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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 -
Antioxidants (Basel, Switzerland) Dec 2023(1) Background: This study aimed to outline the antioxidant, antitumoral, and cytotoxic proprieties of various types of extracts obtained from the leaves of the...
(1) Background: This study aimed to outline the antioxidant, antitumoral, and cytotoxic proprieties of various types of extracts obtained from the leaves of the species. (2) Methods: We determined total polyphenols, flavonoids and anthocyanins contents, as well as the in vitro antioxidant, antitumoral, and cytotoxic actions in three types of ethanolic extracts (E1, E2, E3) and in three types of acetone: ethanol extracts (A1, A2, A3) of according to standardized procedures. (3) Results: We found that ethanolic extracts had the highest total phenol and anthocyanins concentrations. The flavonoids concentration was not statistically different between the extracts. The iron chelating capacity, hydroxyl radical scavenging capacity, superoxide anion radical scavenging capacity, and lipoxygenase inhibition capacity showed a significant increase with higher concentrations of extracts, particularly the ethanolic extracts. Perillyl alcohol had greater cytotoxic capacity in the MG-63 cell line and E1 extract showed similar significant cytotoxic effects in the A431 cell line. (4) Conclusions: Both ethanolic and acetone-ethanol extracts from exhibited important antioxidant and antitumoral actions in vitro, which proportionally increased with concentration. The cytotoxic threshold determined in this study for various types of extracts could help determine the best dosage with the maximum antioxidant and antitumoral potential. Our results could serve as a basis for further studies that will investigate the cytotoxic effects of variants on various types of cancer cell lines.
PubMed: 38247482
DOI: 10.3390/antiox13010058 -
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 -
Communications Biology Oct 2021Respiratory syncytial virus (RSV) is a leading cause of severe respiratory tract infections in children. To uncover new antiviral therapies, we developed a live...
Respiratory syncytial virus (RSV) is a leading cause of severe respiratory tract infections in children. To uncover new antiviral therapies, we developed a live cell-based high content screening approach for rapid identification of RSV inhibitors and characterized five drug classes which inhibit the virus. Among the molecular targets for each hit, there was a strong functional enrichment in lipid metabolic pathways. Modulation of lipid metabolites by statins, a key hit from our screen, decreases the production of infectious virus through a combination of cholesterol and isoprenoid-mediated effects. Notably, RSV infection globally upregulates host protein prenylation, including the prenylation of Rho GTPases. Treatment by statins or perillyl alcohol, a geranylgeranyltransferase inhibitor, reduces infection in vitro. Of the Rho GTPases assayed in our study, a loss in Rac1 activity strongly inhibits the virus through a decrease in F protein surface expression. Our findings provide new insight into the importance of host lipid metabolism to RSV infection and highlight geranylgeranyltransferases as an antiviral target for therapeutic development.
Topics: Antiviral Agents; Drug Discovery; Respiratory Syncytial Virus Infections; Respiratory Syncytial Virus, Human; Virus Replication
PubMed: 34716403
DOI: 10.1038/s42003-021-02754-2 -
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 -
Journal of Biomedicine & Biotechnology 2002The monoterpene d-limonene exhibits chemotherapeutic and chemopreventive potential in breast cancer patients. D-limonene and its related compounds, perillyl alcohol and...
The monoterpene d-limonene exhibits chemotherapeutic and chemopreventive potential in breast cancer patients. D-limonene and its related compounds, perillyl alcohol and perillyl aldehyde, were chosen as candidate drugs for application in a screen for nontoxic inhibitors of cell migration. Using the nontumorigenic human breast cell line MCF-10A, we delineated the toxicity as greatest for the perillyl aldehyde, intermediate for perillyl alcohol, and least for limonene. A noncytotoxic concentration of 0.5 mmol/L perillyl alcohol inhibited the migration, while the same concentration of limonene failed to do so. Adhesion of the MCF-10A cell line and the human breast cancer cell line MDA-MB 435 to fibronectin was unaffected by 1.5 mmol/L perillyl alcohol. 0.4 mmol/L perillyl alcohol inhibited the growth of MDA-MB 435 cells. All migration-inhibiting concentrations of perillyl alcohol for MDA-MB 435 cells proved to be toxic. These results suggest that subtoxic doses of perillyl alcohol may have prophylactic potential in the treatment of breast cancer.
PubMed: 12488578
DOI: 10.1155/S1110724302207020 -
Journal of Proteome Research Jan 2011Glioblastoma multiform (GBM) is by far the most malignant glioma. We have introduced a new treatment for GBMs that comprises the inhalation of a naturally occurring...
Glioblastoma multiform (GBM) is by far the most malignant glioma. We have introduced a new treatment for GBMs that comprises the inhalation of a naturally occurring terpene with chemotherapeutic properties known as perillyl alcohol (POH). Clinical trial results on recurrent GBM patients showed that POH extends the average life by more than eight months, temporarily slows tumor growth, and in some cases even decreases tumor size. After approximately seven months, the tumor continues to grow and leads to a dismal prognosis. To investigate how these tumors become resistant to POH, we generated an A172 human glioblastoma cell culture tolerant to 0.06 mM of POH (A172r). We used Multidimensional Protein Identification Technology (MudPIT) to compare the protein expression profile of A172r cells to the established glioblastoma A172 cell line. Our results include a list of identified proteins unique to either the resistant or the nonresistant cell line. These proteins are related to cellular growth, negative apoptosis regulation, Ras pathway, and other key cellular functions that could be connected to the underlying mechanisms of resistance.
Topics: Antineoplastic Agents; Blotting, Western; Brain; Cell Line, Tumor; Clinical Trials as Topic; Drug Resistance, Neoplasm; Electrophoresis, Gel, Two-Dimensional; Glioblastoma; Humans; Magnetic Resonance Imaging; Monoterpenes; Peptide Fragments; Proteome; Proteomics; Reproducibility of Results; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
PubMed: 20806975
DOI: 10.1021/pr100677g -
Neuro-oncology Oct 2021The antitumor efficacy of human epidermal growth factor receptor 2 (HER2)-targeted therapies, such as humanized monoclonal antibody trastuzumab (Herceptin®, Roche), in...
BACKGROUND
The antitumor efficacy of human epidermal growth factor receptor 2 (HER2)-targeted therapies, such as humanized monoclonal antibody trastuzumab (Herceptin®, Roche), in patients with breast-to-brain cancer metastasis is hindered by the low permeability of the blood-brain barrier (BBB). NEO100 is a high-purity version of the natural monoterpene perillyl alcohol, produced under current good manufacturing practice (cGMP) regulations, that was shown previously to reversibly open the BBB in rodent models. Here we investigated whether NEO100 could enable brain entry of trastuzumab to achieve greater therapeutic activity.
METHODS
An in vitro BBB, consisting of human astrocytes and brain endothelial cells, was used to determine trastuzumab penetration in the presence or absence of NEO100. For in vivo studies, we administered intravenous (IV) trastuzumab or the trastuzumab-drug conjugate ado-trastuzumab emtansine (T-DM1; Kadcyla®, Roche), to mouse models harboring intracranial HER2+ breast cancer, with or without BBB opening via IA NEO100. Brain and tumor tissues were examined for the presence of trastuzumab and infiltration of immune cells. Therapeutic impact was evaluated based on overall survival.
RESULTS
NEO100 greatly increased trastuzumab penetration across an in vitro BBB. In vivo, IA NEO100-mediated BBB opening resulted in brain tumor-selective accumulation of trastuzumab, without detectable presence in normal brain tissue, along with increased presence of immune cell populations. IV delivery of trastuzumab or T-DM1 achieved significantly greater overall survival of tumor-bearing mice when combined with IA NEO100.
CONCLUSION
IA NEO100 facilitates brain tumor entry of trastuzumab and T-DM1 and significantly enhances their therapeutic efficacy, along with increased antibody-dependent immune cell recruitment.
Topics: Animals; Blood-Brain Barrier; Brain; Brain Neoplasms; Breast Neoplasms; Endothelial Cells; Female; Humans; Mice; Monoterpenes; Receptor, ErbB-2; Trastuzumab
PubMed: 33659980
DOI: 10.1093/neuonc/noab041 -
Journal of Pharmacological Sciences 2010An adverse effect of statins, cholesterol-lowering drugs, is contractile dysfunction of skeletal muscles. We investigated the mechanism underlying this effect in...
An adverse effect of statins, cholesterol-lowering drugs, is contractile dysfunction of skeletal muscles. We investigated the mechanism underlying this effect in cultured myofibers isolated from rats. Fluvastatin (Flv) for 72 h decreased caffeine- and ionomycin-induced contraction of myofibers and Ca(2+) release from sarcoplasmic reticulum (SR). Ca(2+)-shortening curves measured in skinned myofibers indicated that myofibrillar Ca(2+) sensitivity was unaffected by Flv. A luciferin-luciferase assay revealed less ATP contents in Flv-treated myofibers. Among mevalonate metabolites, including geranylgeranylpyrophosphate (GGPP), farnesylpyrophosphate (FPP), coenzyme Q9, and coenzyme Q10, only GGPP prevented Flv-induced ATP reduction. A selective Rab geranylgeranyltransferase (GG transferase) inhibitor, perillyl alcohol (POH), and a specific GG transferase-I inhibitor, GGTI-298, both mimicked Flv in decreasing ATP and contraction. Mitochondrial membrane potential was decreased by Flv, and this effect was rescued by GGPP and mimicked by POH and GGTI-298. An endoplasmic reticulum (ER)-to-Golgi traffic inhibitor, brefeldin A, and a Rho inhibitor, membrane permeable exoenzyme C3 transferase, both decreased ATP. We conclude that statin-induced contractile dysfunction is due to reduced Ca(2+) release from SR and reduced ATP levels in myofibers with damaged mitochondria. GGPP depletion and subsequent inactivation of Rab1, possibly along with Rho, may underlie the mitochondrial damage by Flv.
Topics: Adenosine Triphosphate; Animals; Autophagy; Calcium; Cells, Cultured; Fatty Acids, Monounsaturated; Fluvastatin; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Male; Mitochondria, Muscle; Muscle Contraction; Muscle, Skeletal; Myofibrils; Polyisoprenyl Phosphates; Rats; Rats, Wistar; Sarcoplasmic Reticulum; rab1 GTP-Binding Proteins
PubMed: 21127387
DOI: 10.1254/jphs.10229fp -
Molecular Cancer May 2015Na/K-ATPase (NKA) is inhibited by perillyl alcohol (POH), a monoterpene used in the treatment of tumors, including brain tumors. The NKA α1 subunit is known to be...
BACKGROUND
Na/K-ATPase (NKA) is inhibited by perillyl alcohol (POH), a monoterpene used in the treatment of tumors, including brain tumors. The NKA α1 subunit is known to be superexpressed in glioblastoma cells (GBM). This isoform is embedded in caveolar structures and is probably responsible for the signaling properties of NKA during apoptosis. In this work, we showed that POH acts in signaling cascades associated with NKA that control cell proliferation and/or cellular death.
METHODS
NKA activity was measured by the amount of non-radioactive Rb(+) incorporation into cultured GBM cell lines (U87 and U251) and non-tumor cells (mouse astrocytes and VERO cells). Cell viability was measured by lactate dehydrogenase levels in the supernatants of POH-treated cells. Activated c-Jun N-terminal Kinase (JNK) and p38 were assessed by western blotting. Apoptosis was detected by flow cytometry and immunocytochemistry, and the release of interleukins was measured by ELISA.
RESULTS
All four cell types tested showed a similar sensitivity for POH. Perillic acid (PA), the main metabolite of POH, did not show any effect on these cells. Though the cell viability decreased in a dose-dependent manner when cells were treated with POH, the maximum cytotoxic effect of PA obtained was 30% at 4 mM. 1.5 mM POH activated p38 in U87 cells and JNK in both U87 and U251 cells as well as mouse astrocytes. Dasatinib (an inhibitor of the Src kinase family) and methyl β-cyclodextrin (which promotes cholesterol depletion in cell membranes) reduced the POH-induced activation of JNK1/2 in U87 cells, indicating that the NKA-Src complex participates in this mechanism. Inhibition of JNK1/2 by the JNK inhibitor V reduced the apoptosis of GBM cells that resulted from POH administration, indicating the involvement of JNK1/2 in programmed cell death. 1.5 mM POH increased the production of interleukin IL-8 in the U251 cell supernatant, which may indicate a possible strategy by which cells avoid the cytotoxic effects of POH.
CONCLUSIONS
A signaling mechanism mediated by NKA may have an important role in the anti-tumor action of POH in GBM cells.
Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Survival; Cyclohexenes; Cytokines; Dasatinib; Enzyme Activation; Humans; JNK Mitogen-Activated Protein Kinases; Mice; Models, Biological; Molecular Targeted Therapy; Monoterpenes; Sodium-Potassium-Exchanging ATPase; beta-Cyclodextrins; p38 Mitogen-Activated Protein Kinases
PubMed: 25976744
DOI: 10.1186/s12943-015-0374-5