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European Journal of Pharmacology Jan 2015Perillyl alcohol (PA) is a monoterpene found in essential oils of mints, cherries, citreous fruits and lemon grass, reported to have antioxidant and anti-inflammatory...
Perillyl alcohol improves functional and histological outcomes against ischemia-reperfusion injury by attenuation of oxidative stress and repression of COX-2, NOS-2 and NF-κB in middle cerebral artery occlusion rats.
Perillyl alcohol (PA) is a monoterpene found in essential oils of mints, cherries, citreous fruits and lemon grass, reported to have antioxidant and anti-inflammatory properties. However, the role of PA in stroke is still illusive. Since oxidative stress and inflammation play a pivotal role in ischemia-reperfusion (I-R) injury, this study was designed to elucidate the potential effects of PA against I-R induced pathology in rat׳s brain. Middle cerebral artery occlusion (MCAO) for 2h followed by 22h reperfusion in Wistar male rats (250-280g, 14-16 weeks old) induced the behavioral and histological alterations along with exhausted antioxidant status and enhanced inflammatory mediators. However, PA administration (25, 50 and 100mg/kg b.wt orally once daily for 7 days) prior to MCAO significantly attenuated neurological deficits related to flexion test and spontaneous motor activity, improved grip strength and motor coordination in a dose dependent manner. PA treatment also inhibited oxidative stress in MCAO rats as evident from decreased lipid peroxidation and augmented level of reduced glutathione and restored activities of catalase, glutathione peroxidase, and glutathione reductase and thus, reduced infarct volume and protected the brain histology after I-R injury. Furthermore, PA markedly suppressed the level of proinflammatory cytokines (IL-1β, TNF α and IL-6) and down regulated expressions of cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (NOS-2) and nuclear factor κB (NF-κB) in MCAO group. In conclusion, PA mediates neuroprotection against I-R injury via mitigation of oxidative stress and inflammation and thus, may be a good therapeutic approach in stroke prone patient.
Topics: Animals; Brain; Cyclooxygenase 2; Cytokines; Gene Expression Regulation, Enzymologic; Infarction, Middle Cerebral Artery; Male; Monoterpenes; NF-kappa B; Neuroprotective Agents; Nitric Oxide Synthase Type II; Oxidative Stress; Rats; Rats, Wistar; Reperfusion Injury
PubMed: 25240714
DOI: 10.1016/j.ejphar.2014.09.015 -
Therapeutic Advances in Medical Oncology 2019Mycosis fungoides (MF) and Sézary syndrome (SS) are subtypes of primary cutaneous lymphomas and represent complex diseases regarding their physiopathology and...
BACKGROUND
Mycosis fungoides (MF) and Sézary syndrome (SS) are subtypes of primary cutaneous lymphomas and represent complex diseases regarding their physiopathology and management. Depending on the stage of the disease, different treatment regimens are applied, but there is no consensus on an optimal approach. Prognosis for patients with early stage MF is favorable, but significantly worsens in advanced disease and in SS, where patients frequently relapse and require multiple therapies.
METHODS
We investigated the potential anticancer effects of NEO212, a novel compound generated by covalently conjugating perillyl alcohol (a natural monoterpene) to temozolomide (an alkylating agent), on MF and SS cell lines . HUT-78, HUT-102, and MyLa cells were treated with NEO212 under different conditions, and drug effects on proliferation, viability, and apoptosis were characterized.
RESULTS
NEO212 inhibited proliferation, diminished viability, and stimulated apoptosis in all cell lines, although with varying degrees of potency in the different cell lines. It down-regulated c-myc and cyclin D1 proteins, which are required for cell proliferation, but triggered endoplasmic reticulum stress and activation of caspases. Pretreatment of cells with antioxidants ascorbic acid and beta-mercaptoethanol prevented these NEO212-induced effects.
CONCLUSIONS
NEO212 exerted promising anticancer effects on SS and MF cell lines. The generation of reactive oxygen species (ROS) appears to play a key role in the NEO212-induced cell death process, because the blockage of ROS with antioxidants prevented caspase activation. We propose that NEO212 should be investigated further toward clinical testing in these tumor types.
PubMed: 31839810
DOI: 10.1177/1758835919891567 -
Cell Death & Disease Feb 2018The DNA repair enzyme O-methylguanin-DNA-methltransferase (MGMT) is able to remove products of alkylating agent such as O-meG and emerges as a central determinant of...
Temozolomide-perillyl alcohol conjugate downregulates O-methylguanin DNA methltransferase via inducing ubiquitination-dependent proteolysis in non-small cell lung cancer.
The DNA repair enzyme O-methylguanin-DNA-methltransferase (MGMT) is able to remove products of alkylating agent such as O-meG and emerges as a central determinant of cancer resistance to temozolomide (TMZ). Temozolomide-perillyl alcohol conjugate (TMZ-POH), a novel TMZ analog developed based on the conjugation of TMZ and POH, displayed strong anticancer potency in multiple cancer types, but seemed not to experience the chemoresistance even in cells with high MGMT expression unlike TMZ and other alkylating agents. In this study, we demonstrated TMZ-POH inhibited MGMT dependent on proteasomal pathway and this inhibition is a significant factor in its toxic effect in the non-small cell lung cancer (NSCLC) cells.
Topics: A549 Cells; Antineoplastic Agents, Alkylating; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; DNA Modification Methylases; DNA Repair Enzymes; Down-Regulation; Humans; Lung Neoplasms; Monoterpenes; Proteasome Endopeptidase Complex; Temozolomide; Tumor Suppressor Proteins; Ubiquitination
PubMed: 29426908
DOI: 10.1038/s41419-017-0193-2 -
ACS Applied Bio Materials Jan 2019Peptide nanosponges of low polydispersity are spontaneously formed from trigonal supramolecular building blocks in aqueous buffers, which feature cationic and/or anionic...
Peptide nanosponges of low polydispersity are spontaneously formed from trigonal supramolecular building blocks in aqueous buffers, which feature cationic and/or anionic oligopeptides ( = 5-20) and a hydrophobic unit. In contrast to classical liposomes/vesicles, nanosponges feature interwoven hydrophilic and hydrophobic nanodomains and are readily taken up by mammalian cells. Perillyl alcohol is known to be a simple, but effective small molecule drug against glioma multiforme. However, its efficacy is limited by a poor bioavailability. In order to make perillyl alcohol bioavailable, two nanosponges consisting of 10 aspartates, to which perillyl alcohol is attached by means of an ester bond, and 20 lysines or arginines (type (D-POH)K and (D-POH)R) were synthesized, purified, and characterized by dynamic light scattering (DLS) and atomic force microscopy (AFM). These nanosponges were then tested in cell cultures of murine glioma cells (GL26) and murine neural progenitor cells (NPC) because the latter was previously utilized in cell-based cancer therapy. The two nanosponges exhibited significantly different biophysical properties (size distribution and ζ potentials). Consequently, different efficacies in killing GL26 and NPC were observed in serum-containing culture media. The results from these experiments confirmed that the type (D-POH)K nanosponge is a promising candidate for the (cell-mediated) cytotherapy of glioblastoma.
PubMed: 35016330
DOI: 10.1021/acsabm.8b00305 -
Journal of Experimental & Clinical... Oct 2018Temozolomide-perillyl alcohol conjugate (TMZ-POH), a novel Temozolomide (TMZ) analog developed based on the conjugation of TMZ and perillyl alcohol (POH), displayed...
BACKGROUND
Temozolomide-perillyl alcohol conjugate (TMZ-POH), a novel Temozolomide (TMZ) analog developed based on the conjugation of TMZ and perillyl alcohol (POH), displayed strong anticancer potency in multiple cancer types. In this study, we aimed to clarify the relationship between TMZ-POH and autophagy, and explore the underlying mechanisms involved in.
METHODS
The proteins involved in autophagy, mitochondrial fission, lysosomal function and membrane traffic were detected by western blots; Autophagosome, mitochondria and lysosome were visualized by transmission electron microscope (TEM) and immunostaining; Apoptosis analysis and fluorescence probe detection were applied by flow cytometry.
RESULTS
TMZ-POH blocked mitophagy flux although the number of autophagosomes which colocalized with mitochondria in the cells was increased via inducing lysosomal dysfunction as evidence from impaired lysosomal acidification, maturation and hampered autophagosome- lysosome fusion, which largely depended on its downregulation on the small GTPase RAB7A via mevalonate pathway. More importantly, our data demonstrated TMZ-POH sensitized cancer cell to irradiation induced apoptosis.
CONCLUSIONS
Temozolomide-perillyl alcohol conjugate impairs mitophagy flux by inducing lysosomal dysfunction in Non-Small Cell Lung Cancer (NSCLC) cells and sensitizes them to irradiation, thereby proposing TMZ-POH as a potential radiosensitizer.
Topics: Antineoplastic Agents, Alkylating; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Humans; Lung Neoplasms; Lysosomes; Mitophagy; Monoterpenes; Radiation-Sensitizing Agents; Temozolomide
PubMed: 30326943
DOI: 10.1186/s13046-018-0905-1 -
Scientific Reports Mar 2021Perillyl alcohol (POH) has been extensively studied for the treatment of peripheral and primary brain tumors. The intranasal route of administration has been preferred...
Perillyl alcohol (POH) has been extensively studied for the treatment of peripheral and primary brain tumors. The intranasal route of administration has been preferred for dosing POH in early-stage clinical trials associated with promising outcomes in primary brain cancer. However, it is unclear how intranasal POH targets brain tumors in these patients. Multiple studies indicate that intranasally applied large molecules may enter the brain and cerebrospinal fluid (CSF) through direct olfactory and trigeminal nerve-associated pathways originating in the nasal mucosa that bypass the blood-brain barrier. It is unknown whether POH, a small molecule subject to extensive nasal metabolism and systemic absorption, may also undergo direct transport to brain or CSF from the nasal mucosa. Here, we compared CSF and plasma concentrations of POH and its metabolite, perillic acid (PA), following intranasal or intravascular POH application. Samples were collected over 70 min and assayed by high-performance liquid chromatography. Intranasal administration resulted in tenfold higher CSF-to-plasma ratios for POH and tenfold higher CSF levels for PA compared to equal dose intravascular administration. Our preclinical results demonstrate POH undergoes direct transport from the nasal mucosa to the CSF, a finding with potential significance for its efficacy as an intranasal chemotherapeutic for brain cancer.
Topics: Administration, Intranasal; Animals; Blood-Brain Barrier; Brain; Brain Neoplasms; Chromatography, High Pressure Liquid; Disease Models, Animal; Humans; Monoterpenes; Nasal Mucosa; Rats; Trigeminal Nerve
PubMed: 33737566
DOI: 10.1038/s41598-021-85293-4 -
Perillyl alcohol attenuates Ras-ERK signaling to inhibit murine skin inflammation and tumorigenesis.Chemico-biological Interactions May 2009In the present study, the chemopreventive effect of topical application of perillyl alcohol (POH) on 9,10-dimethylbenz(a)anthracene (DMBA)-initiated and...
In the present study, the chemopreventive effect of topical application of perillyl alcohol (POH) on 9,10-dimethylbenz(a)anthracene (DMBA)-initiated and 12-O-tetradecanoylphorbol-13-acetate (TPA)-promoted skin tumorigenesis and its possible mechanisms of action in Swiss albino mice were investigated. We evaluated the effect of pretreatment of POH (6 and 12 mg/kg body weight) on TPA (2 microg/200 microl of acetone)-induced skin edema, hyperplasia, peroxidase damage and modulation in activities of catalase, glutathione reductase, glutathione peroxidase, glutathione-S-transferase and reduced glutathione contents. Application of POH 30 min prior to TPA treatment, showed a protective effect in almost all the investigated parameters. Additionally, pretreatment with POH showed a significant inhibition of ornithine decarboxylase (ODC) activity and [(3)H] thymidine incorporation into epidermal DNA. In promotion phase, a significant reduction was found in tumor incidence and tumor burden in mice pretreated with POH (12 mg/kg body weight) with extension of the latency period from 4 to 8 weeks as compared to those treated with TPA alone. POH significantly suppressed the Ras/Raf/ERK pathway and induced apoptosis in Swiss albino mice skin. Our findings suggested that the chemopreventive efficacy of POH is probably due to the inhibition of oxidative stress responses, inhibition of the Ras cell proliferation pathway and induction of apoptosis in murine skin tumor promotion phase.
Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Apoptosis; Disease Models, Animal; Drug Screening Assays, Antitumor; Edema; Extracellular Signal-Regulated MAP Kinases; Female; Hyperplasia; Inflammation; Mice; Monoterpenes; Oxidative Stress; Signal Transduction; Skin; Skin Neoplasms; Tetradecanoylphorbol Acetate; Time Factors; ras Proteins
PubMed: 19161993
DOI: 10.1016/j.cbi.2008.12.016 -
The Journal of Surgical Research Jun 2008Chemotherapy has been largely unsuccessful in pancreatic cancer. Measurement of cell-specific biological endpoints may clarify the evaluation of a newer generation of... (Clinical Trial)
Clinical Trial
BACKGROUND
Chemotherapy has been largely unsuccessful in pancreatic cancer. Measurement of cell-specific biological endpoints may clarify the evaluation of a newer generation of compounds. Perillyl alcohol has shown chemotherapeutic activity in preclinical systems through enhancing apoptosis.
AIMS
To pilot a new trial template for testing novel agents in pancreatic cancer and to assess the biological activity of perillyl alcohol in patients with resectable pancreatic cancer.
METHODS
Apoptosis was quantified with ApopTag in situ, Bak staining, and light microscopy. Tumor size, serum CA 19-9 level, and survival were also measured.
RESULTS
Eight patients enrolled. Toxicity was mild and perillyl alcohol was generally well tolerated. Tumor size and CA 19-9 level were unchanged with perillyl alcohol treatment. Survival time was longer in patients who received full perillyl alcohol treatment (288 +/- 32 days) compared to those who did not (204 +/- 96 days), but this result did not achieve statistical significance (P = 0.2). There was a trend toward greater apoptosis in patients receiving perillyl alcohol compared to fresh operative controls; there was also a suggestion of greater apoptosis in tumor compared to normal pancreatic tissue in the same patient.
CONCLUSIONS
Incorporation of cell-specific biological endpoints is challenging but feasible and should be used in clinical studies of pancreatic cancer treatment. Our pilot study suggests that perillyl alcohol may indeed have effects on biological endpoints. This study will serve as a useful template for examining cell-specific biological endpoints in the testing of future agents that are thought to induce apoptosis in pancreatic cancer.
Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Apoptosis; CA-19-9 Antigen; Female; Humans; Male; Middle Aged; Monoterpenes; Pancreas; Pancreatic Neoplasms; Pilot Projects; Treatment Outcome; bcl-2 Homologous Antagonist-Killer Protein
PubMed: 18498869
DOI: 10.1016/j.jss.2008.02.005 -
Cellular Immunology Apr 2000Perillyl alcohol (POH) inhibits isoprenylation and has shown anticancer and chemopreventive properties in rodent models. The mechanism that underlies the anticancer...
Perillyl alcohol (POH) inhibits isoprenylation and has shown anticancer and chemopreventive properties in rodent models. The mechanism that underlies the anticancer activity of POH and other isoprenylation inhibitors is unknown but has been postulated to involve decreased levels of isoprenylated Ras and Ras-related proteins. Previously we demonstrated that POH effectively inhibits human T cell proliferation in vitro and can prevent acute and chronic rejection in a rat cardiac transplant model. In this report, we investigate the effects of POH on T lymphocytes at the single-cell level. POH disrupts the polarized shape and motility of antigen-specific murine 1E5 T cells. Using an optical trap to position anti-CD3-coated beads in contact with 1E5 T cells, we demonstrate that POH inhibits their TCR-mediated calcium response. Furthermore, we show that POH preferentially induces apoptosis in PHA-activated human T cells as well as in 1E5 T cells.
Topics: Adult; Alkyl and Aryl Transferases; Animals; Apoptosis; Calcium; Cell Movement; Cell Polarity; Cell Size; Enzyme Inhibitors; Humans; Mice; Monoterpenes; Receptors, Antigen, T-Cell; Signal Transduction; T-Lymphocytes; Terpenes
PubMed: 10805968
DOI: 10.1006/cimm.2000.1637 -
Surgical Neurology Dec 2006In recent years, molecular genetics and biology are exerting significant influence on the practice of neuro-oncology, with oligodendrogliomas being the most prominent... (Review)
Review
BACKGROUND
In recent years, molecular genetics and biology are exerting significant influence on the practice of neuro-oncology, with oligodendrogliomas being the most prominent example. To explore therapeutic strategies and evaluate the clinical results, we report a case of a patient with anaplastic oligodendroglioma managed with intranasal delivery of POH.
CASE DESCRIPTION
A 62 year-old white woman presented with complaints of seizures and frontal headache in June 1999. Nervous system examination was normal. Her Karnofsky performance score was 90. A contrast-enhanced MRI scan of the brain revealed a regular space-occupying lesion in the right frontal lobe that enhanced with gadolinium. A radical surgical excision of the tumor was carried out, and the histopathological diagnosis was an anaplastic oligodendroglioma. Subsequently, there were 2 recurrent/progressive lesions, in July 2002 and October 2004, despite combination treatment using surgery, radiotherapy, and chemotherapy. Intranasal delivery of 0.3% concentration of POH 4 times daily was performed. A follow-up MRI scan after 5 months of treatment revealed reduction in size of the enhancing lesion.
CONCLUSION
Whereas surgery continues to be the primary treatment for oligodendroglioma, the scheme for postoperative therapy has shifted primarily because of the lesion's relative chemosensitivity. This article evaluates the effects of intranasal delivery of POH in a case of regression of anaplastic oligodendroglioma.
Topics: Administration, Inhalation; Administration, Intranasal; Antineoplastic Agents; Brain Neoplasms; Combined Modality Therapy; Disease Progression; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Frontal Lobe; Humans; Karnofsky Performance Status; Magnetic Resonance Imaging; Middle Aged; Monoterpenes; Oligodendroglioma; Treatment Outcome
PubMed: 17145324
DOI: 10.1016/j.surneu.2006.02.034