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Cancers Dec 2022Many patients with acute myeloid leukemia (AML) are still dying from this disease. In the past, the alkylating agent temozolomide (TMZ) has been investigated for AML and...
Many patients with acute myeloid leukemia (AML) are still dying from this disease. In the past, the alkylating agent temozolomide (TMZ) has been investigated for AML and found to be partially effective; however, the presence of O6-methylguanine DNA methyltransferase (MGMT; a DNA repair enzyme) in tumor cells confers profound treatment resistance against TMZ. We are developing a novel anticancer compound, called NEO212, where TMZ was covalently conjugated to perillyl alcohol (a naturally occurring monoterpene). NEO212 has revealed robust therapeutic activity in a variety of preclinical cancer models, including AML. In the current study, we investigated its impact on a panel of human AML cell lines and found that it exerted cytotoxic potency even against MGMT-positive cells that were highly resistant to TMZ. Furthermore, NEO212 strongly stimulated the expression of a large number of macrophage-associated marker genes, including CD11b/ITGAM. This latter effect could not be mimicked when cells were treated with TMZ or an equimolar mix of individual agents, TMZ plus perillyl alcohol. The superior cytotoxic impact of NEO212 appeared to involve down-regulation of MGMT protein levels. In a mouse model implanted with TMZ-resistant, MGMT-positive AML cells, two 5-day cycles of 25 mg/kg NEO212 achieved an apparent cure, as mice survived >300 days without any signs of disease. In parallel toxicity studies with rats, a 5-day cycle of 200 mg/kg NEO212 was well tolerated by these animals, whereas animals that were given 200 mg/kg TMZ all died due to severe leukopenia. Together, our results show that NEO212 exerts pleiotropic effects on AML cells that include differentiation, proliferation arrest, and eventual cell death. In vivo, NEO212 was well tolerated even at dosages that far exceed the therapeutic need, indicating a large therapeutic window. These results present NEO212 as an agent that should be considered for development as a therapeutic agent for AML.
PubMed: 36551551
DOI: 10.3390/cancers14246065 -
Sheng Wu Gong Cheng Xue Bao = Chinese... May 2018Perillyl alcohol, [4-isopropylene-1-cyclohexene] methanol, is a monocyclic monoterpene alcohol with special odorous similar to that of linalool and terpineol. It has...
Perillyl alcohol, [4-isopropylene-1-cyclohexene] methanol, is a monocyclic monoterpene alcohol with special odorous similar to that of linalool and terpineol. It has application potential in pharmaceutical, daily chemical and food industries. In this study, one method for the synthesis of perillyl alcohol through the MVA pathway was studied. First, the MVA metabolic pathway originated from Enterococcus faecalis was constructed in Escherichia coli to synthesize limonene. Limonene was further transformed to perillyl alcohol by the hydroxylation of cytochrome P450 alkane hydroxylase. Furthermore, the shake flask fermentation condition of the engineered E. coli strain was optimized. The results showed that the engineered E. coli could produce about 50.12 mg/L perillyl alcohol through MVA pathway using glucose as raw material. In this study, the method of the MVA pathway for perillyl alcohol synthesis was constructed successfully in engineered E. coli, which provides both theoretical and technical support for terpenoids biosynthesis.
Topics: Escherichia coli; Hydroxylation; Industrial Microbiology; Metabolic Engineering; Metabolic Networks and Pathways; Mevalonic Acid; Monoterpenes
PubMed: 29893080
DOI: 10.13345/j.cjb.170472 -
Biochemical and Biophysical Research... Jan 2014Perillyl alcohol (POH) is an isoprenoid which inhibits farnesyl transferase and geranylgeranyl transferase, key enzymes that induce conformational and functional changes...
Perillyl alcohol (POH) is an isoprenoid which inhibits farnesyl transferase and geranylgeranyl transferase, key enzymes that induce conformational and functional changes in small G proteins to conduct signal production for cell proliferation. Thus, it has been tried for the treatment of cancers. However, although it affects the proliferation of immunocytes, its influence on immune responses has been examined in only a few studies. Notably, its effect on antigen-induced immune responses has not been studied. In this study, we examined whether POH suppresses Ag-induced immune responses with a mouse model of allergic airway inflammation. POH treatment of sensitized mice suppressed proliferation and cytokine production in Ag-stimulated spleen cells or CD4(+) T cells. Further, sensitized mice received aerosolized OVA to induce allergic airway inflammation, and some mice received POH treatment. POH significantly suppressed indicators of allergic airway inflammation such as airway eosinophilia. Cytokine production in thoracic lymph nodes was also significantly suppressed. These results demonstrate that POH suppresses antigen-induced immune responses in the lung. Considering that it exists naturally, POH could be a novel preventive or therapeutic option for immunologic lung disorders such as asthma with minimal side effects.
Topics: Animals; Antigens; CD4-Positive T-Lymphocytes; Cytokines; Disease Models, Animal; Hypersensitivity; Immunosuppression Therapy; Immunosuppressive Agents; Inflammation; Lung; Male; Mice; Mice, Inbred BALB C; Monoterpenes; Ovalbumin; Pulmonary Eosinophilia
PubMed: 24309112
DOI: 10.1016/j.bbrc.2013.11.106 -
Preclinical development and clinical use of perillyl alcohol for chemoprevention and cancer therapy.American Journal of Cancer Research 2015Perillyl alcohol (POH) is a naturally occurring dietary monoterpene isolated from the essential oils of lavender, peppermint, and other plants. Medical interest in this... (Review)
Review
Perillyl alcohol (POH) is a naturally occurring dietary monoterpene isolated from the essential oils of lavender, peppermint, and other plants. Medical interest in this compound was generated by research findings showing that POH was able to inhibit the growth of tumor cells in cell culture and exert cancer preventive and therapeutic activity in a variety of animal tumor models. Based on this promising preclinical work, POH was formulated in soft gelatine capsules and orally administered to cancer patients several times a day on a continuous basis. However, such clinical trials in humans yielded disappointing results, also because the large number of capsules that had to be swallowed caused hard-to-tolerate intestinal side effects, causing many patients to withdraw from treatment due to unrelenting nausea, fatigue, and vomiting. As a result, efforts to treat cancer patients with oral POH were abandoned and did not enter clinical practice. Intriguingly, clinical trials in Brazil have explored intranasal POH delivery as an alternative to circumvent the toxic limitations of oral administration. In these trials, patients with recurrent malignant gliomas were given comparatively small doses of POH via simple inhalation through the nose. Results from these studies show this type of long-term, daily chemotherapy to be well tolerated and effective. In this review, we will present the vicissitudes of POH's evaluation as an anticancer agent, and its most recent success in therapy of patients with malignant brain tumors.
PubMed: 26175929
DOI: No ID Found -
Brazilian Oral Research 2022This study evaluated the orofacial antinociceptive effect of (S)-(-)-perillyl alcohol (PA) associated with codeine (C) and investigated the possible molecular anchorage...
This study evaluated the orofacial antinociceptive effect of (S)-(-)-perillyl alcohol (PA) associated with codeine (C) and investigated the possible molecular anchorage mechanisms of PA. Mice (n = 5 per group) were treated with PA alone and associated with codeine and assigned to the following groups: 75.0 mg/kg PA; 75.0 mg/kg PA + C 30 mg/kg; PA 37.5 mg/kg + C 15.0 mg/kg; C 30.0 mg/kg; and control. Nociception was induced by formalin, capsaicin, and glutamate, and was quantified based on the duration (in seconds) of face grooming. The possible mechanisms of action were evaluated by molecular docking study. In the formalin test, PA75/C30 presented an effect in the neurogenic (p < 0.0001) and inflammatory (p < 0.005) phases. Mice treated with PA75 (p < 0.0001) and PA75/C30 (p < 0.0005) showed a reduced nociceptive behavior in the capsaicin test. Glutamate-induced nociception also was blocked by PA75 (p < 0.0005) and C30 (p < 0.0005). The molecular anchorage analysis indicated high negative binding energy values for the evaluated receptors, especially glutamate receptors (AMPA -79.57 Kcal/mol, mGLUR6 -71.25, and NMDA -66.33 Kcal/mol). PA associated with codeine showed orofacial antinociceptive activity, with theoretical evidence of interaction with glutamate receptors.
Topics: Analgesics; Animals; Capsaicin; Codeine; Facial Pain; Glutamic Acid; Mice; Molecular Docking Simulation; Monoterpenes; Receptors, Glutamate
PubMed: 35946737
DOI: 10.1590/1807-3107bor-2022.vol36.0109 -
International Journal of Biological... Apr 2018Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common type of dementia in elderly ( >65years of age). Excessive extra cellular...
Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common type of dementia in elderly ( >65years of age). Excessive extra cellular deposits of amyloid beta (Aβ) are a pathological feature of AD. Aβ can cause cell death through oxidative damage; recent studies have implicated opening of mPTP as a detrimental event in AD-related mitochondrial dysfunctions. Over the past few years, natural compounds with antioxidant properties have shown promise for intervention in AD.
Topics: Amyloid beta-Peptides; Apoptosis; Cell Line, Tumor; Cell Survival; Cytochromes c; DNA Fragmentation; Drug Synergism; Humans; Ion Channel Gating; Membrane Potential, Mitochondrial; Mitochondria; Mitochondrial Membrane Transport Proteins; Mitochondrial Permeability Transition Pore; Monoterpenes; Reactive Oxygen Species
PubMed: 29154879
DOI: 10.1016/j.ijbiomac.2017.11.082 -
Journal of Applied Microbiology Oct 2023The use of phytochemicals to improve the effectiveness of antibiotics is a promising strategy for the development of novel antimicrobials. In this study, the antibiofilm...
AIMS
The use of phytochemicals to improve the effectiveness of antibiotics is a promising strategy for the development of novel antimicrobials. In this study, the antibiofilm activity of perillyl alcohol and hydrocinnamic acid, both phytochemicals present in several plants, and two antibiotics from different classes (amoxicillin and chloramphenicol) was tested, alone and in combination, against Escherichia coli.
METHODS AND RESULTS
Each molecule was tested at the minimum inhibitory concentration (MIC), 5 × MIC, and 10 × MIC, and characterized concerning biomass removal, metabolic inactivation, and cellular culturability. The highest percentages of metabolic inactivation (88.5% for 10 × MIC) and biomass reduction (61.7% for 10 × MIC) were obtained with amoxicillin. Interestingly, for 5 × MIC and 10 × MIC, phytochemicals provided a total reduction of colony-forming units (CFUs). Dual and triple combinations of phytochemicals and antibiotics (at MIC and 5 × MIC) demonstrated high efficacy in metabolic inactivation, moderate efficacy in terms of biomass reduction, and total reduction of cellular culturability for 5 × MIC.
CONCLUSIONS
The results demonstrated the antibiofilm potential of phytochemicals, highlighting the advantage of phytochemical/antibiotic combinations for biofilm control.
Topics: Anti-Bacterial Agents; Escherichia coli; Biofilms; Amoxicillin; Phytochemicals; Microbial Sensitivity Tests
PubMed: 37827567
DOI: 10.1093/jambio/lxad234 -
Journal of Cardiovascular Pharmacology Jun 2021Pulmonary arterial hypertension (PAH) is a pulmonary vascular disease causing right ventricular (RV) hypertrophy, failure, and death. Some miRNAs are involved in the... (Comparative Study)
Comparative Study
Quercetin, Perillyl Alcohol, and Berberine Ameliorate Right Ventricular Disorders in Experimental Pulmonary Arterial Hypertension: Effects on miR-204, miR-27a, Fibrotic, Apoptotic, and Inflammatory Factors.
Pulmonary arterial hypertension (PAH) is a pulmonary vascular disease causing right ventricular (RV) hypertrophy, failure, and death. Some miRNAs are involved in the pathophysiology of PAH. As the current treatments cannot prevent the progression of the disease, we investigated whether 3 plant derivatives, namely perillyl alcohol (PA), quercetin (QS), and berberine (BBR), can improve RV function and affect the expression of miR-204, miR-27a, and biochemical factors in monocrotaline-induced PAH (MCT-PAH). Thirty-six rats were divided into control (CTL), MCT, MCT+Veh (vehicle), MCT+PA, MCT+QS, and MCT + BBR groups (n = 6 each). After inducing PAH using MCT (60 mg/kg), PA (50 mg/kg), QS (30 mg/kg), and BBR (30 mg/kg) were administrated daily for 3 weeks. miR-204 expression, total antioxidant capacity, and antiapoptotic protein Bcl-2 significantly declined in the RV of PAH rats, and PA, QS, and BBR treatment significantly compensated for these decreases. Proapoptotic protein Bax and p21 cell cycle inhibitor increased in the RV. All 3 herbal derivatives compensated for Bax increase, and BBR caused a decrease in p21. TNFα, IL-6, and malondialdehyde increased in the RV, and PA, QS, and BBR significantly counterbalanced these increases. miR-27a expression was not affected by MCT and plant derivatives. Overall, PA, QS, and BBR improved ventricular disorders in rats with PAH by decreasing inflammation, apoptosis, and fibrosis and increasing the antioxidant-to-oxidant ratio. Therefore, these herbal derivatives may be considered as target therapeutic goals for this disease either alone or in combination with current medications.
Topics: Animals; Antioxidants; Apoptosis; Berberine; Disease Models, Animal; Fibrosis; Hypertrophy, Right Ventricular; Male; MicroRNAs; Monocrotaline; Monoterpenes; Pulmonary Arterial Hypertension; Quercetin; Rats; Rats, Wistar; Ventricular Function, Right
PubMed: 34016844
DOI: 10.1097/FJC.0000000000001015 -
Neurotoxicity Research Aug 2020In this study, we aim to assess the phytomedicinal potential of perillyl alcohol (PA), a dietary monoterpenoid, in a unilateral 6-hydroxydopamine (6-OHDA) lesion rat...
Perillyl Alcohol Mitigates Behavioural Changes and Limits Cell Death and Mitochondrial Changes in Unilateral 6-OHDA Lesion Model of Parkinson's Disease Through Alleviation of Oxidative Stress.
In this study, we aim to assess the phytomedicinal potential of perillyl alcohol (PA), a dietary monoterpenoid, in a unilateral 6-hydroxydopamine (6-OHDA) lesion rat model of Parkinson's disease (PD). We observed that PA supplementation alleviated behavioural abnormalities such as loss of coordination, reduced rearing and motor asymmetry in lesioned animals. We also observed that PA-treated animals exhibited reduced oxidative stress, DNA fragmentation and caspase 3 activity indicating alleviation of apoptotic cell death. We found reduced mRNA levels of pro-apoptotic regulator BAX and pro-inflammatory mediators IL18 and TNFα in PA-treated animals. Further, PA treatment successfully increased mRNA and protein levels of Bcl2, mitochondrial biogenesis regulator PGC1α and tyrosine hydroxylase (TH) in lesioned animals. We observed that PA treatment blocked BAX and Drp1 translocation to mitochondria, an event often associated with the inception of apoptosis. Further, 6-OHDA exposure reduced expression of electron transport chain complexes I and IV, thereby disturbing energy metabolism. Conversely, expression levels of both complexes were upregulated with PA treatment in lesioned rats. Finally, we found that protein levels of Nrf2, the transcription factor responsible for antioxidant gene expression, were markedly reduced in cytosolic and nuclear fraction on 6-OHDA exposure, and PA increased expression of Nrf2 in both fractions. We believe that our data hints towards PA having the ability to provide cytoprotection in a hemiparkinsonian rat model through alleviation of motor deficits, oxidative stress, mitochondrial dysfunction and apoptosis.
Topics: Animals; Behavior, Animal; Caspase 3; DNA Fragmentation; Dynamins; Electron Transport Complex I; Electron Transport Complex IV; Enzyme Inhibitors; Mitochondria; Monoterpenes; Movement; NF-E2-Related Factor 2; Oxidative Stress; Oxidopamine; Parkinsonian Disorders; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Proto-Oncogene Proteins c-bcl-2; Rats; Sympatholytics; Tyrosine 3-Monooxygenase; bcl-2-Associated X Protein
PubMed: 32394056
DOI: 10.1007/s12640-020-00213-0 -
Biomedicines Oct 2023Perillyl alcohol (PA), a naturally existing monocyclic terpene related to limonene, is characterized by its poor aqueous solubility and very limited bioavailability. Its...
Perillyl alcohol (PA), a naturally existing monocyclic terpene related to limonene, is characterized by its poor aqueous solubility and very limited bioavailability. Its potential anti-cancer activity against malignant glioma has been reported. The aim was to develop PA-loaded lipid-based nanocarriers (LNCs), and to investigate their anti-cancer activity against two different brain cell lines. Non-medicated and PA-loaded LNCs were prepared and characterized. The mechanism of cytotoxic activity of PA was conducted using a molecular docking technique. The cell viabilities against A172 and ANGM-CSS cells were evaluated. The results revealed that the average particle size of the prepared LNCs ranged from 248.67 ± 12.42 to 1124.21 ± 12.77 nm, the polydispersity index was 0.418 ± 0.043-0.509 ± 0.064, while the zeta potential ranged from -36.91 ± 1.31 to -15.20 ± 0.96 mV. The molecular docking studies demonstrated that the drug had binding activity to human farnesyltransferase. Following exposure of the two glioblastoma cell lines to the PA-loaded nanoformulations, MTS assays were carried out, and the data showed a far lower half-maximal inhibitory concentration in both cell lines when compared to pure drug and non-medicated nanocarriers. These results indicate the potential in vitro antiproliferative activity of PA-loaded LNCs. Therefore, the prepared PA-loaded nanocarriers could be used to enhance drug delivery across the blood-brain barrier (BBB) in order to treat brain cancer, especially when formulated in a suitable dosage form. The size, surface charge, and lipid composition of the LNCs make them promising for drug delivery across the BBB. Detailed pharmacokinetic and pharmacodynamic assessments, including the evaluation of BBB penetration, are necessary to better understand the compound's distribution and effects within the brain.
PubMed: 37893144
DOI: 10.3390/biomedicines11102771