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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 -
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 -
Brazilian Oral Research 2022This study evaluated the orofacial antinociceptive effect of (S)-(-)-perillyl alcohol (PA) associated with codeine (C) and investigated the possible molecular anchorage...
This study evaluated the orofacial antinociceptive effect of (S)-(-)-perillyl alcohol (PA) associated with codeine (C) and investigated the possible molecular anchorage mechanisms of PA. Mice (n = 5 per group) were treated with PA alone and associated with codeine and assigned to the following groups: 75.0 mg/kg PA; 75.0 mg/kg PA + C 30 mg/kg; PA 37.5 mg/kg + C 15.0 mg/kg; C 30.0 mg/kg; and control. Nociception was induced by formalin, capsaicin, and glutamate, and was quantified based on the duration (in seconds) of face grooming. The possible mechanisms of action were evaluated by molecular docking study. In the formalin test, PA75/C30 presented an effect in the neurogenic (p < 0.0001) and inflammatory (p < 0.005) phases. Mice treated with PA75 (p < 0.0001) and PA75/C30 (p < 0.0005) showed a reduced nociceptive behavior in the capsaicin test. Glutamate-induced nociception also was blocked by PA75 (p < 0.0005) and C30 (p < 0.0005). The molecular anchorage analysis indicated high negative binding energy values for the evaluated receptors, especially glutamate receptors (AMPA -79.57 Kcal/mol, mGLUR6 -71.25, and NMDA -66.33 Kcal/mol). PA associated with codeine showed orofacial antinociceptive activity, with theoretical evidence of interaction with glutamate receptors.
Topics: Analgesics; Animals; Capsaicin; Codeine; Facial Pain; Glutamic Acid; Mice; Molecular Docking Simulation; Monoterpenes; Receptors, Glutamate
PubMed: 35946737
DOI: 10.1590/1807-3107bor-2022.vol36.0109 -
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 -
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 -
Oncotarget May 2023
Topics: Humans; Blood-Brain Barrier; Groin; Brain; Glioma; Brain Neoplasms; Monoterpenes
PubMed: 37141417
DOI: 10.18632/oncotarget.28414 -
Antimicrobial Agents and Chemotherapy May 2023Cerebral malaria (CM) is a severe immunovasculopathy which presents high mortality rate (15-20%), despite the availability of artemisinin-based therapy. More effective...
Cerebral malaria (CM) is a severe immunovasculopathy which presents high mortality rate (15-20%), despite the availability of artemisinin-based therapy. More effective immunomodulatory and/or antiparasitic therapies are urgently needed. Experimental Cerebral Malaria (ECM) in mice is used to elucidate aspects involved in this pathology since manifests many of the neurological features of CM. In the present study, we evaluated the potential mechanisms involved in the protection afforded by perillyl alcohol (POH) in mouse strains susceptible to CM caused by ANKA (PbA) infection through intranasal preventive treatment. Additionally, to evaluate the interaction of POH with the cerebral endothelium using an model of human brain endothelial cells (HBEC). Pharmacokinetic approaches demonstrated constant and prolonged levels of POH in the plasma and brain after a single intranasal dose. Treatment with POH effectively prevented vascular dysfunction. Furthermore, treatment with POH reduced the endothelial cell permeability and PbA s in the brain and spleen. Finally, POH treatment decreased the accumulation of macrophages and T and B cells in the spleen and downregulated the expression of endothelial adhesion molecules (ICAM-1, VCAM-1, and CD36) in the brain. POH is a potent monoterpene that prevents cerebrovascular dysfunction and decreases parasite sequestration, and modulates different processes related to the activation, permeability, and integrity of the blood brain barrier (BBB), thereby preventing cerebral oedema and inflammatory infiltrates.
PubMed: 33649109
DOI: 10.1128/AAC.00004-21