Perillyl alcohol and perillic acid induced cell cycle arrest and apoptosis in non small cell lung cancer cells

Yeruva, Laxmi; Pierre, Keon J.; Elegbede, Abiodun; Wang, Robert C.; Carper, Stephen W.

doi:10.1016/j.canlet.2007.07.020

Cited by 113 publications

(71 citation statements)

References 27 publications

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“…There is substantial evidence from other tumor models that POH treatment induced growth arrest and cell death by a variety of mechanisms (2,3). POH treatment significantly suppressed the Ras/Raf/ERK pathway (4,24).…”

Section: Discussionmentioning

confidence: 99%

“…Perillyl alcohol (POH) is a naturally occurring monoterpene that has been used orally for the treatment of a variety of cancers, including breast, pancreas, and lung carcinomas (1)(2)(3). POH was shown to be a cytotoxic agent by functioning as a Ras inhibitor, cell-cycle inhibitor, and upregulator of the proapoptotic protein Bax (3,4).…”

Section: Introductionmentioning

confidence: 99%

“…POH was shown to be a cytotoxic agent by functioning as a Ras inhibitor, cell-cycle inhibitor, and upregulator of the proapoptotic protein Bax (3,4). However, because of its significant gastrointestinal side effects, POH was not well tolerated as an oral anticancer agent.…”

Section: Introductionmentioning

confidence: 99%

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Perillyl Alcohol for the Treatment of Temozolomide-Resistant Gliomas

Cho

Wang

Jhaveri

et al. 2012

Molecular Cancer Therapeutics

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Perillyl alcohol (POH) is a monoterpene that has been used orally for the treatment of systemic cancer. However, when used orally significant gastrointestinal side effects and lack of overall efficacy were documented. Recently, in a phase II trial in Brazil for the treatment of temozolomide (TMZ)-resistant malignant gliomas, POH was well tolerated when administered intranasally. The present study explores the effects and mechanisms of POH on TMZ-sensitive and TMZ-resistant glioma cells. In vitro studies showed that POH was cytotoxic to TMZ-resistant as well as TMZ-sensitive glioma cells, and this effect was independent of O 6 -methylguanine-DNA methyltransferase expression. POH induced cytotoxicity, in part, through the endoplasmic reticulum (ER) stress pathway as shown by the increased expression of glucose-regulated protein-78 (GRP78), activating transcription factor 3, and C/EBP-homologous protein. In addition, POH impeded survival pathways, such as mTOR and Ras. As well, POH reduced the invasive capacity of sensitive and resistant glioma cells. POH alone and/or in combination with other ER stress-inducing cytotoxic drugs (i.e., 2, 5-dimethyl-celecoxib, nelfinavir) further induced apoptosis in TMZ-sensitive and TMZ-resistant glioma cells. To show whether intranasal delivery of POH was effective for the treatment of TMZ-resistant gliomas, animals bearing intracranial tumors were given POH intranasally. Animals treated through intranasal administration of POH exhibited a decrease in tumor growth and an increase in survival. Our data show that POH is an effective anti-glioma cytotoxic agent for TMZ-resistant gliomas when administered intranasally.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Perillyl Alcohol for the Treatment of Temozolomide-Resistant Gliomas

Cho

Wang

Jhaveri

et al. 2012

Molecular Cancer Therapeutics

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“…For maximum activity, temozolomide is given at fairly high doses, often associated with deleterious effects such as myelosuppression (6), as well as the development of drug resistance (7,8). The choice of POH as a linkage partner for temozolomide was based on the knowledge that this agent has recognized anticancer activity and is cytotoxic to temozolomide-resistant gliomas (5,(9)(10)(11). Furthermore, preliminary data using the blood-brain barrier (BBB) prediction program demonstrated that conjugating POH, which is amphophilic, to temozolomide would increase the lipophilicity of this new compound.…”

Section: Introductionmentioning

confidence: 99%

NEO212, Temozolomide Conjugated to Perillyl Alcohol, Is a Novel Drug for Effective Treatment of a Broad Range of Temozolomide-Resistant Gliomas

Cho¹,

Wang²,

Jhaveri³

et al. 2014

Molecular Cancer Therapeutics

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Patients with glioblastoma multiforme (GBM), a malignant primary brain tumor, inevitably develop resistance to standard-of-care chemotherapy, temozolomide. This study explores the effects of the novel agent NEO212, a conjugate of temozolomide to perillyl alcohol, on temozolomide-resistant gliomas. NEO212 was tested for cytotoxic activity on three human temozolomide-resistant glioma cell lines, which were resistant to temozolomide based on overexpression of the base excision repair (BER) pathway, mismatch repair (MMR) deficiency, or overexpression of O 6 methyl-guanine-DNA methyltransferase (MGMT). BER expression was evaluated by Western blotting and PARP activity. MMR deficiency was determined by Western blotting and microsatellite instability. MGMT overexpression was evaluated by Western blotting and O 6 -benzylguanine (O 6 BG) inhibition. For in vivo evaluation of NEO212, temozolomide-resistant glioma cells were implanted into immune-incompetent mice, and NEO212 was administered. NEO212, at equimolar concentrations of temozolomide, was more cytotoxic for temozolomideresistant cells than temozolomide and not toxic to normal cells. NEO212-induced cell death in temozolomide-resistant glioma cells was independent of such mechanisms of resistance as high levels of MGMT, MMR deficiencies, or overexpression of BER proteins. NEO212 functions as a DNA alkylating agent, similar to temozolomide; however, this novel conjugate is unique for it may induce endoplasmic reticulum (ER) stress and inhibits autophagy. In vivo studies show that NEO212 reduces intracranial tumor growth and increases animal survival without significant toxicity. These results demonstrate that NEO212 is an effective drug against malignant gliomas that can be used for a broad range of newly diagnosed and temozolomide-resistant gliomas.

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“…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.…”

Section: Introductionmentioning

confidence: 99%

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

Marson

Vilhena

Pontes

et al. 2017

J. Braz. Chem. Soc.

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Perillyl alcohol has been studied in the treatment of cancer disease. However, its high toxicity is a drawback, which can be overcome by its incorporation in nanostructured systems. The aim of this work was to develop and validate a chromatographic method for determination of perillyl alcohol encapsulation efficiency in a polymeric nanoparticles formulation and evaluation of the presence of related degradation products. Perillyl alcohol was subjected to forced conditions of hydrolysis (acidic, alkaline and neutral), oxidation, photolysis and thermal stress, as suggested in the International Conference of Harmonization (ICH) guidelines. The drug showed significant degradation under acidic conditions. The degradation products could be adequately separated on an XBridge C18 column (100 × 2.1 mm, 3.5 μm) using isocratic elution (350 μL min , precise (relative standard deviation (RSD) < 2.0%), accurate (98.07 to 101.99%) and robust for minor changes. The method was successfully applied to determine the encapsulation efficiency of perillyl alcohol in polymeric nanoparticles, both for product development and for quality control purposes. After nanoparticles production, the presence of degradation products was not observed indicating that the single-emulsion solvent-evaporation technique used does not favor chemical degradation of the drug.

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Perillyl alcohol and perillic acid induced cell cycle arrest and apoptosis in non small cell lung cancer cells

Cited by 113 publications

References 27 publications

Perillyl Alcohol for the Treatment of Temozolomide-Resistant Gliomas

Perillyl Alcohol for the Treatment of Temozolomide-Resistant Gliomas

NEO212, Temozolomide Conjugated to Perillyl Alcohol, Is a Novel Drug for Effective Treatment of a Broad Range of Temozolomide-Resistant Gliomas

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

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