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International Journal of Molecular... Jan 2018Despite the introduction of new therapies for multiple myeloma (MM), many patients are still dying from this disease and novel treatments are urgently needed. We have...
Despite the introduction of new therapies for multiple myeloma (MM), many patients are still dying from this disease and novel treatments are urgently needed. We have designed a novel hybrid molecule, called NEO214, that was generated by covalent conjugation of the natural monoterpene perillyl alcohol (POH), an inducer of endoplasmic reticulum (ER) stress, to rolipram (Rp), an inhibitor of phosphodiesterase-4 (PDE4). Its potential anticancer effects were investigated in a panel of MM cell lines. We found that NEO214 effectively killed MM cells in vitro with a potency that was over an order of magnitude stronger than that of its individual components, either alone or in combination. The cytotoxic mechanism of NEO214 involved severe ER stress and prolonged induction of CCAAT/enhancer-binding protein homologous protein (CHOP), a key pro-apoptotic component of the ER stress response. These effects were prevented by salubrinal, a pharmacologic inhibitor of ER stress, and by gene knockout. Conversely, combination of NEO214 with bortezomib, a drug in clinical use for patients with MM, resulted in synergistic enhancement of MM cell death. Combination with the adenylate cyclase stimulant forskolin did not enhance NEO214 impact, indicating that cyclic adenosine 3',5'-monophosphate (AMP) pathways might play a lesser role. Our study introduces the novel agent NEO214 as a potent inducer of ER stress with significant anti-MM activity in vitro. It should be further investigated as a potential MM therapy aimed at exploiting this tumor's distinct sensitivity to ER stress.
Topics: Antineoplastic Agents; Apoptosis; Biomarkers; Cell Line, Tumor; Cell Survival; Dose-Response Relationship, Drug; Endoplasmic Reticulum Stress; Humans; Molecular Structure; Monoterpenes; Multiple Myeloma; Phosphodiesterase 4 Inhibitors; Rolipram
PubMed: 29342125
DOI: 10.3390/ijms19010277 -
Archivum Immunologiae Et Therapiae... Aug 2017Monoterpenes such as limonene and perillyl alcohol (POH) are promising natural compounds with pro-oxidant properties partly due to endoplasmic reticulum (ER)... (Review)
Review
Monoterpenes such as limonene and perillyl alcohol (POH) are promising natural compounds with pro-oxidant properties partly due to endoplasmic reticulum (ER) stress-induced cytotoxicity, and antioxidant activity owing to their activity as free radical scavengers, inhibition of coenzyme Q synthesis, activation of antioxidant-responsive elements (inducing detoxification enzymes) and induction of apoptosis. Activation of ER-stress responses generates reactive oxygen species (ROS), which are highly reactive free radicals mainly produced during mitochondrial electron transfer for adenosine triphosphate (ATP) synthesis. When cells are subjected to oxidative stress conditions, there is an accumulation of ROS that can lead to irreversible cell injury caused primarily by lipid peroxidation, protein aggregation and/or DNA damage. Malignant tumors, such as glioblastoma multiforme, display elevated rates of oxygen consumption, necrosis and abnormal structural microvasculature. Alterations in the tumor microenvironment are tightly linked to tumor progression and occur as a result of activation of complex signaling networks involving inter-clonal cooperation, cell-matrix interactions and an ongoing inflammatory response leading to genetic and epigenetic alterations. This review will focus on the pro- and anti-oxidant activities of POH, which are greatly dependent on the respective ROS levels within the tumor microenvironment and involve the ER stress response system. As well, some critical aspects of tumor-associated metabolic changes and the consequences of endogenous ROS production for tumor progression will be discussed.
Topics: Animals; Antineoplastic Agents; Brain Neoplasms; Carcinogenesis; Endoplasmic Reticulum Stress; Free Radical Scavengers; Glioblastoma; Humans; Hypoxia; Lipid Peroxidation; Monoterpenes; Oxidative Stress; Reactive Oxygen Species; Tumor Microenvironment; Unfolded Protein Response
PubMed: 28314870
DOI: 10.1007/s00005-017-0459-5 -
Phytochemistry Feb 2017Perilla produces the cyclohexanoid monoterpene perillaldehyde as a major constituent of an essential oil that is accumulated in its glandular trichomes. Perillaldehyde...
Perilla produces the cyclohexanoid monoterpene perillaldehyde as a major constituent of an essential oil that is accumulated in its glandular trichomes. Perillaldehyde is a marker compound for quality control of soyo and has biological activities such as antibacterial, sedative, or vasodilatory effects. The predicted perillaldehyde formation involves the cyclization of geranyl diphosphate, hydroxylation, and oxidation, and cytochrome P450 plays a crucial role in perillaldehyde biosynthesis. In this study, a cytochrome P450-type enzyme with perillyl alcohol and perillaldehyde synthase activities was isolated by analyzing an expressed sequence tag library from several oil types of pure lines of perilla. A recombinant protein with a sequence that was highly specific for the type of perillaldehyde was expressed in Saccharomyces cerevisiae and evaluated by an in vitro enzymatic reaction. The recombinant protein catalyzed the hydroxylation and oxidation of limonene to perillyl alcohol and perillaldehyde. Cytochrome P450 limonene-7-hydroxylase cDNA from Perilla frutescens has been previously isolated. The cytochrome P450 isolated in this study shares 37% amino-acid identity with the previously isolated enzyme; however, it may have different characteristics.
Topics: Cloning, Molecular; Cyclohexenes; Cytochrome P-450 Enzyme System; Diphosphates; Diterpenes; Gene Library; Limonene; Monoterpenes; Oils, Volatile; Perilla frutescens; Recombinant Proteins; Terpenes
PubMed: 27890582
DOI: 10.1016/j.phytochem.2016.11.009 -
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 -
International Journal of Molecular... Sep 2016Metastasis to the central nervous system remains difficult to treat, and such patients are faced with a dismal prognosis. The blood-brain barrier (BBB), despite being... (Review)
Review
Metastasis to the central nervous system remains difficult to treat, and such patients are faced with a dismal prognosis. The blood-brain barrier (BBB), despite being partially compromised within malignant lesions in the brain, still retains much of its barrier function and prevents most chemotherapeutic agents from effectively reaching the tumor cells. Here, we review some of the recent developments aimed at overcoming this obstacle in order to more effectively deliver chemotherapeutic agents to the intracranial tumor site. These advances include intranasal delivery to achieve direct nose-to-brain transport of anticancer agents and covalent modification of existing drugs to support enhanced penetration of the BBB. In both of these areas, use of the natural product perillyl alcohol, a monoterpene with anticancer properties, contributed to promising new results, which will be discussed here.
Topics: Administration, Intranasal; Animals; Antineoplastic Agents; Blood-Brain Barrier; Brain Neoplasms; Drug Carriers; Humans; Monoterpenes
PubMed: 27598140
DOI: 10.3390/ijms17091463 -
Scientific Reports Mar 2016Temozolomide-perillyl alcohol conjugate (TMZ - POH), a novel temozolomide analog, was reported to play a cytotoxic role in triple-negative breast cancer and...
Temozolomide-perillyl alcohol conjugate (TMZ - POH), a novel temozolomide analog, was reported to play a cytotoxic role in triple-negative breast cancer and TMZ-resistant gliomas. In a current study we had demonstrated how TMZ - POH also exhibited its cytotoxicity against non-small cell lung cancer (NSCLC), the most common type of lung cancer, as evidence from cell/tumor proliferation inhibition, G2/M arrest, DNA damage and mitochondrial apoptosis. Importantly, TMZ - POH's cytotoxicity is closely related to reactive oxygen species (ROS) accumulation because it can be reversed by two ROS scavengers, catalase (CAT) and N-acetyl-L-cysteine (NAC). TMZ - POH induces mitochondrial transmembrane potential (MTP) decrease and ROS accumulation, in turn activates mitogen-activated protein kinase (MAPKs) signaling and mitochondrial apoptosis, and then exerts its cytotoxicity, thus proposing TMZ - POH as a potential therapeutic candidate for NSCLC.
Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Proliferation; Cell Survival; Dacarbazine; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms; MAP Kinase Signaling System; Membrane Potential, Mitochondrial; Monoterpenes; Reactive Oxygen Species; Temozolomide
PubMed: 26949038
DOI: 10.1038/srep22762 -
Surgical Neurology International 2016Gliomas display a high degree of intratumor heterogeneity, including changes in physiological parameters and lipid composition of the plasma membrane, which may...
BACKGROUND
Gliomas display a high degree of intratumor heterogeneity, including changes in physiological parameters and lipid composition of the plasma membrane, which may contribute to the development of drug resistance. Biophysical interactions between therapeutic agents and the lipid components at the outer plasma membrane interface are critical for effective drug uptake. Amphipathic molecules such as perillyl alcohol (POH) have a high partition coefficient and generally lead to altered lipid acyl tail dynamics near the lipid-water interface, impacting the lipid bilayer structure and transport dynamics. We therefore hypothesized that glioma cells may display enhanced sensitivity to POH-induced apoptosis due to plasma membrane alterations, while in non-transformed cells, POH may be expelled through thermal agitation.
METHODS
Interactions between POH and the plasma membrane was studied using molecular dynamics simulations. In this phase I/II trial, we set up to evaluate the clinical effectiveness of long-term (up to 5 years) daily intranasal administration of POH in a cohort of 19 patients with low-grade glioma (LGG). Importantly, in a series of clinical studies previously published by our group, we have successfully established that intranasal delivery of POH to patients with malignant gliomas is a viable and effective therapeutic strategy.
RESULTS
POH altered the plasma membrane potential of the lipid bilayer of gliomas and prolonged intranasal administration of POH in a cohort of patients with LGG halted disease progression with virtually no toxicity.
CONCLUSION
Altogether, the results suggest that POH-induced alterations of the plasma membrane might be contributing to its therapeutic efficacy in preventing LGG progression.
PubMed: 26862440
DOI: 10.4103/2152-7806.173301 -
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 -
Omics : a Journal of Integrative Biology Jan 2016The objective of the present study was to repurpose L-menthol, which is frequently used in oral health and topical formulations, for cancer therapeutics. In this...
The objective of the present study was to repurpose L-menthol, which is frequently used in oral health and topical formulations, for cancer therapeutics. In this article, we argue that monoterpenes such as L-menthol might offer veritable potentials in systems medicine, for example, as cheaper anti-cancer compounds. Other monoterpenes such as limonene, perillyl alcohol, and geraniol have been shown to induce apoptosis in various cancer cell lines, but their mechanisms of action are yet to be completely elucidated. Earlier, we showed that L-menthol modulates tubulin polymerization and apoptosis to inhibit cancer cell proliferation. In the present report, we used an apoptosis-related gene microarray in conjunction with proteomics analyses, as well as in silico interpretations, to study gene expression modulation in human adenocarcinoma Caco-2 cell line in response to L-menthol treatment. The microarray analysis identified caspase 10 as the important initiator caspase, instead of caspase 8. The proteomics analyses showed downregulation of HSP90 protein (also corroborated by its low transcript abundance), which in turn indicated inhibition of AKT-mediated survival pathway, release of pro-apoptotic factor BAD from BAD and BCLxL complex, besides regulation of other factors related to apoptosis. Based on the combined microarray, proteomics, and in silico data, a signaling pathway for L-menthol-induced apoptosis is being presented for the first time here. These data and literature analysis have significant implications for "repurposing" L-menthol beyond oral medicine, and in understanding the mode of action of plant-derived monoterpenes towards development of cheaper anticancer drugs in future.
Topics: Animals; Apoptosis; Caspase 10; Cell Line, Tumor; HSP90 Heat-Shock Proteins; Humans; Menthol; Systems Analysis
PubMed: 26760959
DOI: 10.1089/omi.2015.0118 -
International Journal of Molecular... Jan 2016Recent studies have revealed the high cytotoxicity of p-menthane derivatives against human tumor cells. In this study, the substance perillaldehyde 8,9-epoxide, a...
Recent studies have revealed the high cytotoxicity of p-menthane derivatives against human tumor cells. In this study, the substance perillaldehyde 8,9-epoxide, a p-menthane class derivative obtained from (S)-(-)-perillyl alcohol, was selected in order to assess antitumor activity against experimental sarcoma 180 tumors. Toxicological effects related to the liver, spleen, kidneys and hematology were evaluated in mice submitted to treatment. The tumor growth inhibition rate was 38.4%, 58.7%, 35.3%, 45.4% and 68.1% at doses of 100 and 200 mg/kg/day for perillaldehyde 8,9-epoxide, perillyl alcohol and 25 mg/kg/day for 5-FU intraperitoneal treatments, respectively. No toxicologically significant effect was found in liver and kidney parameters analyzed in Sarcoma 180-inoculated mice treated with perillaldehyde 8,9-epoxide. Histopathological analyses of the liver, spleen, and kidneys were free from any morphological changes in the organs of the animals treated with perillaldehyde 8,9-epoxide. In conclusion, the data suggest that perillaldehyde 8,9-epoxide possesses significant antitumor activity without systemic toxicity for the tested parameters. By comparison, there was no statistical difference for the antitumor activity between perillaldehyde 8,9-epoxide and perillyl alcohol.
Topics: Animals; Antineoplastic Agents; Female; Fluorouracil; Mice; Monoterpenes; Neoplasm Transplantation; Neoplasms
PubMed: 26742032
DOI: 10.3390/ijms17010032