Perillyl Alcohol Inhibits Human Breast Cancer Cell Growth in vitro and in vivo

Yuri, Takashi; Danbara, Naoyuki; Tsujita-Kyutoku, Miki; Kiyozuka, Yasuhiko; Senzaki, Hideto; Shikata, Nobuaki; Kanzaki, Hideharu; Tsubura, Airo

doi:10.1023/b:brea.0000019966.97011.4d

Cited by 67 publications

(39 citation statements)

References 23 publications

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“…Previous studies showed that POH is able to exert cytotoxic effects in cancer cells, although concentrations approaching the millimolar range were required (34,35). We therefore tested whether simply mixing the 2 compounds TMZ and POH could mimic the effects of the T-P conjugate.…”

Section: Resultsmentioning

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: Resultsmentioning

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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“…Perillyl alcohol (POH) which is the hydroxylated analogue of d-limonene, has the ability to interfere with angiogenesis (Loutrari et al, 2004). POH either alone or with PA (perillic acid, the major metabolite of POH in the body), has a potential use as an anticancer drug that stimulates different types of tumors to apoptosis, inhibits their proliferation, or overcomes their resistance to chemo-/radiotherapy (Yuri et al, 2004;Samaila et al, 2004;Elegbede et al, 2003;Clark et al, 2003;Ahn et al, 2003;Bardon et al, 2002;Burke et al, 2002;Bardon et al, 1998). The antitumor activity of POH emanates from its activity of modulating cellular processes that control cell growth and differentiation (Azzoli et al, 2003;Clark et al, 2002;Ariazi et al, 1999;Ren and Gould, 1998;Gould, 1997 andGould, 1995).…”

Section: Cancer Suppressionmentioning

confidence: 99%

Pharmaceutical and therapeutic Potentials of essential oils and their individual volatile constituents: a review

Edris

2007

Phytotherapy Research

1,086

688

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Essential oils and their volatile constituents are used widely to prevent and treat human disease. The possible role and mode of action of these natural products is discussed with regard to the prevention and treatment of cancer, cardiovascular diseases including atherosclerosis and thrombosis, as well as their bioactivity as antibacterial, antiviral, antioxidants and antidiabetic agents. Their application as natural skin penetration enhancers for transdermal drug delivery and the therapeutic properties of essential oils in aroma and massage therapy will also be outlined.

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“…POH has been shown to inhibit tumor growth in different solid tumor systems (11)(12)(13)(14)(15). As angiogenesis is a Cho et al…”

Section: Poh Affects Proangiogenic Cytokine Productionmentioning

confidence: 99%

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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Perillyl Alcohol Inhibits Human Breast Cancer Cell Growth in vitro and in vivo

Cited by 67 publications

References 23 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

Pharmaceutical and therapeutic Potentials of essential oils and their individual volatile constituents: a review

Perillyl Alcohol for the Treatment of Temozolomide-Resistant Gliomas

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