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Molecular and Cellular Biochemistry Jan 2016Cell metastasis, especially the process of invasion and migration, is considered as the main cause for the high mortality rate of hepatocellular carcinoma (HCC), which...
Cell metastasis, especially the process of invasion and migration, is considered as the main cause for the high mortality rate of hepatocellular carcinoma (HCC), which has become the sixth most common cancer worldwide and the third leading cause of cancer death. In this present study, we aimed to exploit the effects of perillyl alcohol on cell invasion and migration and the underlying molecular mechanisms in HCC. According to the transwell assays, cell invasiveness and migratory capacity were markedly higher in hepatoma cells (HepG2, SMMC-7721 and MHCC97H) than those in normal liver cells (HL-7702), and then significantly suppressed by perillyl alcohol treatment (P < 0.05). Meanwhile, the mRNA levels of Notch signaling pathway downstream target genes, HES1, HES5, and HEY1, were notably higher in hepatoma cells detected with real-time reverse transcription polymerase chain reaction (RT-PCR) (P < 0.05). After treated with perillyl alcohol, these mRNA levels were significantly decreased in hepatoma cells (P < 0.05). In addition, compared with the normal liver cells, the protein expression levels of Notch1 intracellular domain (N1ICD) and Snail were significantly increased, while E-cadherin protein expression was significantly decreased in hepatoma cells (P < 0.05). However, perillyl alcohol treatment significantly decreased N1ICD and Snail protein expressions and increased E-cadherin protein expression in hepatoma cells (P < 0.05). In conclusion, perillyl alcohol might play an important role in the process of hepatoma cell invasion and migration via decreasing the activity of Notch signaling pathway and increasing E-cadherin expression regulated by Snail.
Topics: Carcinoma, Hepatocellular; Cell Line, Tumor; Humans; Liver Neoplasms; Monoterpenes; Neoplasm Invasiveness; Neoplasm Metastasis; Receptors, Notch; Signal Transduction
PubMed: 26475687
DOI: 10.1007/s11010-015-2593-x -
Infectious Disorders Drug Targets 2020Considering the emergence of multidrug resistance (MDR) in prevalent human fungal pathogen, Candida albicans, there is parallel spurt in the development of novel...
Lipidomic Insight of Anticandidal Perillyl Alcohol and Sesamol Induced Candida Membrane Disruption: Implications of Lipid Alteration, Impaired Fluidity and Flippase Activity.
BACKGROUND
Considering the emergence of multidrug resistance (MDR) in prevalent human fungal pathogen, Candida albicans, there is parallel spurt in the development of novel strategies aimed to disrupt MDR. The cell envelope of C. albicans comprises a wealth of lipid moieties contributing towards long-term survival of pathogen that could be exploited as efficient antifungal target owing to the advancements made in mass spectrometry based lipidomics technology.
OBJECTIVE
This study aimed to utilize the lipidomics approach to unveil several lipid-associated changes in response to two natural anticandidal compounds perillyl alcohol (PA) and sesamol (Ses).
METHODS
Lipidomics is performed through ESI-MS, flippase activity by FACS, fluorescence spectrometric analysis is used to assess membrane fluidity.
RESULTS
Lipidomic analyses revealed that phosphatidylcholine (PtdCho) were decreased in the presence of Ses with considerable differences at specie level. Concurrently, we explored increased inward translocation (flip) of fluorophore labelled PtdCho across the plasma membrane attributed to enhanced PtdCho specific flippase activity. A considerable decrement in phosphatidylethanolamine (PtdEtn) leading to altered membrane fluidity was observed in response to PA and Ses. Additionally, we could detect alteration in the levels of phohatidylserine (PtdSer) and phosphatidylglycerol (PtdGro) along with decreased triacylglycerides (TAG). The differential expressions of various lipid biosynthetic pathway genes by RT-PCR corroborated with the lipidomics data. Furthermore, PA and Ses leads to potentiation of membrane targeting drugs (azole and polyene) and displayed additive effect.
CONCLUSION
Our work offers the basis of further understanding the regulation of lipid homeostasis in C. abicans so that better therapeutic targets could be identified to combat MDR.
Topics: Benzodioxoles; Candida; Humans; Lipidomics; Lipids; Monoterpenes; Phenols
PubMed: 31657691
DOI: 10.2174/1871526519666191023125020 -
Molecules (Basel, Switzerland) May 2014Two series of amino-modified derivatives of (S)-perillyl alcohol were designed and synthesized using (S)-perillaldehyde as the starting material. These derivatives...
Two series of amino-modified derivatives of (S)-perillyl alcohol were designed and synthesized using (S)-perillaldehyde as the starting material. These derivatives showed increased antiproliferative activity in human lung cancer A549 cells, human melanoma A375-S2 cells and human fibrosarcoma HT-1080 cells comparing with that of (S)-perillyl alcohol. Among these derivatives, compounds VI5 and VI7 were the most potent agents, with the IC50s below 100 μM. It was demonstrated that the antiproliferative effect of VI5 was mediated through the induction of apoptosis in A549 cells.
Topics: Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Chemistry Techniques, Synthetic; Drug Screening Assays, Antitumor; Humans; Monoterpenes; Structure-Activity Relationship
PubMed: 24858099
DOI: 10.3390/molecules19056671 -
Journal of Medicinal Chemistry Sep 2014A facile route to perillyl alcohol (POH) differential glycosylation and the corresponding synthesis of a set of 34 POH glycosides is reported. Subsequent in vitro...
A facile route to perillyl alcohol (POH) differential glycosylation and the corresponding synthesis of a set of 34 POH glycosides is reported. Subsequent in vitro studies revealed a sugar dependent antiproliferative activity and the inhibition of S6 ribosomal protein phosphorylation as a putative mechanism of representative POH glycosides. The most active glycoside from this cumulative study (4'-azido-d-glucoside, PG9) represents one of the most cytotoxic POH analogues reported to date.
Topics: Adaptor Proteins, Signal Transducing; Antineoplastic Agents; Blotting, Western; Cell Cycle Proteins; Cell Line, Tumor; Cell Proliferation; Cell Survival; Dose-Response Relationship, Drug; Glycosides; Humans; Inhibitory Concentration 50; Models, Chemical; Molecular Structure; Monoterpenes; Phosphoproteins; Phosphorylation
PubMed: 25121720
DOI: 10.1021/jm500870u -
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 -
Breast Cancer Research and Treatment Apr 2004The effect of monoterpene perillyl alcohol (POH) on cell growth, cell cycle progression, and expression of cell cycle-regulatory proteins in estrogen receptor...
The effect of monoterpene perillyl alcohol (POH) on cell growth, cell cycle progression, and expression of cell cycle-regulatory proteins in estrogen receptor (ER)-positive (KPL-1 and MCF-7) and ER-negative (MKL-F and MDA-MB-231) human breast cancer cell lines was examined. POH inhibited cell proliferation in a dose-dependent manner in all cell lines tested. POH at a dose of 500 micro M had a cytostatic effect, in which growth inhibition was due to accumulation of cells in G1-phase. Cell cycle progression was preceded by a decrease in G1 cyclins (cyclin D1 and E), followed by an increase in p21(Cip1/Waf1) and a decrease in proliferating cell nuclear antigen level. Levels of p53 and cyclin A were unchanged. POH at a dose of 75 mg/kg administered intraperitoneally three times a week throughout the entire 6-week experimental period suppressed orthotopically transplanted KPL-1 tumor cell growth and regional lymph node metastasis in a nude mouse system. POH inhibited both ER-positive and -negative human breast cancer cell growth in vitro, and suppressed growth and metastasis in vivo.
Topics: Animals; Antineoplastic Agents; Blotting, Western; Breast Neoplasms; Cell Cycle; Cyclins; Dose-Response Relationship, Drug; Female; Humans; Immunohistochemistry; Infusions, Parenteral; Mice; Mice, Nude; Monoterpenes; Neoplasm Metastasis; Proliferating Cell Nuclear Antigen; Receptors, Estrogen; Tumor Cells, Cultured
PubMed: 15026623
DOI: 10.1023/B:BREA.0000019966.97011.4d -
Cancers Jul 2021Despite progress in the treatment of acute myeloid leukemia (AML), the clinical outcome remains suboptimal and many patients are still dying from this disease....
Despite progress in the treatment of acute myeloid leukemia (AML), the clinical outcome remains suboptimal and many patients are still dying from this disease. First-line treatment consists of chemotherapy, which typically includes cytarabine (AraC), either alone or in combination with anthracyclines, but drug resistance can develop and significantly worsen prognosis. Better treatments are needed. We are developing a novel anticancer compound, NEO212, that was created by covalent conjugation of two different molecules with already established anticancer activity, the alkylating agent temozolomide (TMZ) and the natural monoterpene perillyl alcohol (POH). We investigated the anticancer activity of NEO212 in several in vitro and in vivo models of AML. Human HL60 and U937 AML cell lines, as well as different AraC-resistant AML cell lines, were treated with NEO212 and effects on cell proliferation, cell cycle, and cell death were investigated. Mice with implanted AraC-sensitive or AraC-resistant AML cells were dosed with oral NEO212, and animal survival was monitored. Our in vitro experiments show that treatment of cells with NEO212 results in growth inhibition via potent G2 arrest, which is followed by apoptotic cell death. Intriguingly, NEO212 was equally potent in highly AraC-resistant cells. In vivo, NEO212 treatment strikingly extended survival of AML mice and the majority of treated mice continued to thrive and survive without any signs of illness. At the same time, we were unable to detect toxic side effects of NEO212 treatment. All in all, the absence of side effects, combined with striking therapeutic activity even in an AraC-resistant context, suggests that NEO212 should be developed further toward clinical testing.
PubMed: 34298603
DOI: 10.3390/cancers13143385 -
Oncotarget May 2023
Topics: Humans; Blood-Brain Barrier; Groin; Brain; Glioma; Brain Neoplasms; Monoterpenes
PubMed: 37141417
DOI: 10.18632/oncotarget.28414 -
Life Sciences Oct 2003The role of the monoterpenes, especially limonene and perillyl alcohol, in the treatment of certain cancers is currently being evaluated in clinical trials. In this...
The role of the monoterpenes, especially limonene and perillyl alcohol, in the treatment of certain cancers is currently being evaluated in clinical trials. In this study, the effects of perillyl alcohol (POH) and its analog, perillaldehyde (PALD), on human carcinoma cell lines (BroTo and A549) cultured in vitro were investigated using proliferation assays (MTT and colony formation) and DNA content analysis by flow cytometry. POH and PALD elicited dose- and time-dependent inhibition of proliferation in both cell lines. Concentrations of POH and PALD that inhibited cell proliferation by 50% (IC50) in 24 hr were 1 and 3 mM, respectively. DNA content analysis revealed that 1 mM of either POH or PALD caused cell cycle arrest in the G1 phase in both cell lines while POH alone caused increased hypodiploid and annexin V-positive populations in both BroTo and A549 cells. POH induced apoptosis and was more effective than PALD at inhibiting the proliferation of BroTo and A549 cells cultured in vitro.
Topics: Adenocarcinoma; Apoptosis; Carcinoma, Squamous Cell; Cell Cycle; Cell Death; Cell Line; Head and Neck Neoplasms; Humans; Indicators and Reagents; Lung Neoplasms; Monoterpenes; Oxidoreductases; Phosphatidylserines; Tumor Cells, Cultured; Tumor Stem Cell Assay
PubMed: 14511768
DOI: 10.1016/s0024-3205(03)00701-x -
Toxicology Jan 2011Oxidative stress and inflammation are two major etiological factors that are suggested to play key roles in the development of ethanol induced liver injury. Release of...
Perillyl alcohol protects against ethanol induced acute liver injury in Wistar rats by inhibiting oxidative stress, NFκ-B activation and proinflammatory cytokine production.
Oxidative stress and inflammation are two major etiological factors that are suggested to play key roles in the development of ethanol induced liver injury. Release of proinflammatory cytokine like tumor necrosis factor alpha (TNF-α) and activation of nuclear factor kappa-B (NFκ-B) may strongly intensify inflammation and cell damage. Additionally, reactive oxygen species (ROS) also exerts significant effect in this whole cell signaling machinery. The present study was designed to investigate the protective effects of perillyl alcohol (POH) on ethanol-induced acute liver injury in Wistar rats and its probable mechanism. We have successfully demonstrated that pre-treatment with POH, besides exerting antioxidant activity might be able to modulate TNF-α release and NFκ-B activation. Rats were divided into five groups and treated with ethanol or POH via an intragastric tube for one week. Control group was treated with vehicle, and ethanol treated group was given ethanol (5 g/kg body wt). Animal of treatment groups were pretreated with POH (50 & 100 mg/kg body wt) and have been given ethanol. Serum aspartate aminotransferase, alanine aminotransferase and lactate dehydrogenase and hepatic malondialdehyde were increased significantly by ethanol treatment. Ethanol administration decreased hepatic reduced glutathione content and various antioxidant enzymes activity. TNF-α production and NFκ-B activation was also found to be increased after ethanol administration. POH pre-treatment significantly ameliorates ethanol induced acute liver injury possibly by inhibition of lipid peroxidation, replenishment of endogenous enzymatic and non-enzymatic defense system, downregulation of TNF-α as well as NFκ-B.
Topics: Animals; Chemical and Drug Induced Liver Injury; Cytokines; Dose-Response Relationship, Drug; Down-Regulation; Enzyme Inhibitors; Ethanol; Inflammation Mediators; Lipid Peroxidation; Male; Monoterpenes; NF-kappa B; Oxidative Stress; Rats; Rats, Wistar; Tumor Necrosis Factor-alpha
PubMed: 20923693
DOI: 10.1016/j.tox.2010.09.017