The effects of β-caryophyllene oxide and trans-nerolidol on the efficacy of doxorubicin in breast cancer cells and breast tumor-bearing mice

Hanušová, Veronika; Caltová, Kateřina; Svobodová, Hana; Ambrož, Martin; Skarka, Adam; Murínová, Natálie; Králová, Věra; Tomšík, Pavel; Skálová, Lenka

doi:10.1016/j.biopha.2017.09.008

Cited by 59 publications

(42 citation statements)

References 25 publications

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“…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%

“…Accordingly, we previously highlighted that the natural sesquiterpenes β-caryophyllene and its metabolite β-caryophyllene oxide produced chemosensitizing effects in different combined anticancer protocols [15,16]. β-caryophyllene was also reported to potentiate the antiproliferative activity of paclitaxel [17], whereas β-caryophyllene oxide improved the cytotoxic and pro-apoptotic effects of paclitaxel and doxorubicin in human myeloma and human prostate cancer cells [18] and synergized doxorubicin in the inhibition of breast cancer cell proliferation [19]. Furthermore, β-caryophyllene oxide was found able to enhance the antiproliferative effects of 5-fluorouracil and oxaliplatin in colon cancer cell lines, partly by the disruption of mitochondrial membrane potential and activation of initiator caspases [20].…”

Section: Introductionmentioning

confidence: 99%

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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

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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).

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

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

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“…Activated the JAK1/STAT3 pathway [153,155]. Enhanced doxorubicin sensitivity [155][156][157][158][159].…”

Section: β-Caryophyllene and Metabolite Caryophyllene Oxidementioning

confidence: 99%

Anti-Cancer Potential of Cannabinoids, Terpenes, and Flavonoids Present in Cannabis

Tomko

Whynot

Ellis

et al. 2020

Cancers

135

136

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In recent years, and even more since its legalization in several jurisdictions, cannabis and the endocannabinoid system have received an increasing amount of interest related to their potential exploitation in clinical settings. Cannabinoids have been suggested and shown to be effective in the treatment of various conditions. In cancer, the endocannabinoid system is altered in numerous types of tumours and can relate to cancer prognosis and disease outcome. Additionally, cannabinoids display anticancer effects in several models by suppressing the proliferation, migration and/or invasion of cancer cells, as well as tumour angiogenesis. However, the therapeutic use of cannabinoids is currently limited to the treatment of symptoms and pain associated with chemotherapy, while their potential use as cytotoxic drugs in chemotherapy still requires validation in patients. Along with cannabinoids, cannabis contains several other compounds that have also been shown to exert anti-tumorigenic actions. The potential anti-cancer effects of cannabinoids, terpenes and flavonoids, present in cannabis, are explored in this literature review.

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“…A study has also shown the immunomodulatory actions of trans-nerolidol on the efficacy of doxorubicin in breast cancer cells and in a breast tumor mouse model. The compound increased doxorubicin accumulation into MDA-MB-231 and MCF7 breast cancer cells while blocked cell migration ability, in vitro [216]. In addition, nerolidol demonstrated positive effects on cyclophosphamide (CYP)-induced neuroinflammation, oxidative stress, and cognitive impairment, as well as prevented structural abnormalities in the hippocampus and cortex regions of rodents [217].…”

Section: Nerolidolmentioning

confidence: 94%

Terpenoids, Cannabimimetic Ligands, beyond the Cannabis Plant

et al. 2020

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Medicinal use of Cannabis sativa L. has an extensive history and it was essential in the discovery of phytocannabinoids, including the Cannabis major psychoactive compound—Δ9-tetrahydrocannabinol (Δ9-THC)—as well as the G-protein-coupled cannabinoid receptors (CBR), named cannabinoid receptor type-1 (CB1R) and cannabinoid receptor type-2 (CB2R), both part of the now known endocannabinoid system (ECS). Cannabinoids is a vast term that defines several compounds that have been characterized in three categories: (i) endogenous, (ii) synthetic, and (iii) phytocannabinoids, and are able to modulate the CBR and ECS. Particularly, phytocannabinoids are natural terpenoids or phenolic compounds derived from Cannabis sativa. However, these terpenoids and phenolic compounds can also be derived from other plants (non-cannabinoids) and still induce cannabinoid-like properties. Cannabimimetic ligands, beyond the Cannabis plant, can act as CBR agonists or antagonists, or ECS enzyme inhibitors, besides being able of playing a role in immune-mediated inflammatory and infectious diseases, neuroinflammatory, neurological, and neurodegenerative diseases, as well as in cancer, and autoimmunity by itself. In this review, we summarize and critically highlight past, present, and future progress on the understanding of the role of cannabinoid-like molecules, mainly terpenes, as prospective therapeutics for different pathological conditions.

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The effects of β-caryophyllene oxide and trans-nerolidol on the efficacy of doxorubicin in breast cancer cells and breast tumor-bearing mice

Cited by 59 publications

References 25 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

Anti-Cancer Potential of Cannabinoids, Terpenes, and Flavonoids Present in Cannabis

Terpenoids, Cannabimimetic Ligands, beyond the Cannabis Plant

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