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Biochemical and Biophysical Research... Jan 2018The metabolic pathway such as glyoxylate cycle (GC) enables Candida albicans, to survive under glucose deficient conditions prevalent in the hostile niche. Thus its key...
The metabolic pathway such as glyoxylate cycle (GC) enables Candida albicans, to survive under glucose deficient conditions prevalent in the hostile niche. Thus its key enzymes (Isocitrate lyase; ICL and malate synthase; MLS) represent attractive targets against C. albicans. We have previously reported the antifungal potential of a natural monoterpenoid perillyl alcohol (PA). The present study uncovers additional role of PA as a potent GC inhibitor. We explored that PA phenocopied ICL1 deletion mutant and were hypersensitive under low carbon utilizing conditions. The effect of PA on GC was substantiated by molecular docking analyses, which reveals the in-silico binding affinity of PA with ICL and MLS and explored that PA binds to the active sites of both proteins with better binding energy in comparison to their known inhibitors 3-nitropropionate and bromopyruvate respectively. Enzyme kinetics by Lineweaver-Burk plot unravels that PA inhibits ICL and MLS enzymes in competitive and non-competitive manner respectively. Moreover, semi-quantitative RT-PCR indicated that PA inhibits ICL1 and MLS1 mRNA expressions. Lastly, we demonstrated the antifungal efficacy of PA by enhanced survival of Caenorhabditis elegans model and less hemolytic activity (10.6%) on human blood cells. Further studies are warranted for PA to be considered as viable drug candidate.
Topics: Anti-Bacterial Agents; Bacterial Proteins; Candida albicans; Cell Survival; Dose-Response Relationship, Drug; Gene Expression Regulation, Bacterial; Glyoxylates; Isocitrate Lyase; Malate Synthase; Metabolic Flux Analysis; Metabolic Networks and Pathways; Monoterpenes
PubMed: 29129690
DOI: 10.1016/j.bbrc.2017.11.064 -
The Journal of Biological Chemistry Sep 2003The prognosis for patients with malignant glioma has not significantly changed in two decades, despite advances in surgery, radiation, and chemotherapy, emphasizing the...
The prognosis for patients with malignant glioma has not significantly changed in two decades, despite advances in surgery, radiation, and chemotherapy, emphasizing the growing need for novel approaches to glioma therapy. Perillyl alcohol (POH) is a naturally occurring monoterpene that has been shown to possess chemotherapeutic as well as chemopreventive activity in animal tumor models and is currently in Phase I and Phase II clinical trials. In the present study, we have demonstrated that POH is an effective radiosensitizer at clinically relevant doses of radiation using established glioma cell lines. POH caused a transient arrest in the G2/M phase of the cell cycle and induced apoptosis in glioma cells. POH treatment sensitized glioma cells to Fas-mediated apoptosis, which was further augmented in the presence of ionizing radiation and abrogated in the presence of antagonistic antibody. POH-induced radiosensitization was partially inhibited in glioma cells expressing dominant negative Fas-associated death domain and completely inhibited in glioma cells overexpressing the cytokine response modifier A. In addition, POH treatment resulted in a dose-dependent sensitization to cisplatin and doxorubicin induced cytotoxicity in glioma cells, highlighting its usefulness as a potent radio/chemosensitizer in the treatment of malignant glioma.
Topics: Animals; Antineoplastic Agents; Apoptosis; Blotting, Western; Bromodeoxyuridine; Cell Death; Cell Line; Cell Line, Tumor; Cisplatin; Dose-Response Relationship, Drug; Dose-Response Relationship, Radiation; Doxorubicin; Fas Ligand Protein; G2 Phase; Genes, Dominant; Glioma; Humans; Membrane Glycoproteins; Mitosis; Monoterpenes; Protein Structure, Tertiary; Radiation-Sensitizing Agents; Rats; Reverse Transcriptase Polymerase Chain Reaction; Time Factors; Transfection; Up-Regulation; fas Receptor
PubMed: 12805388
DOI: 10.1074/jbc.M303280200 -
Archives of Biochemistry and Biophysics Sep 2007Previously we demonstrated that secondary products of plant mevalonate metabolism called isoprenoids attenuate 3-hydroxy-3-methylglutaryl coenzyme A reductase mRNA...
Previously we demonstrated that secondary products of plant mevalonate metabolism called isoprenoids attenuate 3-hydroxy-3-methylglutaryl coenzyme A reductase mRNA translational efficiency and cause tumor cell death. Here we compared effects of "pure" isoprenoids (perillyl alcohol and gamma-tocotrienol) and a "mixed" isoprenoid-genistein-on the PKB/Akt/mTOR pathway that controls mRNA translation and m(7)GpppX eIF4F cap binding complex formation. Effects were cell- and isoprenoid-specific. Perillyl alcohol and genistein suppressed 4E-BP1(Ser65) phosphorylation in prostate tumor cell lines, DU145 and PC-3, and in Caco2 adenocarcinoma cells. Suppressive effects were similar to or greater than that observed with a PI3 kinase inhibitor or rapamycin, an mTOR inhibitor. 4E-BP1(Thr37) phosphorylation was reduced by perillyl alcohol and genistein in DU145, but not in PC-3. Conversely, perillyl alcohol but not genistein decreased 4E-BP1(Thr37) phosphorylation in Caco2. PKB/Akt activation via Ser473 phosphorylation was enhanced in DU145 by perillyl alcohol and in PC-3 by gamma-tocotrienol, but was suppressed by genistein. Importantly, perillyl alcohol disrupted interactions between eIF4E and eIF4G, key components of eIF4F (m(7)GpppX) cap binding complex. These results demonstrate that "pure" isoprenoids and genistein differentially impact cap-dependent translation in tumor cell lines.
Topics: Adaptor Proteins, Signal Transducing; Cell Cycle Proteins; Cell Line, Tumor; Dose-Response Relationship, Drug; Eukaryotic Initiation Factor-4E; Eukaryotic Initiation Factor-4G; Gene Expression Regulation, Neoplastic; Genistein; Humans; Monoterpenes; Neoplasms; Phosphoproteins; Phosphorylation; Proto-Oncogene Proteins c-akt; Signal Transduction
PubMed: 17601486
DOI: 10.1016/j.abb.2007.05.022 -
ACS Bio & Med Chem Au Feb 2022Increased incidences of fungal infections and associated mortality have accelerated the need for effective and alternative therapeutics. Perillyl alcohol (PA) is a...
Increased incidences of fungal infections and associated mortality have accelerated the need for effective and alternative therapeutics. Perillyl alcohol (PA) is a terpene produced by the hydroxylation of limonene via the mevalonate pathway. In pursuit of an alternative antifungal agent, we studied the effect of PA on the biofilm community of and on different cellular pathways to decipher its mode of action. PA efficiently inhibited growth and eradicated biofilms by reducing carbohydrate and eDNA content in the extracellular matrix. PA reduced the activity of hydrolytic enzymes in the ECM of biofilm. The chemical profiling study has given insights into the overall mode of action of PA in and the marked involvement of the cell wall and membrane, ergosterol biosynthesis, oxidative stress, and DNA replication. The spectroscopic and RT-PCR studies suggested a strong interaction of PA with chitin, β-glucan, ergosterol, and efflux pump, thus indicating increased membrane fluidity in . Furthermore, the microscopic and flow cytometry analysis emphasized that PA facilitated the change in mitochondrial activity, increased Ca influx via overexpression of voltage-gated Ca channels, and enhanced cytochrome C release from mitochondria. In addition, PA interferes with DNA replication and thus hinders the cell cycle progression at the S-phase. All these studies together established that PA mitigates the biofilms by targeting multiple cellular pathways. Interestingly, PA also potentiated the efficacy of azole drugs, particularly miconazole, against and its clinical isolates. Conclusively, the study demonstrated the use of PA as an effective antifungal agent alone or in combination with FDA-approved conventional drugs for fungal biofilm eradication.
PubMed: 37102177
DOI: 10.1021/acsbiomedchemau.1c00034 -
Pharmaceuticals (Basel, Switzerland) Jul 2023Perillyl alcohol (POH), a bioactive monoterpenoid derived from limonene, shows promise as an antitumor agent for brain tumor treatment. However, its limited oral...
Perillyl alcohol (POH), a bioactive monoterpenoid derived from limonene, shows promise as an antitumor agent for brain tumor treatment. However, its limited oral bioavailability and inadequate brain distribution hinder its efficacy. To address these challenges, this study developed nanostructured lipid carriers (NLCs) loaded with POH to improve its brain biodistribution. The NLCs prepared using hot homogenization exhibited an average diameter of 287 nm and a spherical morphology with a polydispersity index of 0.143. High encapsulation efficiency of 99.68% was achieved. X-ray diffraction analyses confirmed the semicrystalline state of POH-loaded NLCs. In vitro release studies demonstrated a biphasic release profile. Stability studies in simulated gastric and intestinal fluids confirmed their ability to withstand pH variations and digestive enzymes. In vivo pharmacokinetic studies in rats revealed significantly enhanced oral bioavailability of POH when encapsulated in the NLCs. Biodistribution studies showed increased POH concentration in brain tissue with NLCs compared with free POH, which was distributed more in non-target tissues such as the liver, lungs, kidneys, and spleen. These findings underscore the potential of NLCs as effective delivery systems for enhancing oral bioavailability and brain biodistribution of POH, providing a potential therapeutic strategy for brain tumor treatment.
PubMed: 37630970
DOI: 10.3390/ph16081055 -
Biomedicine & Pharmacotherapy =... Nov 2017Ischemia/reperfusion (I/R) injury plays an essential role in renal transplantation, and represents a crucial risk factor for allograft dysfunction and acute renal...
Perillyl alcohol protects human renal tubular epithelial cells from hypoxia/reoxygenation injury via inhibition of ROS, endoplasmic reticulum stress and activation of PI3K/Akt/eNOS pathway.
Ischemia/reperfusion (I/R) injury plays an essential role in renal transplantation, and represents a crucial risk factor for allograft dysfunction and acute renal failure. Modulation of oxidative stress is an effective therapeutic strategy for I/R injury. Perillyl alcohol (POH), a dietary monoterpene with antioxidant activity is found in a variety of plants. The study was carried out to investigate whether treatment of POH could reduce hypoxia/reoxygenation (H/R)-induced injury. H/R induced significant injury in HK-2 cells. H/R caused an increase in ROS level, apoptosis and ER stress. Meanwhile H/R also inhibited the cell viability and PI3K/Akt/eNOS signaling pathway. Pretreatment with POH prior to H/R improved cell viability, reduce ROS level, ER stress and apoptosis. Moreover, POH could also activate the PI3K/Akt/eNOS pathway. Therefore, POH may possess protective effects in H/R-induced cellular damage.
Topics: Apoptosis; Cell Hypoxia; Cell Line; Cytoprotection; Endoplasmic Reticulum Stress; Enzyme Activation; Epithelial Cells; Humans; Kidney Tubules; Monoterpenes; Nitric Oxide Synthase Type III; Oxidative Stress; Oxygen; Phosphatidylinositol 3-Kinases; Protective Agents; Proto-Oncogene Proteins c-akt; Reactive Oxygen Species; Signal Transduction
PubMed: 28886525
DOI: 10.1016/j.biopha.2017.08.129 -
Biochemical and Biophysical Research... May 1966
Topics: Alcohol Oxidoreductases; NAD; Pseudomonas; Soil Microbiology; Spectrophotometry
PubMed: 4289759
DOI: 10.1016/0006-291x(66)90752-2 -
International Journal of Antimicrobial... Mar 2018The development of new drugs is one of the strategies to control malaria. Isoprenoid biosynthesis in Plasmodium falciparum is an essential pathway for parasite survival,...
The development of new drugs is one of the strategies to control malaria. Isoprenoid biosynthesis in Plasmodium falciparum is an essential pathway for parasite survival, and is therefore a potential target for new antimalarial drugs. Indeed, plant-derived secondary metabolites, such as terpenes, exhibit antimalarial activity in vitro by inhibiting isoprenoid biosynthesis in P. falciparum. In this study, the in vitro antiplasmodial activity of perillyl alcohol (POH) was evaluated, along with its in vitro toxicity and its effect on the isoprenylation process. In addition, the efficacy of intranasally administered POH in preventing Plasmodium berghei ANKA-induced experimental cerebral malaria (ECM) was determined. The 50% inhibitory concentrations of POH for 3D7 and K1 P. falciparum were 4.8 µM and 10.4 µM, respectively. POH inhibited farnesylation of 20-37 kDa proteins in P. falciparum (3D7), but no toxic effects in Vero cells were observed. A 500 mg/kg/d dose of POH had no effect on P. berghei ANKA parasitaemia, but showed marked efficacy in preventing ECM development (70% survival compared with 30% for untreated animals). This effect was associated with the downregulation of cerebrovascular inflammation and damage, with marked decreases in brain leucocyte accumulation and the incidence of brain microhaemorrhage. POH also downregulated interleukin (IL)-10, IL-6, tumour necrosis factor-α, interferon-γ, IL-12 and monocyte chemoattractant protein-1 levels in the brain and spleen. In conclusion, POH shows antiplasmodial activity in vitro and, despite there being no evidence of antiplasmodial activity in vivo following intranasal administration, POH prevented cerebrovascular inflammation/damage and expression of pro-inflammatory cytokines.
Topics: Administration, Intranasal; Animals; Antimalarials; Brain; Cell Survival; Chlorocebus aethiops; Disease Models, Animal; Epithelial Cells; Inhibitory Concentration 50; Malaria, Cerebral; Male; Mice, Inbred C57BL; Monoterpenes; Parasitic Sensitivity Tests; Plasmodium berghei; Plasmodium falciparum; Treatment Outcome; Vero Cells
PubMed: 28843818
DOI: 10.1016/j.ijantimicag.2017.08.025 -
Drug Testing and Analysis Feb 2020The inhalational administration of drugs is a practical and non-invasive approach with the potential to reduce side effects and with a quick onset of therapeutic...
The inhalational administration of drugs is a practical and non-invasive approach with the potential to reduce side effects and with a quick onset of therapeutic activity. Perillyl alcohol (POH) is a monoterpene with antitumor activity that currently is undergoing clinical evaluation as an inhalational anticancer agent. A detection method was developed that will be applicable to pharmacokinetic studies of not only POH, but also its longer-lived main metabolite, perillic acid (PA), in lung tissue and plasma after inhalational delivery. The anticancer activity of POH was investigated in vitro with the use of various lung cancer cell lines. Toxicity was established by a standard MTT assay, and apoptosis markers were analyzed by Western blot. For the detection of POH and PA in lungs and plasma, albino Wistar rats were used that were exposed to POH inhalation. Tissues were subjected to chromatographic separation on an Agilent Zorbax Eclipse XDB C column, followed by detection of absorption in the ultraviolet (UV) range. In vitro, POH exerted cytotoxic activity against six different lung tumor cell lines, and apoptotic cell death was indicated by induction of active caspase 3 and cleavage of poly (ADP-ribose) polymerase 1 (PARP1). These results demonstrate that inhalational delivery of POH results in effective biodistribution and metabolism of POH in the systemic circulation. In addition, our study introduces a simple, rapid HPLC-UV method with high accuracy for simultaneous detection of POH and its metabolite PA in plasma, and for sensitive detection of PA in lung tissue, which should prove useful for applications in clinical studies.
Topics: Administration, Inhalation; Animals; Antineoplastic Agents; Cell Line, Tumor; Chromatography, High Pressure Liquid; Cyclohexenes; Drug Monitoring; Humans; Lung; Lung Neoplasms; Male; Monoterpenes; Rats; Rats, Wistar; Tissue Distribution
PubMed: 31800149
DOI: 10.1002/dta.2722 -
Molecular Cancer Therapeutics Mar 2019Glioblastoma (GBM) is a highly aggressive primary brain tumor with a poor prognosis. Treatment with temozolomide, standard of care for gliomas, usually results in drug...
Glioblastoma (GBM) is a highly aggressive primary brain tumor with a poor prognosis. Treatment with temozolomide, standard of care for gliomas, usually results in drug resistance and tumor recurrence. Therefore, there is a great need for drugs that target GBM. NEO214 was generated by covalently linking rolipram to perillyl alcohol (POH) via a carbamate bond to form the rolipram-perillyl alcohol conjugate. We show here that NEO214 is effective against both temozolomide-sensitive and temozolomide-resistant glioma cells. Furthermore, NEO214 is effective for different mechanisms of temozolomide resistance: overexpression of MGMT (O-methylguanine methyl-transferase); deficiency in specific mismatch repair proteins; and overexpression of base excision repair (BER) proteins. NEO214-induced cytotoxicity involves apoptosis triggered by endoplasmic reticulum (ER) stress, as well as activating the Death Receptor 5 (DR5)/TNF-related apoptosis-inducing ligand (TRAIL/Apo2L) pathway. studies show that glioma cells treated with NEO214 express DR5 and exhibit cell death in the presence of recombinant TRAIL, a growth factor constitutively produced by astrocytes. Our 3D coculture data show that induction of DR5 in glioma cells with NEO214 and TRAIL cause tumor cell death very effectively and specifically for glioma cells. studies show that NEO214 has antitumor efficacy in orthotropic syngeneic rodent tumor models. Furthermore, NEO214 has therapeutic potential especially for brain tumors because this drug can cross the blood-brain barrier (BBB), and is effective in the TRAIL-rich astrocyte microenvironment. NEO214 is a strong candidate for use in the treatment of GBMs.
Topics: Animals; Apoptosis; Astrocytes; Blood-Brain Barrier; Drug Resistance, Neoplasm; Endoplasmic Reticulum Stress; Gene Expression Regulation, Neoplastic; Glioblastoma; Humans; Mice; Monoterpenes; Receptors, TNF-Related Apoptosis-Inducing Ligand; Rolipram; Signal Transduction; TNF-Related Apoptosis-Inducing Ligand; Temozolomide; Tumor Microenvironment; Xenograft Model Antitumor Assays
PubMed: 30647121
DOI: 10.1158/1535-7163.MCT-18-0465