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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 -
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 -
Molecules (Basel, Switzerland) Sep 2018Six new cyclodiprenyl phenols were synthesized by direct coupling of perillyl alcohol and the appropriate phenol. Their structures were established by IR, HRMS and...
Six new cyclodiprenyl phenols were synthesized by direct coupling of perillyl alcohol and the appropriate phenol. Their structures were established by IR, HRMS and mainly NMR. Three human cancer cell lines-breast (MCF-7), prostate (PC-3) and colon (HT-29)-were used in antiproliferative assays, with daunorubicin and dunnione as positive controls. Results described in the article suggest that dihydroxylated compounds ⁻ and monohydroxylated compound display selectivity against cancer cell lines, cytotoxicity, apoptosis induction, and mitochondrial membrane impairment capacity. Compound was identified as the most effective of the series by displaying against all cancer cell lines a cytotoxicity close to dunnione antineoplastic agent, suggesting that the cyclodiprenyl phenols from perillyl alcohol deserve more extensive investigation of their potential medicinal applications.
Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Cell Survival; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; HT29 Cells; Humans; MCF-7 Cells; Mitochondrial Membranes; Molecular Structure; Phenols; Structure-Activity Relationship
PubMed: 30213053
DOI: 10.3390/molecules23092323 -
International Journal of Nanomedicine 20183-Bromopyruvate (3BP) is a promising powerful general anticancer agent. Unfortunately, 3BP release faces many practical and biochemical problems in clinical human...
3-Bromopyruvate (3BP) is a promising powerful general anticancer agent. Unfortunately, 3BP release faces many practical and biochemical problems in clinical human oncology, for example, 3BP induces burning venous sensation (during intravenous infusion) and rapid inactivation by thiol groups of glutathione and proteins. 3BP exhibits resistance in glutathione-rich tumors without being able to exert selective targeting. 3BP does not cross the blood-brain barrier and cannot treat nervous system tumors. Importantly, 3BP cannot persist in tumor tissues due to the phenomenon of enhanced permeability and retention effect. Here, the author presents the practical solutions for clinical problems facing 3BP use in clinical oncology, based on over 10 years of experience in 3BP research. Crude (unformulated 3BP that is purchased from chemical companies without being formulated in liposomes or other nanocarriers) should not be administered in clinical oncology. Instead, 3BP is better formulated with liposomes, polyethylene glycol (PEG), PEGylated liposomes (stealth liposomes) or perillyl alcohol that are used currently with many chemotherapeutics for treating clinical tumors in cancer patients. Formulating 3BP with targeted liposomes, for example, with folate, transferrin or other ligands, improves tumor targeting. Formulating 3BP with liposomes, PEG, stealth liposomes or perillyl alcohol may improve its pharmacokinetics, hide it from thiols in the circulation, protect it from serum proteins and enzymes, prevent burning sensation, prolong 3BP's longevity and facilitate crossing the BBB. Formulating 3BP with stealth liposomes protects 3BP from the reticuloendothelial cells. Liposomal 3BP formulations may retain 3BP better inside the relatively large tumor capillary pores (abolish enhanced permeability and retention effect) sparing normal tissues, facilitate new delivery routes for 3BP (eg, topical and intranasal 3BP administration using perillyl alcohol) and improve cancer cytotoxicity. Formulating 3BP may be promising in overcoming many obstacles in clinical oncology.
Topics: Animals; Enzyme Inhibitors; Humans; Liposomes; Neoplasms; Polyethylene Glycols; Pyruvates; Translational Research, Biomedical
PubMed: 30154655
DOI: 10.2147/IJN.S170564 -
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 -
International Journal of Molecular... May 2018Tumor infiltration into brain tissue usually remains undetected even by high-resolution imaging. Molecular markers are used to increase diagnostic accuracy, but with...
Tumor infiltration into brain tissue usually remains undetected even by high-resolution imaging. Molecular markers are used to increase diagnostic accuracy, but with limited continuous monitoring application. We evaluated the potential of circulating cell-free DNA (cfDNA) as a molecular indicator of the response to therapy by the intranasal administration (ITN) of perillyl alcohol (POH) in brain tumors. The cohort included 130 healthy subjects arranged as control-paired groups and patients at terminal stages with glioblastoma (GBM, = 122) or brain metastasis (BM, = 55) from stage IV adenocarcinomas. Serum cfDNA was isolated and quantified by fluorimetry. Compared with the controls (40 ng/mL), patients with brain tumors before ITN-POH treatment had increased ( < 0.0001) cfDNA median levels: GBM (286 ng/mL) and BM (588 ng/mL). ITN-POH treatment was significantly correlated (rho = -0.225; = 0.024) with survival of >6 months at a concentration of 599 ± 221 ng/mL and of.
Topics: Adult; Aged; Aged, 80 and over; Brain Neoplasms; Cell-Free Nucleic Acids; Female; Glioblastoma; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Monoterpenes; Prognosis; Retrospective Studies
PubMed: 29848970
DOI: 10.3390/ijms19061610 -
The Journal of Biological Chemistry Jun 2018The enzymatic functionalization of hydrocarbons is a central step in the global carbon cycle initiating the mineralization of methane, isoprenes, and monoterpenes, the...
The enzymatic functionalization of hydrocarbons is a central step in the global carbon cycle initiating the mineralization of methane, isoprenes, and monoterpenes, the most abundant biologically produced hydrocarbons. Also, terpene-modifying enzymes have found many applications in the energy-economic biotechnological production of fine chemicals. Here, we describe a limonene dehydrogenase that was purified from the facultatively anaerobic betaproteobacterium 65Phen grown on monoterpenes under denitrifying conditions in the absence of molecular oxygen. The purified limonene:ferrocenium oxidoreductase activity hydroxylated the methyl group of limonene (1-methyl-4-(1-methylethenyl)-cyclohex-1-ene) yielding perillyl alcohol ([4-(prop-1-en-2-yl)cyclohex-1-en-1-yl]methanol). The enzyme had a DTT:perillyl alcohol oxidoreductase activity yielding limonene. Mass spectrometry and molecular size determinations revealed a heterodimeric enzyme comprising CtmA and CtmB. Recently, the two proteins had been identified by transposon mutagenesis and proteomics as part of the cyclic terpene metabolism () in and are annotated as FAD-dependent oxidoreductases of the protein domain family phytoene dehydrogenases and related proteins (COG1233). CtmAB is the first heterodimeric enzyme in this protein superfamily. Flavins in the purified CtmAB are oxidized by ferrocenium and are reduced by limonene. Heterologous expression of CtmA, CtmB, and CtmAB in demonstrated that limonene dehydrogenase activity required both subunits, each carrying a flavin cofactor. Native CtmAB oxidized a wide range of monocyclic monoterpenes containing the allylic methyl group motif (1-methyl-cyclohex-1-ene). In conclusion, we have identified CtmAB as a hydroxylating limonene dehydrogenase and the first heteromer in a family of FAD-dependent dehydrogenases acting on allylic methylene or methyl CH-bonds. We suggest placing in Enzyme Nomenclature as new entry EC 1.17.99.8.
Topics: Alcaligenaceae; Amino Acid Sequence; Bacterial Proteins; Hydroxylation; Limonene; Monoterpenes; Oxidoreductases; Sequence Alignment
PubMed: 29716998
DOI: 10.1074/jbc.RA117.001557 -
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 -
Cell Death & Disease Feb 2018The DNA repair enzyme O-methylguanin-DNA-methltransferase (MGMT) is able to remove products of alkylating agent such as O-meG and emerges as a central determinant of...
Temozolomide-perillyl alcohol conjugate downregulates O-methylguanin DNA methltransferase via inducing ubiquitination-dependent proteolysis in non-small cell lung cancer.
The DNA repair enzyme O-methylguanin-DNA-methltransferase (MGMT) is able to remove products of alkylating agent such as O-meG and emerges as a central determinant of cancer resistance to temozolomide (TMZ). Temozolomide-perillyl alcohol conjugate (TMZ-POH), a novel TMZ analog developed based on the conjugation of TMZ and POH, displayed strong anticancer potency in multiple cancer types, but seemed not to experience the chemoresistance even in cells with high MGMT expression unlike TMZ and other alkylating agents. In this study, we demonstrated TMZ-POH inhibited MGMT dependent on proteasomal pathway and this inhibition is a significant factor in its toxic effect in the non-small cell lung cancer (NSCLC) cells.
Topics: A549 Cells; Antineoplastic Agents, Alkylating; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; DNA Modification Methylases; DNA Repair Enzymes; Down-Regulation; Humans; Lung Neoplasms; Monoterpenes; Proteasome Endopeptidase Complex; Temozolomide; Tumor Suppressor Proteins; Ubiquitination
PubMed: 29426908
DOI: 10.1038/s41419-017-0193-2 -
Oncology Letters Jan 2018It has been hypothesized that persistent ketotic hypoglycemia represents a potential therapeutic strategy against high-grade gliomas. Perillyl alcohol (POH) is a...
It has been hypothesized that persistent ketotic hypoglycemia represents a potential therapeutic strategy against high-grade gliomas. Perillyl alcohol (POH) is a non-toxic, naturally-occurring, hydroxylated monoterpene that exhibits cytotoxicity against temozolomide-resistant glioma cells, regardless of O6-methylguanine-methyltransferase promoter methylation status. The present study aimed to evaluate the toxicity and therapeutic efficacy of intranasal POH when administered in combination with a ketogenic diet (KD) program for the treatment of patients with recurrent glioblastoma. The 32 enrolled patients were divided into two groups, KD or standard diet, with intranasal POH treatment (n=17 and n=15, respectively). The nutritional status and anthropometric parameters of the patients were measured. Patients that adhered to the KD maintained a strict dietary regimen, in addition to receiving 55 mg POH four times daily, in an uninterrupted administration schedule for three months. Neurological examination and magnetic resonance imaging analysis were used to monitor disease progression. A total of 9/17 patients in the KD group survived and maintained compliance with the KD. After three months of well-tolerated treatment, a partial response (PR) was observed for 77.8% (7/9) of the patients, stable disease (SD) in 11.1% (1/9) and 11.1% (1/9) presented with progressive disease (PD). Among the patients assigned to the standard diet group, the PR rate was 25% (2/8 patients), SD 25% (2/8) and PD 50% (4/8 patients). The patients assigned to the KD group presented with reduced serum lipid levels and decreased low-density lipoprotein cholesterol levels. These results are encouraging and suggest that KD associated with intranasal POH may represent a viable option as an adjunct therapy for recurrent GBM.
PubMed: 29391903
DOI: 10.3892/ol.2017.7362