-
PloS One 2016This study explored the antifungal potential of perillyl alcohol (PA), a natural monoterpene alcohol, against most prevalent human fungal pathogen C. albicans, its...
This study explored the antifungal potential of perillyl alcohol (PA), a natural monoterpene alcohol, against most prevalent human fungal pathogen C. albicans, its clinical isolates and four non-albicans species of Candida. To resolve the potential mechanisms, we used whole genome transcriptome analyses of PA treated Candida cells to examine the affected cellular circuitry of this pathogen. The transcriptome data revealed a link between calcineurin signaling and PA as among the several categories of PA responsive genes the down regulation of calcineurin signaling gene CNB1 was noteworthy which was also confirmed by both molecular docking and susceptibility assays. We observed that PA treated Candida phenocopied compromised calcineurin pathway stress responses and turned sensitive to alkaline pH, ionic, membrane, salinity, endoplasmic reticulum and serum stresses. Indispensability of functional calcineurin was further confirmed as calcineurin mutant was hypersensitive to PA while constitutively expressed calcineurin strain remained resistant. We explored that PA leads to perturbed membrane integrity as depicted through depleted ergosterol levels and disrupted pH homeostasis. Moreover, PA caused cell wall damage which was evident from hypersensitivity against cell wall perturbing agents (congo red, calcoflour white), SEM and enhanced rate of cell sedimentation. Furthermore, PA inhibited potential virulence traits including morphological transition, biofilm formation and displayed diminished capacity to adhere both to the polystyrene surface and buccal epithelial cells. The study also revealed that PA leads to cell cycle arrest and mitochondrial dysfunction in C. albicans. Together, the present study provides enough evidence for further work on PA so that better strategies could be employed to treat Candida infections.
Topics: Antifungal Agents; Biofilms; Calcineurin; Candida albicans; Cell Membrane; DNA Repair; Mitochondria; Monoterpenes; Morphogenesis; Signal Transduction; Transcriptome
PubMed: 27627759
DOI: 10.1371/journal.pone.0162465 -
Molecules (Basel, Switzerland) Jun 2018The present study used isometric tension recording to investigate the vasorelaxant effect of limonene (LM), carveol (CV), and perillyl alcohol (POH) on contractility...
The present study used isometric tension recording to investigate the vasorelaxant effect of limonene (LM), carveol (CV), and perillyl alcohol (POH) on contractility parameters of the rat aorta, focusing in particular on the structure-activity relationship. LM, CV, and POH showed a reversible inhibitory effect on the contraction induced by electromechanical and pharmacomechanical coupling. In the case of LM, but not CV and POH, this effect was influenced by preservation of the endothelium. POH and CV but not LM exhibited greater pharmacological potency on BayK-8644-induced contraction and on electromechanical coupling than on pharmacomechanical coupling. In endothelium-denuded preparations, the order of pharmacological potency on electrochemical coupling was LM < CV < POH. These compounds inhibited also, with grossly similar pharmacological potency, the contraction induced by phorbol ester dibutyrate. The present results suggest that LM, CV and POH induced relaxant effect on vascular smooth muscle by means of different mechanisms likely to include inhibition of PKC and IP3 pathway. For CV and POH, hydroxylated compounds, it was in electromechanical coupling that the greater pharmacological potency was observed, thus suggesting a relative specificity for a mechanism likely to be important in electromechanical coupling, for example, blockade of voltage-dependent calcium channel.
Topics: 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; Animals; Aorta, Thoracic; Cyclohexane Monoterpenes; Cyclohexenes; Isometric Contraction; Limonene; Molecular Structure; Monoterpenes; Muscle, Smooth, Vascular; Phenylephrine; Phorbol 12,13-Dibutyrate; Rats; Structure-Activity Relationship; Terpenes; Vasodilator Agents
PubMed: 29899230
DOI: 10.3390/molecules23061430 -
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 -
Molecules (Basel, Switzerland) Nov 2021Cyclic oxyterpenes are natural products that are mostly used as fragrances, flavours and drugs by the cosmetic, food and pharmaceutical industries. However, only a few...
Cyclic oxyterpenes are natural products that are mostly used as fragrances, flavours and drugs by the cosmetic, food and pharmaceutical industries. However, only a few cyclic oxyterpenes are accessible via chemical syntheses, which are far from being ecofriendly. We report here the synthesis of six cyclic oxyterpenes derived from ß-pinene while respecting the principles of green and sustainable chemistry. Only natural or biosourced catalysts were used in mild conditions that were optimised for each synthesis. A new generation of ecocatalysts, derived from Mn-rich water lettuce, was prepared via green processes, characterised by MP-AES, XRPD and TEM analyses, and tested in catalysis. The epoxidation of ß-pinene led to the platform molecule, ß-pinene oxide, with a good yield, illustrating the efficacy of the new generation of ecocatalysts. The opening ß-pinene oxide was investigated in green conditions and led to new and regioselective syntheses of myrtenol, 7-hydroxy-α-terpineol and perillyl alcohol. Successive oxidations of perillyl alcohol could be performed using no hazardous oxidant and were controlled using the new generation of ecocatalysts generating perillaldehyde and cuminaldehyde.
Topics: Benzaldehydes; Bicyclic Monoterpenes; Catalysis; Cymenes; Elements; Green Chemistry Technology; Monoterpenes; Principal Component Analysis; Terpenes; X-Ray Diffraction
PubMed: 34885776
DOI: 10.3390/molecules26237194 -
Pharmaceutical Biology 2016Biotransformation systems are profitable tools for structural modification of bioactive natural compounds into valuable biologically active terpenoids.
CONTEXT
Biotransformation systems are profitable tools for structural modification of bioactive natural compounds into valuable biologically active terpenoids.
OBJECTIVE
This study determines the biological effect of (R)-(+)-limonene and (-)-α-pinene, and their oxygenated derivatives, (a) perillyl alcohol and (S)-(+)- and (R)-(-)-carvone enantiomers and (b) linalool, trans-verbenol and verbenone, respectively, on human colon tumour cells and normal colonic epithelium.
MATERIALS AND METHODS
Biotransformation procedures and in vitro cell culture tests were used in this work. Cells were incubated for 24 h with terpenes at concentrations of 5-500 μg/mL for NR, MTT, DPPH, and NO assays. IL-6 was determined by ELISA with/without 2 h pre-activation with 10 μg/mL LPS.
RESULTS
trans-Verbenol and perillyl alcohol, obtained via biotransformation, produced in vitro effect against tumour cells at lower concentrations (IC50 value = 77.8 and 98.8 μg/mL, respectively) than their monoterpene precursors, (R)-(+)-limonene (IC50 value = 171.4 μg/mL) and (-)-α-pinene (IC50 value = 206.3 μg/mL). They also showed lower cytotoxicity against normal cells (IC50 > 500 and > 200 μg/mL, respectively). (S)-(+)-Carvone was 59.4% and 27.1% more toxic to tumour and normal cells, respectively, than the (R)-(-)-enantiomer. (R)-(+)-limonene derivatives decreased IL-6 production from normal cells in media with or without LPS (30.2% and 13.9%, respectively), while (-)-α-pinene derivatives induced IL-6 (verbenone had the strongest effect, 60.2% and 29.1% above control, respectively). None of the terpenes had antioxidative activity below 500 μg/mL.
DISCUSSION AND CONCLUSIONS
Bioactivity against tumour cells decreased in the following order: alcohols > ketones > hydrocarbons. (R)-(+)-limonene, (-)-α-pinene, and their derivatives expressed diverse activity towards normal and tumour cells with noticeable enantiomeric differences.
Topics: Antineoplastic Agents; Biotechnology; Biotransformation; Biphenyl Compounds; Cell Survival; Chrysosporium; Colon; Drug Discovery; HT29 Cells; Humans; Intestinal Mucosa; Mortierella; Nitric Oxide; Picrates; Terpenes
PubMed: 26808720
DOI: 10.3109/13880209.2015.1103753 -
Frontiers in Oncology 2021Drug resistance remains a serious challenge to rituximab therapy in B-NHL (B cell non-Hodgkin's lymphoma). CDC (complement-dependent cytotoxicity) has been proposed as a...
BACKGROUND
Drug resistance remains a serious challenge to rituximab therapy in B-NHL (B cell non-Hodgkin's lymphoma). CDC (complement-dependent cytotoxicity) has been proposed as a major antitumor mechanism of rituximab, and direct abrogation of CD59 function partially restores rituximab sensitivity with high efficacy. However, universal blockade of CD59 may have deleterious effects on normal cells. Sp1 regulates constitutive CD59 expression, whereas NF-κB and CREB regulate inducible CD59 expression.
METHODS
Immunohistochemistry (IHC) assay was used to detect the expression levels of CD59 and other related molecules. Quantitative Real-time PCR (RT-PCR) analysis was used to explore the levels of transcripts in the original and resistant cells. We chose LY8 cells to test the effects of NF-κB and CBP/p300 inhibition on CD59 expression using flow cytometry (FACS). Immunoblotting analysis was employed to detect the effects of curcumin and POH. The and experiments were used to evaluate the toxicity and combined inhibitory effect on tumor cells of curcumin and POH.
RESULTS
We demonstrated that herbal (curcumin and perillyl alcohol) blockade of NF-κB specifically suppresses the expression of inducible CD59 but not CD20, thus sensitizing resistant cells to rituximab-mediated CDC. Moreover, activation of NF-κB and CREB is highly correlated with CD59 expression in B-NHL tissues.
CONCLUSIONS
Our findings suggest the potential of CD59 expression as a predictor of therapeutic efficacy of NF-κB inhibitors in clinical application as well as the rationality of a NF-κB inhibitor-rituximab regimen in B-NHL therapy.
PubMed: 34956875
DOI: 10.3389/fonc.2021.751904 -
Pharmaceuticals (Basel, Switzerland) Sep 2022In this study, incorporation of the cytotoxic agent paclitaxel and the P-glycoprotein inhibitor elacridar in hyaluronic acid (HA)-modified nanoemulsions was studied for...
In this study, incorporation of the cytotoxic agent paclitaxel and the P-glycoprotein inhibitor elacridar in hyaluronic acid (HA)-modified nanoemulsions was studied for intraductal delivery and breast cancer localized treatment. To improve cytotoxicity, we investigated the incorporation of perillyl alcohol or tributyrin as components of the nanoemulsion oil phase. The nanoemulsions presented size <180 nm and negative zeta potential. Both tributyrin and perillyl alcohol increased nanoemulsion cytotoxicity in MCF-7 cells, but not in MDA-MB-231. However, perillyl alcohol reduced nanoemulsion stability in the presence of the drugs. Concomitant incorporation of paclitaxel and elacridar in HA- and tributyrin-containing nanoemulsions (PE-NETri) increased cytotoxicity and reduced IC50 by 1.6 to 3-fold in MCF-7 and MDA-MB-231 cells compared to the nanoemulsion containing only paclitaxel (P-NE). This nanoemulsion also produced a 3.3-fold reduction in the viability of MDA-MB-231 spheroids. Elacridar incorporated in the nanoemulsion was capable of inhibiting P-glycoprotein in membranes. In vivo intraductal administration of the NE containing HA resulted in a three-fold higher retention of a fluorescent marker compared to a solution or nanoemulsion without HA, demonstrating the importance of HA. The nanoemulsion produced no histological changes in the mammary tissue. These results support the potential applicability of the nanoemulsion for local breast cancer management.
PubMed: 36145331
DOI: 10.3390/ph15091110 -
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 -
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 -
Journal of Neurosurgery. Case Lessons Aug 2022Intranasal delivery of NEO100, a pharmaceutical-grade version of the natural monoterpene perillyl alcohol (POH), is undergoing clinical phase IIa testing as a treatment...
BACKGROUND
Intranasal delivery of NEO100, a pharmaceutical-grade version of the natural monoterpene perillyl alcohol (POH), is undergoing clinical phase IIa testing as a treatment for glioblastoma (GBM). However, so far there is no evidence that intranasal delivery of NEO100 indeed results in POH reaching intracranial malignancies in a patient.
OBSERVATIONS
After surgical removal of her recurrent GBM tumor, a patient received daily intranasal NEO100 therapy for more than 3 years before a second recurrence emerged. At that time, a final dose of NEO100 was given shortly before the tumor tissue was surgically removed, and the tissue was processed for high-performance liquid chromatography analysis of POH and its primary metabolite, perillic acid (PA). Both molecules could readily be detected in the tumor tissue.
LESSONS
This is the first demonstration of POH and PA in brain tumor tissue from any patient. It reveals that intranasal administration of NEO100 is a valid approach to achieve delivery of this agent to a brain tumor. In view of the noninvasive and safe nature of this method, along with tentative indications of activity, our findings add confidence to the notion that intranasal administration of NEO100 holds potential as a new treatment option for brain-localized malignancies.
PubMed: 36088606
DOI: 10.3171/CASE22215