β-Caryophyllene promotes oxidative stress and apoptosis in KB cells through activation of mitochondrial-mediated pathway – An <i>in-vitro</i> and <i>in-silico</i> study

Duraisamy, Revathi; Sankaranarayanan, Chandrasekaran; Murali, Raju; Babukumar, Sukumar; Vinothkumar, Veerasamy

doi:10.1080/13813455.2019.1669057

Cited by 21 publications

(29 citation statements)

References 76 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…β-caryophyllene induced a significant ROS-increase in cancer cells and a marked upregulation of GSH defenses, especially after 24 h exposure, without affecting cell viability: this could be ascribed to a perturbation of cell biomembrane homeostasis, due to the high lipophilicity of the sesquiterpene. Indeed, β-caryophyllene is known to possess a great capacity to alter phospholipid cooperativity, membrane permeability and protein functions [45,81], which in turn can lead to cell morphology changes and increased of intracellular oxidative stress [46].…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, it produces cytoprotective effects by modulating oxidative stress, apoptosis and inflammation [38][39][40][41], through the interference with different inflammatory pathways, such as the inducible nitric oxide synthase (iNOS), tumor necrosis factor-alfa (TNF-α) and nuclear factor-κB (NF-κB) [37]. Also, it exhibited chemopreventive properties, such as genoprotective and antiproliferative ones, by inhibiting DNA damage and STAT3 (signal transducer and activator of transcription 3) activation induced by environmental pollutants [31,32,42,43] and through affecting multiple cascades involved in cancer growth [37,[44][45][46][47]. Similar properties have been also reported for the metabolite β-caryophyllene oxide [48,49].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Modulation of STAT3 Signaling, Cell Redox Defenses and Cell Cycle Checkpoints by β-Caryophyllene in Cholangiocarcinoma Cells: Possible Mechanisms Accounting for Doxorubicin Chemosensitization and Chemoprevention

Sotto

Giacomo

Rubini

et al. 2020

Cells

View full text Add to dashboard Cite

Cholangiocarcinoma (CCA) is an aggressive group of biliary tract cancers, characterized by late diagnosis, low effective chemotherapies, multidrug resistance, and poor outcomes. In the attempt to identify new therapeutic strategies for CCA, we studied the antiproliferative activity of a combination between doxorubicin and the natural sesquiterpene β-caryophyllene in cholangiocarcinoma Mz-ChA-1 cells and nonmalignant H69 cholangiocytes, under both long-term and metronomic schedules. The modulation of STAT3 signaling, oxidative stress, DNA damage response, cell cycle progression and apoptosis was investigated as possible mechanisms of action. β-caryophyllene was able to synergize the cytotoxicity of low dose doxorubicin in Mz-ChA-1 cells, while producing cytoprotective effects in H69 cholangiocytes, mainly after a long-term exposure of 24 h. The mechanistic analysis highlighted that the sesquiterpene induced a cell cycle arrest in G2/M phase along with the doxorubicin-induced accumulation in S phase, reduced the γH2AX and GSH levels without affecting GSSG. ROS amount was partly lowered by the combination in Mz-ChA-1 cells, while increased in H69 cells. A lowered expression of doxorubicin-induced STAT3 activation was found in the presence of β-caryophyllene in both cancer and normal cholangiocytes. These networking effects resulted in an increased apoptosis rate in Mz-ChA-1 cells, despite a lowering in H69 cholangiocytes. This evidence highlighted a possible role of STAT3 as a final effector of a complex network regulated by β-caryophyllene, which leads to an enhanced doxorubicin-sensitivity of cholangiocarcinoma cells and a lowered chemotherapy toxicity in nonmalignant cholangiocytes, thus strengthening the interest for this natural sesquiterpene as a dual-acting chemosensitizing and chemopreventive agent.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Modulation of STAT3 Signaling, Cell Redox Defenses and Cell Cycle Checkpoints by β-Caryophyllene in Cholangiocarcinoma Cells: Possible Mechanisms Accounting for Doxorubicin Chemosensitization and Chemoprevention

Sotto

Giacomo

Rubini

et al. 2020

Cells

View full text Add to dashboard Cite

show abstract

“…Accordingly, β-caryophyllene is known to bind to the CB2 receptor as an agonist and to induce anti-inflammatory, analgesic and neuroprotective effects [46][47][48]. Furthermore, both sesquiterpenes have been highlighted to possess interesting chemopreventing properties, due to their ability to counteract cell injury induced by environmental pollutants [49][50][51][52] and to inhibit cancer cell growth and proliferation, through affecting several key pathways for cancer development, such as mitogen-activated protein kinase (MAPK), PI3K/AKT/mTOR/S6K1 and STAT3 pathways [47,[53][54][55][56]. Also, they were reported to potentiate the efficacy of some anticancer drugs, acting as chemosensitizers [15][16][17]19,20].…”

Section: Discussionmentioning

confidence: 99%

Potentiation of Low-Dose Doxorubicin Cytotoxicity by Affecting P-Glycoprotein through Caryophyllane Sesquiterpenes in HepG2 Cells: an in Vitro and in Silico Study

Sotto

Irannejad

Eufemi

et al. 2020

IJMS

View full text Add to dashboard Cite

Doxorubicin represents a valuable choice for different cancers, although the severe side effects occurring at the high effective dose limits its clinical use. In the present study, potential strategies to potentiate low-dose doxorubicin efficacy, including a metronomic schedule, characterized by a short and repeated exposure to the anticancer drug, and the combination with the natural chemosensitizing sesquiterpenes β-caryophyllene and β-caryophyllene oxide, were assessed in human hepatoma HepG2 cells. The involvement of P-glycoprotein (P-gp) in the HepG2-chemosensitization to doxorubicin was evaluated. Also, the direct interaction of caryophyllene sesquiterpenes with P-gp was characterized by molecular docking and dynamic simulation studies. A metronomic schedule allowed us to enhance the low-dose doxorubicin cytotoxicity and the combination with caryophyllane sesquiterpenes further potentiated this effect. Also, an increased intracellular accumulation of doxorubicin and rhodamine 123 induced by caryophyllane sesquiterpenes was found, thus suggesting their interference with P-gp function. A lowered expression of P-gp induced by the combinations, with respect to doxorubicin alone, was observed too. Docking studies found that the binding site of caryophyllane sesquiterpene was next to the ATP binding domain of P-gp and that β-caryophyllene possessed the stronger binding affinity and higher inhibition potential calculated by MM-PBSA. Present findings strengthen our hypothesis about the potential chemosensitizing power of caryophyllane sesquiterpenes and suggest that combining a chemosensitizer and a metronomic schedule can represent a suitable strategy to overcome drawbacks of doxorubicin chemotherapy while exploiting its powerful activity.Int. J. Mol. Sci. 2020, 21, 633 2 of 28 Int. J. Mol. Sci. 2020, 21, 633 5 of 28 oxide were selected for the combination experiments. Under our experimental conditions, both the sesquiterpenes were able to potentiate the effect of doxorubicin in different experimental conditions, although with different profiles. Particularly, after 24 h exposure, the lower chemosensitizing concentration (50 µM) of β-caryophyllene significantly enhanced the doxorubicin-cytotoxicity starting from the concentration of 10 µM, achieving almost the maximum potentiation of about 32% at concentration of 20 µM (Figure 2a).

show abstract

“…β-caryophyllene is a natural CB2 receptor agonist that potentially inhibits cell survival proteins [11] and also modulates the activation of NFκB and PPARγ; thus, it has been tested to reduce proliferation and activate apoptosis in glioblastoma. To investigate this issue, U373 and U87 cells were used: U373 is a human glioblastoma cell line with a p53 mutation in codon 273 of the p53 gene and cannot Cancers 2020, 12, 1038 9 of 14 transactivate a reporter gene containing a p53-responsive transcriptional promoter, eventually causing tumor progression for p53 loss of function [14].…”

Section: Discussionmentioning

confidence: 99%

β-Caryophyllene Inhibits Cell Proliferation through a Direct Modulation of CB2 Receptors in Glioblastoma Cells

Irrera

D’Ascola

Pallio

et al. 2020

Cancers

View full text Add to dashboard Cite

Glioblastomas are aggressive cancers characterized by uncontrolled proliferation and inflammation. b-caryophyllene (BCP) is a cannabinoid receptor 2 (CB2) agonist that showed an important anti-inflammatory effect through the interaction of CB2 and peroxisome proliferator-activated receptor gamma (PPARg) receptors. BCP effects were investigated in an in vitro model of glioblastoma. U-373 and U87, derived from a human glioblastoma, and human glioma stem-like cells (GSCs) were treated with BCP at different doses and time-points. AM360, a specific CB2 antagonist, was added 2 h before BCP treatment. BCP showed a significant anti-proliferative effect, reducing cell viability, inhibiting cell cycle, and increasing apoptosis, as demonstrated by Tunel assay, caspase-3 and caspase -9 activation. In addition, the pro-apoptotic BAX expression was increased, whereas the anti-apoptotic Bcl-2 expression was reduced. Treatment with BCP decreased Beclin-1, LC3 and p62/SQSTM1 expression, indicating a possible switch of autophagy to apoptosis. BCP’s anti-inflammatory effect was demonstrated by NF-κB reduction, PPARg activation and TNF-a decrease; BCP significantly reduced Jun N-Terminal Kinase (JNK) expression as a consequence of TNF-α inhibition. AM360 abrogated BCP effects, thus demonstrating the BCP mechanism of action through the CB2 receptor. These findings let us hypothesize that BCP may act as a tumor suppressor in glioblastoma, acting on CB2 receptor and modulating JNK.

show abstract

β-Caryophyllene promotes oxidative stress and apoptosis in KB cells through activation of mitochondrial-mediated pathway – An in-vitro and in-silico study

Cited by 21 publications

References 76 publications

Modulation of STAT3 Signaling, Cell Redox Defenses and Cell Cycle Checkpoints by β-Caryophyllene in Cholangiocarcinoma Cells: Possible Mechanisms Accounting for Doxorubicin Chemosensitization and Chemoprevention

Modulation of STAT3 Signaling, Cell Redox Defenses and Cell Cycle Checkpoints by β-Caryophyllene in Cholangiocarcinoma Cells: Possible Mechanisms Accounting for Doxorubicin Chemosensitization and Chemoprevention

Potentiation of Low-Dose Doxorubicin Cytotoxicity by Affecting P-Glycoprotein through Caryophyllane Sesquiterpenes in HepG2 Cells: an in Vitro and in Silico Study

β-Caryophyllene Inhibits Cell Proliferation through a Direct Modulation of CB2 Receptors in Glioblastoma Cells

Contact Info

Product

Resources

About