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Applied Microbiology and Biotechnology May 2003The past 5 years have seen significant progress in the field of limonene biotransformation, especially with regard to the regiospecificity of microbial biocatalysts.... (Review)
Review
The past 5 years have seen significant progress in the field of limonene biotransformation, especially with regard to the regiospecificity of microbial biocatalysts. Whereas earlier only regiospecific biocatalysts for the 1,2 position (limonene-1,2-diol) and the 8-position (alpha-terpineol) were available, recent reports describe microbial biocatalysts specifically hydroxylating the 3-position (isopiperitenol), 6-position (carveol and carvone), and 7-position (perillyl alcohol, perillylaaldehyde, and perillic acid). The present review also includes the considerable progress made in the characterization of plant P-450 limonene hydroxylases and the cloning of the encoding genes.
Topics: Bacteria; Biodegradation, Environmental; Biotransformation; Cyclohexenes; Fungi; Limonene; Plants; Terpenes; Yeasts
PubMed: 12743755
DOI: 10.1007/s00253-003-1221-y -
International Journal of Nanomedicine 2012In the present study, a novel poly-lactic glycolic acid (PLGA)-based microparticle formulation of perillyl alcohol (POH) was prepared and characterized. Further, its...
In the present study, a novel poly-lactic glycolic acid (PLGA)-based microparticle formulation of perillyl alcohol (POH) was prepared and characterized. Further, its efficacy was evaluated against di-methyl benzo anthracene-induced skin papilloma in Swiss albino mice. The characterization studies showed that POH-bearing PLGA microparticles were of the size 768 ± 215 nm with a ζ-potential value of -7.56 ± 0.88 mV. The entrapment efficiency of the active drug in particles was 42.4% ± 3.5%. POH-bearing PLGA microparticles were stable and released entrapped drug gradually over an extended time period. The in vitro efficacy of POH-bearing PLGA microparticles was evaluated by examining their differential cytotoxicity and assessing their ability to inhibit epidermoid carcinoma cell line (A253). The POH-based microparticles when administered to tumor-bearing animals caused greater tumor regression and increased survival rate (∼80%) as compared with the group receiving free form of POH (survival rate 40%). The superiority of POH-PLGA microparticles over free form of POH was further evident from their ability to modulate apoptosis-regulating factors.
Topics: Analysis of Variance; Animals; Antineoplastic Agents; Apoptosis; Apoptosis Regulatory Proteins; Cell Line, Tumor; Female; Kaplan-Meier Estimate; Lactic Acid; Mice; Microspheres; Monoterpenes; Papilloma; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Skin Neoplasms; Xenograft Model Antitumor Assays
PubMed: 22275821
DOI: 10.2147/IJN.S24920 -
BMC Cancer Apr 2020Polymorphisms in MTHFR gene influence risk and overall survival of patients with brain tumor. Global genomic DNA (gDNA) methylation profile from tumor tissues is... (Clinical Trial)
Clinical Trial
BACKGROUND
Polymorphisms in MTHFR gene influence risk and overall survival of patients with brain tumor. Global genomic DNA (gDNA) methylation profile from tumor tissues is replicated in peripheral leukocytes. This study aimed to draw a correlation between rs1801133 MTHFR variants, gDNA methylation and overall survival of patients with recurrent glioblastoma (rGBM) under perillyl alcohol (POH) treatment.
METHODS
gDNA from whole blood was extracted using a commercially available kit (Axygen) and quantified by spectrophotometry. Global gDNA methylation was determined by ELISA and rs1801133 polymorphism by PCR-RFLP. Statistical analysis of gDNA methylation profile and rs1801133 variants included Mann-Whitney, Kruskal-Wallis, Spearman point-biserial correlation tests (SPSS and Graphpad Prism packages; significant results for effect size higher than 0.4). Prognostic value of gDNA methylation and rs1801133 variants considered survival profiles at 25 weeks of POH treatment, having the date of protocol adhesion as starting count and death as the final event.
RESULTS
Most rGBM patients showed global gDNA hypomethylation (median = 31.7%) and a significant, moderate and negative correlation between TT genotype and gDNA hypomethylation (median = 13.35%; rho = - 0.520; p = 0.003) compared to CC variant (median = 32.10%), which was not observed for CT variant (median = 33.34%; rho = - 0.289; p = 0.06). gDNA hypermethylated phenotype (median = 131.90%) exhibited significant, moderate and negative correlations between TT genotype (median = 112.02%) and gDNA hypermethylation levels when compared to CC (median = 132.45%; rho = - 0,450; p = 0.04) or CT (median = 137.80%; rho = - 0.518; p = 0.023) variants. TT variant of rs1801133 significantly decreased gDNA methylation levels for both patient groups, when compared to CC (d values: hypomethylated = 1.189; hypermethylated = 0.979) or CT (d values: hypomethylated = 0.597; hypermethylated = 1.167) variants. Positive prognostic for rGBM patients may be assigned to gDNA hypermethylation for survivors above 25 weeks of treatment (median = 88 weeks); and TT variant of rs1801133 regardless POH treatment length.
CONCLUSION
rGBM patients under POH-based therapy harboring hypermethylated phenotype and TT variant for rs1801133 had longer survival. Intranasal POH therapy mitigates detrimental effects of gDNA hypomethylation and improved survival of patients with rGBM harboring TT mutant variant for MTHFR rs1801133 polymorphism.
TRIAL REGISTRATION
CONEP -9681- 25,000.009267 / 2004. Registered 12th July, 2004.
Topics: Administration, Intranasal; Adolescent; Adult; Aged; Antineoplastic Agents; Biomarkers, Tumor; Brain Neoplasms; DNA Methylation; Female; Glioblastoma; Humans; Leukocytes; Male; Methylenetetrahydrofolate Reductase (NADPH2); Middle Aged; Monoterpenes; Neoplasm Recurrence, Local; Polymorphism, Single Nucleotide; Young Adult
PubMed: 32264844
DOI: 10.1186/s12885-020-06802-8 -
Bioscience Reports Dec 2018Monocyclic monoterpenes have been recognized as useful pharmacological ingredients due to their ability to treat numerous diseases. Limonene and perillyl alcohol as well... (Review)
Review
Monocyclic monoterpenes have been recognized as useful pharmacological ingredients due to their ability to treat numerous diseases. Limonene and perillyl alcohol as well as their metabolites (especially perillic acid and its methyl ester) possess bioactivities such as antitumor, antiviral, anti-inflammatory, and antibacterial agents. These therapeutic properties have been well documented. Based on the aforementioned biological properties of limonene and its metabolites, their structural modification and development into effective drugs could be rewarding. However, utilization of these monocyclic monoterpenes as scaffolds for the design and developments of more effective chemoprotective agents has not received the needed attention by medicinal scientists. Recently, some derivatives of limonene metabolites have been synthesized. Nonetheless, there have been no thorough studies on their pharmacokinetic and pharmacodynamic properties as well as their inhibition against isoprenylation enzymes. In this review, recent research progress in the biochemical significance of limonene and its metabolites was summarized with emphasis on their antitumor effects. Future prospects of these bioactive monoterpenes for drug design and development are also highlighted.
Topics: Cyclohexenes; Drug Design; Humans; Limonene; Methyl Ethers; Monoterpenes; Neoplasms
PubMed: 30287506
DOI: 10.1042/BSR20181253 -
Molecular Cancer Therapeutics Mar 2018Glioblastoma multiforme is a malignant brain tumor noted for its extensive vascularity, aggressiveness, and highly invasive nature, suggesting that cell migration plays...
Glioblastoma multiforme is a malignant brain tumor noted for its extensive vascularity, aggressiveness, and highly invasive nature, suggesting that cell migration plays an important role in tumor progression. The poor prognosis in GBM is associated with a high rate of tumor recurrence, and resistance to the standard of care chemotherapy, temozolomide (TMZ). The novel compound NEO212, a conjugate of TMZ and perillyl alcohol (POH), has proven to be 10-fold more cytotoxic to glioma stem cells (GSC) than TMZ, and is active against TMZ-resistant tumor cells. In this study, we show that NEO212 decreases migration and invasion of primary cultures of patient-derived GSCs, in both mesenchymal USC02 and proneural USC04 populations. The mechanism by which NEO212 reduces migration and invasion appears to be independent of its DNA alkylating effects, which cause cytotoxicity during the first hours of treatment, and is associated with a decrease in the FAK/Src signaling pathway, an effect not exhibited by TMZ. NEO212 also decreases the production of matrix metalloproteinases MMP2 and MMP9, crucial for GSC invasion. Gene expression analysis of epithelial and mesenchymal markers suggests that NEO212 increases the expression of epithelial-like characteristics, suggesting a reversion of the epithelial-to-mesenchymal transition process. Furthermore, in an orthotopic glioma model, NEO212 decreases tumor progression by reducing invasion of GSCs, thereby increasing survival time of mice. These studies indicate that NEO212, in addition to cytotoxicity, can effectively reduce migration and invasion in GSCs, thus exhibiting significant clinical value in the reduction of invasion and malignant glioma progression. .
Topics: Animals; Brain Neoplasms; Cell Line, Tumor; Cell Movement; Dacarbazine; Drug Resistance, Neoplasm; Epithelial-Mesenchymal Transition; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Glioma; Male; Mice, Inbred NOD; Mice, SCID; Neoplasm Invasiveness; Neoplastic Stem Cells; Survival Analysis; Tumor Cells, Cultured; Xenograft Model Antitumor Assays
PubMed: 29440289
DOI: 10.1158/1535-7163.MCT-17-0591 -
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 -
ACS Sustainable Chemistry & Engineering May 2024Photocurable liquid formulations have been a key research focus for the preparation of mechanically robust and thermally stable networks. However, the development of...
Photocurable liquid formulations have been a key research focus for the preparation of mechanically robust and thermally stable networks. However, the development of renewable resins to replace petroleum-based commodities presents a great challenge in the field. From this perspective, we disclose the design of photoactive resins based on terpenes and itaconic acid, both potentially naturally sourced, to prepare photosets with adjustable thermomechanical properties. Biobased perillyl itaconate (PerIt) was synthesized from renewable perillyl alcohol and itaconic anhydride via a scalable solvent-free method. Photoirradiation of PerIt in the presence of a multiarm thiol and photoinitiator led to the formation of networks over a range of compositions. Addition of nonmodified terpenes (perillyl alcohol, linalool, or limonene) as reactive diluents allowed for more facile preparation of photocured networks. Photosets within a wide range of properties were accessed, and these could be adjusted by varying diluent type and thiol stoichiometry. The resins showed rapid photocuring kinetics and the ability to form either brittle or elastic materials, with Young's modulus and strain at break ranging from 3.6 to 358 MPa and 15 to 367%, respectively, depending on the chemical composition of the resin. Glass transition temperatures () were influenced by thioether content, with temperatures ranging from 5 to 43 °C, and all photosets displayed good thermal resistance with > 190 °C. Selected formulations containing PerIt and limonene demonstrated suitability for additive manufacturing technologies and high-resolution objects were printed via digital light processing (DLP). Overall, this work presents a simple and straightforward route to prepare renewable resins for rapid prototyping applications.
PubMed: 38725455
DOI: 10.1021/acssuschemeng.3c08191 -
Pharmaceutics Feb 2021The low solubility and high volatility of perillyl alcohol (POH) compromise its bioavailability and potential use as chemotherapeutic drug. In this work, we have...
The low solubility and high volatility of perillyl alcohol (POH) compromise its bioavailability and potential use as chemotherapeutic drug. In this work, we have evaluated the anticancer activity of POH complexed with β-cyclodextrin (β-CD) using three complexation approaches. Molecular docking suggests the hydrogen-bond between POH and β-cyclodextrin in molar proportion was 1:1. Thermal analysis and Fourier-transform infrared spectroscopy (FTIR) confirmed that the POH was enclosed in the β-CD cavity. Also, there was a significant reduction of particle size thereof, indicating a modification of the β-cyclodextrin crystals. The complexes were tested against human L929 fibroblasts after 24 h of incubation showing no signs of cytotoxicity. Concerning the histopathological results, the treatment with POH/β-CD at a dose of 50 mg/kg promoted approximately 60% inhibition of tumor growth in a sarcoma S180-induced mice model and the reduction of nuclear immunoexpression of the Ki67 antigen compared to the control group. Obtained data suggest a significant reduction of cycling cells and tumor proliferation. Our results confirm that complexation of POH/β-CD not only solves the problem related to the volatility of the monoterpene but also increases its efficiency as an antitumor agent.
PubMed: 33578857
DOI: 10.3390/pharmaceutics13020245 -
BMC Complementary Medicine and Therapies Jul 2020Pulmonary artery hypertension (PAH) is a vascular disease in the lung characterized by elevated pulmonary arterial pressure (PAP). Many miRNAs play a role in the...
Perillyle alcohol and Quercetin ameliorate monocrotaline-induced pulmonary artery hypertension in rats through PARP1-mediated miR-204 down-regulation and its downstream pathway.
BACKGROUND
Pulmonary artery hypertension (PAH) is a vascular disease in the lung characterized by elevated pulmonary arterial pressure (PAP). Many miRNAs play a role in the pathophysiology of PAH. Perillyle alcohol (PA) and Quercetin (QS) are plant derivatives with antioxidant and anti-proliferative properties. We investigated the effect of PA and QS on PAP, expression of PARP1, miR-204, and their targets, HIF1α and NFATc2, in experimental PAH.
METHODS
Thirty rats were divided into control, MCT, MCT + Veh, MCT + PA and MCT + QS groups. MCT (60 mg/kg) was injected subcutaneously to induce PAH. PA (50 mg/kg daily) and QS (30 mg/kg daily) were administered for 3 weeks after inducing PAH. PAP, lung pathology, expression of miRNA and mRNA, and target proteins were evaluated through right ventricle cannulation, H&E staining, real-time qPCR, and western blotting, respectively.
RESULTS
Inflammation and lung arteriole thickness in the MCT group increased compared to control group. PA and QS ameliorated inflammation and reduced arteriole thickness significantly. miR-204 expression decreased in PAH rats (p < 0.001). PA (p < 0.001) and QS (p < 0.01) significantly increased miR-204 expression. Expression of PARP1, HIF1α, NFATc2, and α-SMA mRNA increased significantly in MCT + veh rats (all p < 0.001), and these were reduced after treatment with PA and QS (both p < 0.01). PA and QS also decreased the expression of PARP1, HIF1α, and NFATc2 proteins that had increased in MCT + Veh group.
CONCLUSION
PA and QS improved PAH possibly by affecting the expression of PARP1 and miR-204 and their downstream targets, HIF1a and NFATc2. PA and QS may be therapeutic goals in the treatment of PAH.
Topics: Animals; Disease Models, Animal; Down-Regulation; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Hypoxia-Inducible Factor 1, alpha Subunit; Male; MicroRNAs; Monocrotaline; Monoterpenes; NFATC Transcription Factors; Poly (ADP-Ribose) Polymerase-1; Pulmonary Artery; Quercetin; Rats; Rats, Wistar
PubMed: 32660602
DOI: 10.1186/s12906-020-03015-1 -
Neuro-oncology Advances 2020NEO212 is a novel small-molecule anticancer agent that was generated by covalent conjugation of the natural monoterpene perillyl alcohol (POH) to the alkylating agent...
BACKGROUND
NEO212 is a novel small-molecule anticancer agent that was generated by covalent conjugation of the natural monoterpene perillyl alcohol (POH) to the alkylating agent temozolomide (TMZ). It is undergoing preclinical development as a therapeutic for brain-localized malignancies. The aim of this study was to characterize metabolism and pharmacokinetic (PK) properties of NEO212 in preclinical models.
METHODS
We used mass spectrometry (MS) and modified high-performance liquid chromatography to identify and quantitate NEO212 and its metabolites in cultured glioblastoma cells, in mouse plasma, brain, and excreta after oral gavage.
RESULTS
Our methods allowed identification and quantitation of NEO212, POH, TMZ, as well as primary metabolites 5-aminoimidazole-4-carboxamide (AIC) and perillic acid (PA). Intracellular concentrations of TMZ were greater after treatment of U251TR cells with NEO212 than after treatment with TMZ. The half-life of NEO212 in mouse plasma was 94 min. In mice harboring syngeneic GL261 brain tumors, the amount of NEO212 was greater in the tumor-bearing hemisphere than in the contralateral normal hemisphere. The brain:plasma ratio of NEO212 was greater than that of TMZ. Excretion of unaltered NEO212 was through feces, whereas its AIC metabolite was excreted via urine.
CONCLUSIONS
NEO212 preferentially concentrates in brain tumor tissue over normal brain tissue, and compared to TMZ has a higher brain:plasma ratio, altogether revealing favorable features to encourage its further development as a brain-targeted therapeutic. Its breakdown into well-characterized, long-lived metabolites, in particular AIC and PA, will provide useful equivalents for PK studies during further drug development and clinical trials with NEO212.
PubMed: 33392507
DOI: 10.1093/noajnl/vdaa160