Sesquiterpenes α-humulene and β-caryophyllene oxide enhance the efficacy of 5-fluorouracil and oxaliplatin in colon cancer cells

Ambrož, Martin; Šmatová, Markéta; Šadibolová, Michaela; Pospíšilová, Eva; Hadravská, Pavlína; Kašparová, Michaela; Skarkova, Veronika; Králová, Věra; Skálová, Lenka

doi:10.2478/acph-2019-0003

Cited by 41 publications

(43 citation statements)

References 13 publications

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“…The doxorubicin chemosensitization by β-caryophyllene in cholangiocarcinoma cells is in agreement with our previous evidence in HepG2 [26]. Similarly, β-caryophyllene oxide produced synergistic effects towards doxorubicin and other anticancer drugs in liver, breast, leukemic and colon cancer cells [24][25][26][72][73][74]. Interestingly, doxorubicin-chemosensitization by β-caryophyllene occurred after both a long-term exposure of 24 h and under the metronomic schedules, like in HepG2 cells [26].…”

Section: Discussionsupporting

confidence: 89%

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

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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.

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Section: Discussionsupporting

confidence: 89%

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

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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%

“…For evaluating the chemosensitizing properties, the anticancer drug and the chemosensitizing agents were administered to cells according to the co-treatment protocol. Two non-cytotoxic concentrations of the sesquiterpenes (about IC 10 and IC 20 concentrations, at which a 10% and 20% cytotoxicity was produced) were tested. Progressive concentrations of the anticancer drug were prepared in sterile tubes and gently mixed with the test substances or the vehicle.…”

Section: Combination Assaymentioning

confidence: 99%

“…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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“…antioxidant, antibacterial, antiparasitic and anticancer). Recently, it has been also shown that CAO enhances the efficacy of 5-fluorouracil and oxaliplatin in colon cancer cells (Ambrož et al 2019).…”

Section: Introductionmentioning

confidence: 99%

β‐caryophyllene Oxide and Trans-nerolidol Affect Enzyme Activity of CYP3A4 – In Vitro and In Silico Studies

Špičáková

Bazgier²,

Skálová³

et al. 2019

Physiol Res

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Evaluation of possible interactions with enzymes of drug metabolism is an important part of studies on safety and, in general, on the properties of any drug or biologically active compound. Here, focus is given on interactions of three sesquiterpenes (β-caryophyllene oxide (CAO), trans-nerolidol (tNER) and farnesol (FAR)) with CYP3A4. To determine the CYP3A4 activity, specific substrates testosterone (TES) and midazolam (MDZ) were used. In human liver microsomes, the CAO inhibited the MDZ 1´-hydroxylation by mixed type inhibition and Ki 46.6 μM; TES 6-hydroxylation was inhibited more strongly by tNER by the same mechanism and with Ki of 32.5 μM. Results indicated a possibility of different mode of interaction of both compounds within the active site of CYP3A4 and this was why the molecular docking study was done. The docking experiments showed that the studied sesquiterpenes (CAO and tNER) bound to the CYP3A4 active site cause a significant decrease of binding affinity of substrates tested which corresponded well to the inhibition studies. The inhibition observed, however, most probably does not pose a real harm to microsomal drug metabolism as the levels of sesquiterpenes in plasma (assuming the use of these compounds as spices or flavoring additives) does not usually exceed micromolar range. Hence, the interaction of drugs metabolized by CYP3A4 with sesquiterpenes is less probable.

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Sesquiterpenes α-humulene and β-caryophyllene oxide enhance the efficacy of 5-fluorouracil and oxaliplatin in colon cancer cells

Cited by 41 publications

References 13 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 Oxide and Trans-nerolidol Affect Enzyme Activity of CYP3A4 – In Vitro and In Silico Studies

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