The cannabinoid beta-caryophyllene (BCP) induces neuritogenesis in PC12 cells by a cannabinoid-receptor-independent mechanism

Santos, Neife Aparecida Guinaim dos; Martins, Nádia Maria; Sisti, F; Fernandes, Liliam; Ferreira, Rafaela Scalco; Freitas, Osvaldo de; Santos, Antônio Cardozo dos

doi:10.1016/j.cbi.2016.11.015

Cited by 24 publications

(8 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These phytochemicals have attracted greater attention by researchers due to their multitarget and pleiotropic bioactivities along with a safety profile [43][44][45]. 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].…”

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

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

show abstract

“…BCP can induce neurogenesis with a mechanism independent from the activation of CB2-R, Nrf2 and NGF, stimulating Tropomyosin receptor kinase A (TrkA) in SH-SY5Y (Cell lines Homo sapiens, human, bone marrow) and PC12 (Cell line derived from a pheochromocytoma of the rat adrenal medulla) neuroblastoma cells [34].…”

Section: β-Caryophyllene and Nervous Systemmentioning

confidence: 99%

β-Caryophyllene: A Sesquiterpene with Countless Biological Properties

et al. 2019

View full text Add to dashboard Cite

β-Caryophyllene (BCP), a natural bicyclic sesquiterpene, is a selective phytocannabinoid agonist of type 2 receptors (CB2-R). It isn’t psychogenic due to the absence of an affinity to cannabinoid receptor type 1 (CB1). Among the various biological activities, BCP exerts anti-inflammatory action via inhibiting the main inflammatory mediators, such as inducible nitric oxide synthase (iNOS), Interleukin 1 beta (IL-1β), Interleukin-6 (IL-6), tumor necrosis factor-alfa (TNF-α), nuclear factor kapp a-light-chain-enhancer of activated B cells (NF-κB), cyclooxygenase 1 (COX-1), cyclooxygenase 2 (COX-2). Peroxisome proliferator-activated receptors alpha (PPAR-α) effects are also mediated by the activation of PPAR-α and PPAR-γ receptors. In detail, many studies, in vitro and in vivo, suggest that the treatment with β-caryophyllene improves the phenotype of animals used to model various inflammatory pathologies, such as nervous system diseases (Parkinson’s disease, Alzheimer’s disease, multiple sclerosis, amyotrophic lateral sclerosis, stroke), atherosclerosis, and tumours (colon, breast, pancreas, lymphoma, melanoma and glioma cancer). Furthermore, pre-clinical data have highlighted that BCP is potentially useful in Streptococcus infections, osteoporosis, steatohepatitis, and exerts anticonvulsant, analgesic, myorelaxing, sedative, and antidepressive effects. BCP is non-toxic in rodents, with a Lethal dose, 50% (LD50) greater than 5000 mg/kg. Nevertheless, it inhibits various cytochrome P450 isoforms (above all, CYP3A4), which metabolise xenobiotics, leading to adverse effects, due to drug levels over therapeutic window. All the reported data have highlighted that both pharmacological and toxicological aspects need to be further investigated with clinical trials.

show abstract

“…It also down‐regulated Bax and matrix metallopeptidase 9 (MMP‐9) expression, while up‐regulating claudin‐5, occludin, zonula occludens‐1 (ZO‐1), growth associated protein 43 (GAP‐43), and Bcl‐2 expression (Tian et al, ). Recently, BCAR at 0.5, 1.0, 1.5, and 2.0 μM, was found to activate trka receptors and induce neuritogenesis by a mechanism independent of nerve growth factor or cannabinoid receptors in PC12 and SH‐SY5Y neuroblastoma cells (Santos et al, ).…”

Section: Neuropharmacological Effects Of β‐Caryophyllenementioning

confidence: 99%

A systematic review on the neuroprotective perspectives of beta‐caryophyllene

Machado

Islam

Ali

et al. 2018

Phytotherapy Research

100

View full text Add to dashboard Cite

Beta (β)-caryophyllene (BCAR) is a major sesquiterpene of various plant essential oils reported for several important pharmacological activities, including antioxidant, anti-inflammatory, anticancer, cardioprotective, hepatoprotective, gastroprotective, nephroprotective, antimicrobial, and immune-modulatory activity. Recent studies suggest that it also possesses neuroprotective effect. This study reviews published reports pertaining to the neuropharmacological activities of BCAR. Databases such as PubMed, Scopus, MedLine Plus, and Google Scholar with keywords "beta (β)-caryophyllene" and other neurological keywords were searched. Data were extracted by referring to articles with information about the dose or concentration/route of administration, test system, results and discussion, and proposed mechanism of action. A total of 545 research articles were recorded, and 41 experimental studies were included in this review, after application of exclusion criterion. Search results suggest that BCAR exhibits a protective role in a number of nervous system-related disorders including pain, anxiety, spasm, convulsion, depression, alcoholism, and Alzheimer's disease.Additionally, BCAR has local anesthetic-like activity, which could protect the nervous system from oxidative stress and inflammation and can act as an immunomodulatory agent. Most neurological activities of this natural product have been linked with the cannabinoid receptors (CBRs), especially the CB2R. This review suggests a possible application of BCAR as a neuroprotective agent.

show abstract

The cannabinoid beta-caryophyllene (BCP) induces neuritogenesis in PC12 cells by a cannabinoid-receptor-independent mechanism

Cited by 24 publications

References 37 publications

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

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: A Sesquiterpene with Countless Biological Properties

A systematic review on the neuroprotective perspectives of beta‐caryophyllene

Contact Info

Product

Resources

About