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Mini Reviews in Medicinal Chemistry 2021Limonene and perillyl alcohol are natural monoterpenes that have attracted the attention of medicinal chemists due to their promising anticancer activities. Considering... (Review)
Review
Limonene and perillyl alcohol are natural monoterpenes that have attracted the attention of medicinal chemists due to their promising anticancer activities. Considering this, both compounds were explored as scaffolds to obtain various derivatives with anticancer activity. In this review, the data are organized for the first time, with a focus on the synthetic methods and strategies to obtain the derivatives throughout the period from 2000 to 2020. A brief discussion regarding the structure and activity relationships of the most active derivatives, stereoisomers, and their mechanisms of action is presented. Among the active compounds, a series of limonenes with thiosemicarbazone groups and perillyl alcohol hybrids with glycosides or drugs are illustrated. Taking all of this into account, this review may help researchers develop new promising anticancer candidates based on the structures of limonene and perillyl alcohol.
Topics: Antineoplastic Agents; Carbohydrates; Cell Survival; Humans; Limonene; Monoterpenes; Neoplasms; Structure-Activity Relationship; Thiosemicarbazones
PubMed: 33583370
DOI: 10.2174/1389557521666210212150504 -
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 -
International Journal of Molecular... Dec 2018Intracranial malignancies, such as primary brain cancers and brain-localized metastases derived from peripheral cancers, are particularly difficult to treat with... (Review)
Review
Intracranial malignancies, such as primary brain cancers and brain-localized metastases derived from peripheral cancers, are particularly difficult to treat with therapeutic agents, because the blood-brain barrier (BBB) effectively minimizes brain entry of the vast majority of agents arriving from the systemic circulation. Intranasal administration of cancer drugs has the potential to reach the brain via direct nose-to-brain transport, thereby circumventing the obstacle posed by the BBB. However, in the field of cancer therapy, there is a paucity of studies reporting positive results with this type of approach. A remarkable exception is the natural compound perillyl alcohol (POH). Its potent anticancer activity was convincingly established in preclinical studies, but it nonetheless failed in subsequent clinical trials, where it was given orally and displayed hard-to-tolerate gastrointestinal side effects. Intriguingly, when switched to intranasal delivery, POH yielded highly promising activity in recurrent glioma patients and was well tolerated. As of 2018, POH is the only intranasally delivered compound in the field of cancer therapy (outside of cancer pain) that has advanced to active clinical trials. In the following, we will introduce this compound, summarize its molecular mechanisms of action, and present the latest data on its clinical evaluation as an intranasally administered agent for glioma.
Topics: Administration, Intranasal; Antineoplastic Agents; Brain Neoplasms; Clinical Trials as Topic; Glioma; Humans; Monoterpenes; Signal Transduction; Treatment Outcome
PubMed: 30563210
DOI: 10.3390/ijms19123905 -
Pharmaceutics Dec 2021Perillyl alcohol (POH) is a naturally occurring monoterpenoid related to limonene that is present in the essential oils of various plants. It has diverse applications... (Review)
Review
Perillyl alcohol (POH) is a naturally occurring monoterpenoid related to limonene that is present in the essential oils of various plants. It has diverse applications and can be found in household items, including foods, cosmetics, and cleaning supplies. Over the past three decades, it has also been investigated for its potential anticancer activity. Clinical trials with an oral POH formulation administered to cancer patients failed to realize therapeutic expectations, although an intra-nasal POH formulation yielded encouraging results in malignant glioma patients. Based on its amphipathic nature, POH revealed the ability to overcome biological barriers, primarily the blood-brain barrier (BBB), but also the cytoplasmic membrane and the skin, which appear to be characteristics that critically contribute to POH's value for drug development and delivery. In this review, we present the physicochemical properties of POH that underlie its ability to overcome the obstacles placed by different types of biological barriers and consequently shape its multifaceted promise for cancer therapy and applications in drug development. We summarized and appraised the great variety of preclinical and clinical studies that investigated the use of POH for intranasal delivery and nose-to-brain drug transport, its intra-arterial delivery for BBB opening, and its permeation-enhancing function in hybrid molecules, where POH is combined with or conjugated to other therapeutic pharmacologic agents, yielding new chemical entities with novel mechanisms of action and applications.
PubMed: 34959448
DOI: 10.3390/pharmaceutics13122167 -
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 -
Engineering in Life Sciences May 2022()-(+)-perillyl alcohol is widely used in agricultural and anticarcinogenic fields. Microbial production of ()-(+)-perillyl alcohol was investigated in this study. We...
()-(+)-perillyl alcohol is widely used in agricultural and anticarcinogenic fields. Microbial production of ()-(+)-perillyl alcohol was investigated in this study. We optimized biosynthesis of ()-(+)-perillyl alcohol in by using neryl pyrophosphate synthase and NADPH regeneration. Engineering neryl pyrophosphate (NPP)-supplied pathway resulted in a 4-fold improvement of ()-(+)-perillyl alcohol titer. Subsequently, combined engineering of p-cymene monooxygenase () expression and module for NADPH regeneration exhibited a 15.4-fold increase of titer over the initial strain S02. Finally, 453 mg/L ()-(+)-perillyl alcohol was achieved in fed-batch fermentation, which is the highest ()-(+)-perillyl alcohol titer in .
PubMed: 35573132
DOI: 10.1002/elsc.202100135 -
Alternative Medicine Review : a Journal... Dec 1998Perillyl alcohol is a monoterpene isolated from the essential oils of lavendin, peppermint, spearmint, cherries, celery seeds, and several other plants. In animal... (Review)
Review
Perillyl alcohol is a monoterpene isolated from the essential oils of lavendin, peppermint, spearmint, cherries, celery seeds, and several other plants. In animal studies it has been shown to regress pancreatic, mammary, and liver tumors, to exhibit possible application as a chemopreventative agent for colon, skin, and lung cancer, and as a chemotherapeutic agent for neuroblastoma, and prostate and colon cancer. Perillyl alcohol is active in inducing apoptosis in tumor cells without affecting normal cells and can revert tumor cells back to a differentiated state. Its mechanism of action is unclear, but it has actions on various cellular substances which control cell growth and differentiation. It has been shown to increase mannose-6-phosphate/insulin-like growth factor II receptors, increase tissue growth factor beta receptors, increase Bak, decrease ras protein prenylation, decrease ubiquinone synthesis, and induce Phase I and Phase II detoxification systems. Preliminary human trials have not demonstrated tumor regression at a four times daily dosage schedule. In addition, significant side-effects, mainly gastrointestinal, have been experienced.
Topics: Animals; Antineoplastic Agents; Clinical Trials, Phase I as Topic; Humans; Monoterpenes; Neoplasms; Terpenes
PubMed: 9855569
DOI: No ID Found -
The Enzymes 2014Natural products have a long history of use in traditional medicines and their activities against different diseases have been the focus of many basic and clinical...
Natural products have a long history of use in traditional medicines and their activities against different diseases have been the focus of many basic and clinical researches in past few decades. The essential oils, volatile liquid containing aroma compound from plants, are known as active ingredients in the herbal medicine. Perillyl alcohol (POH) is usually available through dietary sources and is being explored for its cancer chemoprevention, tumor growth suppression, and regression. Citrus peels are the waste product of juice manufacturing industries and have been considered as a critical problem for environmental green ecology policies for years. One of the most well-known approaches to overcome this problem is transformation of these monoterpene by the use of specific strains of bacteria or yeasts. Limonene (1-methyl-4-isopropyl-cyclohexene) is a monoterpene, as other monoterpenes consists of two isoprene units, that comprises more than 90% of citrus essential oil and it exists in many fruits and vegetables. Although, the anticancer activity of d-limonene has identified nearly two decades ago, it has recently attracted much more attention in translational medicine. In this chapter, we will overview the anticancer effects of POH and d-limonene. Later, we will address the pharmacokinetics of these compounds, highlight the signaling pathways which are targeted by these proteins, review the clinical trials which have been done for these compounds in different cancer models, and finally discuss the future directions of the research in this field that might be more applicable in future cancer therapy strategies.
PubMed: 27102697
DOI: 10.1016/B978-0-12-802215-3.00002-1 -
Frontiers in Bioengineering and... 2022()-(+)-perillyl alcohol is a much valued supplemental compound with a wide range of agricultural and pharmacological characteristics. The aim of this study was to...
()-(+)-perillyl alcohol is a much valued supplemental compound with a wide range of agricultural and pharmacological characteristics. The aim of this study was to improve ()-(+)-perillyl alcohol production using a whole-cell catalytic formula. In this study, we employed plasmids with varying copy numbers to identify an appropriate strain, strain 03. We demonstrated that low levels of alKL provided maximal biocatalyst stability. Upon determination of the optimal conditions, the ()-(+)-perillyl alcohol yield reached 130 mg/L. For cofactor regeneration, we constructed strain 10, expressing FDH from , and achieved ()-(+)-perillyl alcohol production of 230 mg/L. As a result, 1.23 g/L ()-(+)-perillyl alcohol was transformed in a 5 L fermenter. Our proposed method facilitates an alternative approach to the economical biosynthesis of ()-(+)-perillyl alcohol.
PubMed: 35547170
DOI: 10.3389/fbioe.2022.900800 -
Naunyn-Schmiedeberg's Archives of... Jun 2023Allergic asthma is an inflammatory and chronic condition, which is the most common asthma phenotype. It is usually defined by sensitivity to environmental allergens and...
Allergic asthma is an inflammatory and chronic condition, which is the most common asthma phenotype. It is usually defined by sensitivity to environmental allergens and leads to the narrowing of the airways. Around 300 million individuals are suffering from asthma worldwide. The purpose of the current research was to evaluate the effect of perillyl alcohol (PA) on oxidative stress and inflammation parameters in rats with allergic asthma. Experimental asthma was induced by ovalbumin (OVA) sensitization and inhalation in five groups of rats including control, asthma, asthma + vehicle, asthma + PA, and asthma + dexamethasone (Dexa). PA (50 mg/kg) or Dexa (2.5 mg/kg) were administered intraperitoneally for seven consecutive days following asthma induction. Histopathological evaluation was performed via hematoxylin and eosin (H&E) and Masson's trichrome staining. The enzyme-linked immunosorbent assay (ELISA) was used for the evaluation of the cytokine levels, including tumor necrosis factor alpha (TNF-α), interleukin (IL)-6, IL-17, and IL-10, as well as oxidative stress biomarkers including reactive oxygen species (ROS), superoxide dismutase (SOD), malondialdehyde (MDA), total antioxidant capacity (TAC), and glutathione peroxidase (GPx) in the lung tissue and bronchoalveolar lavage fluid (BALF). Real-time polymerase chain reaction (PCR) was utilized for assessing the mRNA expression of FOXP3 and GATA3 and western blot analysis was used for the measurement of nuclear factor kappa B (NF-κB) protein expression. PA and Dexa decreased the pathological alterations and the expression levels of inflammatory factors (cytokines, GATA3, and NF-κB) in the lung tissue and BALF of asthmatic rats. PA restored GPx, SOD, and TAC levels and reduced ROS, MDA, nitrite, and total protein in the lung and BALF. Overall, our findings demonstrated that PA can be used as a therapeutic agent in asthma patients, but it is essential to monitor its effects in future clinical studies.
Topics: Rats; Animals; Mice; NF-kappa B; Reactive Oxygen Species; Asthma; Lung; Cytokines; Bronchoalveolar Lavage Fluid; Superoxide Dismutase; Oxidative Stress; Ovalbumin; Disease Models, Animal; Mice, Inbred BALB C
PubMed: 36707429
DOI: 10.1007/s00210-023-02398-5