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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 -
Autophagy Dec 2023Glioblastoma (GBM) is the most aggressive primary brain tumor, exhibiting a high rate of recurrence and poor prognosis. Surgery and chemoradiation with temozolomide...
Glioblastoma (GBM) is the most aggressive primary brain tumor, exhibiting a high rate of recurrence and poor prognosis. Surgery and chemoradiation with temozolomide (TMZ) represent the standard of care, but, in most cases, the tumor develops resistance to further treatment and the patients succumb to disease. Therefore, there is a great need for the development of well-tolerated, effective drugs that specifically target chemoresistant gliomas. NEO214 was generated by covalently conjugating rolipram, a PDE4 (phosphodiesterase 4) inhibitor, to perillyl alcohol, a naturally occurring monoterpene related to limonene. Our previous studies in preclinical models showed that NEO214 harbors anticancer activity, is able to cross the blood-brain barrier (BBB), and is remarkably well tolerated. In the present study, we investigated its mechanism of action and discovered inhibition of macroautophagy/autophagy as a key component of its anticancer effect in glioblastoma cells. We show that NEO214 prevents autophagy-lysosome fusion, thereby blocking autophagic flux and triggering glioma cell death. This process involves activation of MTOR (mechanistic target of rapamycin kinase) activity, which leads to cytoplasmic accumulation of TFEB (transcription factor EB), a critical regulator of genes involved in the autophagy-lysosomal pathway, and consequently reduced expression of autophagy-lysosome genes. When combined with chloroquine and TMZ, the anticancer impact of NEO214 is further potentiated and unfolds against TMZ-resistant cells as well. Taken together, our findings characterize NEO214 as a novel autophagy inhibitor that could become useful for overcoming chemoresistance in glioblastoma. ATG: autophagy related; BAFA1: bafilomycin A; BBB: blood brain barrier; CQ: chloroquine; GBM: glioblastoma; LAMP1: lysosomal associated membrane protein 1; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MGMT: O-6-methylguanine-DNA methyltransferase; MTOR: mechanistic target of rapamycin kinase; MTORC: MTOR complex; POH: perillyl alcohol; SQSTM1/p62: sequestosome 1; TFEB: transcription factor EB; TMZ: temozolomide.
Topics: Humans; Glioblastoma; Temozolomide; Autophagy; Rolipram; Cell Death; Monoterpenes; Glioma; TOR Serine-Threonine Kinases; Sirolimus; Chloroquine; Lysosomes
PubMed: 37545052
DOI: 10.1080/15548627.2023.2242696 -
Phytomedicine : International Journal... Jun 2024Perillyl alcohol (POH) is a aroma monoterpene commonly obtained from various plants' essential oil. Recently, increasing researches have demonstrated that POH may be... (Review)
Review
BACKGROUND
Perillyl alcohol (POH) is a aroma monoterpene commonly obtained from various plants' essential oil. Recently, increasing researches have demonstrated that POH may be useful, not only as flavor compound, but also as bioactive molecule because of a variety of biological activities.
PURPOSE
The aim of this review is to summarize the production, pharmacological activities and molecular mechanism, active derivatives, toxicity and parmacokinetics, and industrial application of POH.
METHODS
A systematic search of published articles up to January 2024 in Web of Science, China Knowledge Network, and PubMed databases is conducted using the following keywords: POH, POH derivatives, biological or pharmacological, production or synthesis, pharmacokinetics, toxicity and application.
RESULTS
Biotechnological production is considered to be a potential alternative approach to generate POH. POH provides diverse pharmacological benefits, including anticancer, antimicrobial, insecticidal, antioxidant, anti-inflammatory, hypotensive, vasorelaxant, antinociceptive, antiasthmatic, hepatoprotective effects, etc. The underlying mechanisms of action include modulation of NF-κB, JNK/c-Jun, Notch, Akt/mTOR, PI3K/Akt/eNOS, STAT3, Nrf2 and ERS response pathways, mitigation of mitochondrial dysfunction and membrane integrity damage, and inhibition of ROS accumulation, pro-inflammatory cytokines release and NLRP3 activation. What's more, the proteins or genes influenced by POH against diseases refer to Bax, Bcl-2, cyclin D1, CDK, p21, p53, HIF-1α, AP-1, caspase-3, M6P/IGF2R, PARP, VEGF, etc. Some clinical studies report that intranasal delivery of POH is a safe and effective treatment for cancer, but further clinical investigations are needed to confirm other health benefits of POH in human healthy. Depending on these health-promoting properties together with desirable flavor and safety, POH can be employed as dietary supplement, preservative and flavor additive in food and cosmetic fields, as building block in synthesis fields, as anticancer drug in medicinal fields, and as pesticides and herbicides in agricultural fields.
CONCLUSION
This review systematically summarizes the recent advances in POH and highlights its therapeutic effects and potential mechanisms as well as the clinical settings, which is helpful to develop POH into functional food and new candidate drug for prevention and management of diseases. Future studies are needed to conduct more biological activity studies of POH and its derivatives, and check their clinical efficacy and potential side effects.
PubMed: 38897045
DOI: 10.1016/j.phymed.2024.155826 -
Clinical and Experimental Hypertension... Apr 2021: Pulmonary arterial hypertension (PAH) is a disastrous disease that current treatments cannot prevent its progression. The present study investigated the effects of...
: Pulmonary arterial hypertension (PAH) is a disastrous disease that current treatments cannot prevent its progression. The present study investigated the effects of perillyl alcohol (PA), a natural monoterpene, on the experimental PAH in male Wistar rats. : Rats divided into eight groups of control, Monocrotaline (MCT), MCT+vehicle, and MCT+PA with doses of 20, 30, 40, 50, and 60 mg/kg. PAH was induced by a single injection of monocrotaline (60 mg/kg) on day 0. The animals in the groups of MCT+vehicle and MCT+PA received the vehicle or PA from day 22 to 42 once a day. On day 43, under general anesthesia, right ventricular systolic pressure (RVSP), as an index of pulmonary artery systolic pressure, and the ratio of the right ventricle to the left ventricle plus septum weight, as the right ventricular hypertrophy index (RVHI), were measured. Also, some histological and biochemical indices were assessed in the lung tissue. : MCT significantly ( < .001) enhanced the RVSP and RVHI compared to the control group (89.4 ± 8.2 vs 23 ± 3.3 mmHg & 0.63 ± 0.08 vs 0.26 ± 0.04 respectively). It also increased oxidative stress and inflammatory cytokines and reduced Bax/Bcl2 ratio. Treatment with PA significantly recovered RVSP and hypertrophy index and suppressed vascular cell proliferation, oxidant production, and inflammatory processes. : PA exerted noticeable protective and curative effects against MCT-induced PAH and pulmonary vascular remodeling through inhibiting cellular proliferation, oxidative stress, and inflammation. Therefore, PA can be considered as a new therapeutic goal for the treatment of PAH.
Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Apoptosis; Blood Pressure; Cell Cycle; Disease Models, Animal; Heart Ventricles; Hemodynamics; Hypertrophy, Right Ventricular; Inflammation Mediators; Lung; Male; Monocrotaline; Monoterpenes; Oxidative Stress; Pulmonary Arterial Hypertension; Pulmonary Artery; Pulmonary Fibrosis; Rats, Wistar; Survival Analysis; Systole; Vascular Remodeling; Rats
PubMed: 33322932
DOI: 10.1080/10641963.2020.1860080 -
Non-coding RNA Research Mar 2022Non-coding RNAs, including long non-coding RNAs (lncRNAs) and microRNAs (miRNAs), play critical roles in the pathogenesis and progression of pulmonary artery...
BACKGROUND
Non-coding RNAs, including long non-coding RNAs (lncRNAs) and microRNAs (miRNAs), play critical roles in the pathogenesis and progression of pulmonary artery hypertension (PAH). LncRNA H19, myocardial infarction-associated transcript (MIAT), miR-29a, and miR-33a have been suggested as potential targets for treating arterial hypertension. We explored the expression pattern of non-coding RNAs H19, MIAT, miR-29a, and miR-33a in monocrotaline (MCT)-induced PAH rats. Moreover, we investigated whether perillyl alcohol (PA) and quercetin (QS), two plant derivatives with beneficial effects on PAH-induced abnormalities, act through regulating the expression of these non-coding RNAs.
METHODS
Male Wistar rats ( = 30) were divided into five groups. MCT (60 mg/kg) was injected subcutaneously to induce PAH. PA (50 mg/kg daily) and QS (30 mg/kg daily) were administered three weeks after induction of PAH. H&E staining and qRT-PCR were performed to assess arteriole wall thickness and gene expression, respectively.
RESULTS
Right ventricular systolic pressure (RVSP) and right ventricular hypertrophy (RVH) increased in MCT and MCT + Veh. groups compared to the control group (in both < 0.001). QS and PA decreased RVSP and RVH significantly. Wall thickness and fibrosis score in the MCT group (score 3) increased compared to the control group (score 0). PA and QS ameliorated wall thickness and fibrosis to score 1 (mild). Also, the expression of miR-29a and miR-33a decreased in the PAH group (in both, < 0.001). Treatment with PA and QS decreased the expression of H19 ( < 0.001) and MIAT ( < 0.01) and increased the expression of miR-29a ( < 0.01) and miR-33a significantly ( < 0.05 for QS and < 0.001 for PA).
CONCLUSIONS
The beneficial effects of PA and QS on PAH-induced abnormalities were exerted through returning the dysregulated expression of H19, MIAT, miR-29a, and miR-33a to normal levels in rats with MTC-induced PAH. This study emphasized the therapeutic potential of PA and QS in PAH. However, more detailed investigations are needed to clarify the underlying molecular mechanisms.
PubMed: 35155877
DOI: 10.1016/j.ncrna.2022.01.005 -
Antibiotics (Basel, Switzerland) Feb 2023The treatment of bacterial infections has been troubled by the increased resistance to antibiotics, instigating the search for new antimicrobial therapies....
The treatment of bacterial infections has been troubled by the increased resistance to antibiotics, instigating the search for new antimicrobial therapies. Phytochemicals have demonstrated broad-spectrum and effective antibacterial effects as well as antibiotic resistance-modifying activity. In this study, perillyl alcohol and hydrocinnamic acid were characterized for their antimicrobial action against . Furthermore, dual and triple combinations of these molecules with the antibiotics chloramphenicol and amoxicillin were investigated for the first time. Perillyl alcohol had a minimum inhibitory concentration (MIC) of 256 µg/mL and a minimum bactericidal concentration (MBC) of 512 µg/mL. Hydrocinnamic acid had a MIC of 2048 µg/mL and an MBC > 2048 µg/mL. Checkerboard and time-kill assays demonstrated synergism or additive effects for the dual combinations chloramphenicol/perillyl alcohol, chloramphenicol/hydrocinnamic acid, and amoxicillin/hydrocinnamic acid at low concentrations of both molecules. Combenefit analysis showed synergism for various concentrations of amoxicillin with each phytochemical. Combinations of chloramphenicol with perillyl alcohol and hydrocinnamic acid revealed synergism mainly at low concentrations of antibiotics (up to 2 μg/mL of chloramphenicol with perillyl alcohol; 0.5 μg/mL of chloramphenicol with hydrocinnamic acid). The results highlight the potential of combinatorial therapies for microbial growth control, where phytochemicals can play an important role as potentiators or resistance-modifying agents.
PubMed: 36830271
DOI: 10.3390/antibiotics12020360 -
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... 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 -
Pharmacological Reports : PR Oct 2023Melanoma is a highly aggressive and life-threatening form of skin cancer that accounts for a significant proportion of cancer-related deaths worldwide. Although... (Review)
Review
Melanoma is a highly aggressive and life-threatening form of skin cancer that accounts for a significant proportion of cancer-related deaths worldwide. Although conventional cancer therapies, such as surgical excision, chemotherapy, and radiation, have been used to treat malignant melanoma, their efficacy is often limited due to the development of resistance and adverse side effects. Therefore, there is a growing interest in developing alternative treatment options for melanoma that are more effective and less toxic. Terpenes, a diverse group of naturally occurring compounds of plant origin, have emerged as potential anticancer agents due to their ability to inhibit tumor growth and induce apoptosis in cancer cells. In this review, the current understanding of the anticancer effects of terpenes (including, thymoquinone, β-elemene, carvacrol, limonene, α-pinene, β-caryophyllene, perillyl alcohol, taxol, betulinic acid, α-bisabolol, ursolic acid, linalool, lupeol, and artesunate) was summarized, with a special focus on their potential as therapeutic agents for malignant melanoma.
Topics: Humans; Terpenes; Limonene; Antineoplastic Agents; Melanoma; Skin Neoplasms; Melanoma, Cutaneous Malignant
PubMed: 37515699
DOI: 10.1007/s43440-023-00512-1