutics

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“…Although metabolites of the monoterpene limonene are able to inhibit one or more protein:prenyl transferase, none of these specifically inhibits Rab GGTase. For example, perillyl alcohol inhibits Rab GGTase, but also GGTase I in cell-free lysates and intact 3T3 cells (6), whereas other monoterpenes, such as perillic acid, inhibit FTase and GGTase I only (7).…”

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confidence: 99%

Identification of a Novel Phosphonocarboxylate Inhibitor of Rab Geranylgeranyl Transferase That Specifically Prevents Rab Prenylation in Osteoclasts and Macrophages

Coxon

Helfrich²,

Larijani

et al. 2001

Journal of Biological Chemistry

159

162

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Nitrogen-containing bisphosphonate drugs inhibit bone resorption by inhibiting FPP synthase and thereby preventing the synthesis of isoprenoid lipids required for protein prenylation in bone-resorbing osteoclasts. NE10790 is a phosphonocarboxylate analogue of the potent bisphosphonate risedronate and is a weak antiresorptive agent. Although NE10790 was a poor inhibitor of FPP synthase, it did inhibit prenylation in J774 macrophages and osteoclasts, but only of proteins of molecular mass ϳ22-26 kDa, the prenylation of which was not affected by peptidomimetic inhibitors of either farnesyl transferase (FTI-277) or geranylgeranyl transferase I (GGTI-298). These 22-26-kDa proteins were shown to be geranylgeranylated by labelling J774 cells with [ 3 H]geranylgeraniol. Furthermore, NE10790 inhibited incorporation of [ 14 C]mevalonic acid into Rab6, but not into H-Ras or Rap1, proteins that are modified by FTase and GGTase I, respectively. These data demonstrate that NE10790 selectively prevents Rab prenylation in intact cells. In accord, NE10790 inhibited the activity of recombinant Rab GGTase in vitro, but did not affect the activity of recombinant FTase or GGTase I. NE10790 therefore appears to be the first specific inhibitor of Rab GGTase to be identified. In contrast to risedronate, NE10790 inhibited bone resorption in vitro without markedly affecting osteoclast number or the F-actin "ring" structure in polarized osteoclasts. However, NE10790 did alter osteoclast morphology, causing the formation of large intracellular vacuoles and protrusion of the basolateral membrane into large, "domed" structures that lacked microvilli. The anti-resorptive activity of NE10790 is thus likely due to disruption of Rabdependent intracellular membrane trafficking in osteoclasts.

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“…In addition to the parent drug, five major metabolites were identified in the plasma: limonene-1,2-diol, perillic acid, dihydroperillic acid, iso-perillic acid, and uroterpenol. 34 At the recommended dose of 8 gm/m 2 , the mean Cmax was 10.8±6.7 µM and 20.7±13.2 µM for limonene and the major circulating metabolite perillic acid respectively. Pharmacokinetic analysis after 21 days of drug administration showed an absence of accumulation of any of the major metabolites.…”

Section: Discussionmentioning

confidence: 89%

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 protein prenylation by metabolites of limonene

Cited by 78 publications

References 27 publications

A Novel Temozolomide–Perillyl Alcohol Conjugate Exhibits Superior Activity against Breast Cancer Cells In Vitro and Intracranial Triple-Negative Tumor Growth In Vivo

A Novel Temozolomide–Perillyl Alcohol Conjugate Exhibits Superior Activity against Breast Cancer Cells In Vitro and Intracranial Triple-Negative Tumor Growth In Vivo

Identification of a Novel Phosphonocarboxylate Inhibitor of Rab Geranylgeranyl Transferase That Specifically Prevents Rab Prenylation in Osteoclasts and Macrophages

Phase I Study of Perillyl Alcohol in Patients with Refractory Malignancies

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