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Synergistic Effects of Carvacrol and Thymol on Docetaxel-Induced Cytotoxicity in the A549 Cell Line by Evaluating Cell Viability and Oxidative Stress
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Mohammad Shokrzadeh1    , Mahboube Rahmati Kukandeh2 , Mohammad Karami3 , Samane Sadat Besharat *4 |
1- Professor, Department of Toxicology and Pharmacology, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran. Pharmaceutical Sciences Research Center, Hemoglobinopathy Institute, Mazandaran University of Medical Sciences, Sari, Iran.
2- Ph.D Candidate in Toxicology, Department of Toxicology and Pharmacology, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran.
3- Professor, Department of Toxicology and Pharmacology, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran.
4- Pharmacy Student, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran. , samanbst39@gmail.com |
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Keywords: Docetaxel [MeSH], Carvacrol [MeSH], Thymol [MeSH], Oxidative Stress [MeSH], Lipid Peroxidation [MeSH]
Article ID: Vol27-18 |
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Type of Study: Original Articles |
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Abstract: (249 Views) |
Extended Abstract
Introduction
Lung cancer is the second most common cancer diagnosis by gender, following prostate cancer in men and breast cancer in women.
The two main pathological subtypes of lung cancer are non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). SCLC is an aggressive disease with distinct pathological, clinical, and molecular characteristics, differentiating it from NSCLC. It has a high metastatic potential, which leads to a poor clinical prognosis. NSCLC accounts for the majority of lung cancer cases. Depending on the stage of the cancer, patients are eligible for specific treatments ranging from surgery to radiation therapy, chemotherapy, and targeted therapy. Various classes of drugs have been approved by the United States Food and Drug Administration (FDA) for the treatment of lung cancer. Among the most common is docetaxel (DTX), a highly effective chemotherapeutic agent used in the treatment of various cancers, including NSCLC. DTX, an anticancer drug belonging to the taxane family, is a semi-synthetic agent that irreversibly binds to β-actin, thereby altering microtubule polymerization, disrupting cell mitosis, and inducing apoptosis. Chemotherapeutic agents, including taxanes, are associated with severe complications, such as renal and neurotoxicity. DTX has been utilized for a long time in the treatment of several cancer types, including glioblastoma, breast cancer, and prostate cancer. However, this drug exhibits numerous adverse effects on normal tissues, such as the brain and testes. Severe complications, such as bone marrow suppression, alopecia, anaphylaxis, gastrointestinal reactions, weakness, edema, and liver dysfunction, may occur following DTX administration. Limitations, including a high recurrence rate and adverse effects like immune system damage and gastrointestinal tract injury, necessitate the discovery of novel therapeutic strategies for lung cancer. Several studies indicate that DTX-induced toxicity is caused by the overproduction of reactive oxygen species (ROS). There is also evidence suggesting that inflammation and apoptosis may play crucial roles in DTX-induced tissue toxicity. Therefore, there is a continuous search for materials that can be used to create more effective cancer treatments with fewer complications. One promising group of materials comprises natural products. Many medicinal plants have scientifically proven therapeutic properties.
Phenolic compounds are a widely studied group of compounds known for their antimicrobial and antioxidant properties. Thymol (2-isopropyl-5-methylphenol) is a major phenolic compound found in the essential oil of various plants, including Thymus vulgaris (Lamiaceae). Numerous biological properties have been reported for thymol, including anti-inflammatory, antibacterial, antispasmodic, wound-healing, and antioxidant effects. It is also an active compound for inhibiting cancer cells. Thymol is a major phenolic compound present in the essential oil of Thymus vulgaris. Carvacrol is a naturally bioactive monoterpenoid phenol found in the essential oils of the Lamiaceae family, including the genera Origanum and Thymus. Previous studies have shown that carvacrol possesses anti-angiogenic, analgesic, antioxidant, antimicrobial, and anti-inflammatory properties. Furthermore, carvacrol exerts antiproliferative effects on liver, lung, colon, and breast cancer cell lines. These two compounds also demonstrate antifungal, insecticidal, antiviral, antitumor, antiparasitic, free radical scavenging, and lipid antiperoxidative activities. These characteristics form the basis for their widespread use in the cosmetic, food, and pharmaceutical industries.
Research reveals that carvacrol can elevate the levels of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR), and glutathione (GSH). Studies have also confirmed that thymol, when its concentration is increased, exhibits significant antioxidant potential. It effectively blocks the excessive production of ROS, inhibits lipid peroxidation (LPO), and prevents the loss of membrane integrity. Given the established antioxidant and protective effects of carvacrol and thymol, and their ability to inhibit free radicals, this study was conducted to determine the synergistic effects of carvacrol and thymol on DTX-induced cytotoxicity in A549 cell line by evaluating cell viability and oxidative stress. This was achieved by evaluating cell viability and oxidative stress.
Methods
This descriptive-analytical study was conducted on the A549 lung cancer cell line (derived from lung cancerous tissue) at the Faculty of Pharmacy, Mazandaran University of Medical Sciences.
Cellular Culture: In this study, A549 cell lines were purchased from the National Genetic Resources Cell Bank. The cell lines were cultured in the Dulbecco's Modified Eagle Medium (DMEM) (Biowest, France) supplemented with 10% Fetal Bovine Serum (FBS) (Gibco, USA) and 1% penicillin-streptomycin antibiotic. Cells were maintained in an incubator at 37°C with adequate humidity and 5% carbon dioxide. For various experiments, when cell confluence reached at least 70-80%, cells were detached from the flask bottom using trypsin-ethylenediaminetetraacetic acid (EDTA), without any shaking or tapping of the flask, and then centrifuged at 2000 rpm for 5 minutes. The resulting cell pellet was resuspended in 1 mL of culture medium, and the viability percentage of cells in the cell suspension was determined by mixing equal parts of trypan blue and counting with a hemocytometer under a light microscope. After confirming the absence of cell contamination, cells with a viability percentage greater than 80-90% were used for the test.
Study Design: In the initial step, DTX was used as a cytotoxic model and applied to A549 cells across a concentration range of 0-70 µg/mL, increasing from low to high concentrations in order to determine the optimal cytotoxic concentration of DTX for oxidative stress assays (ROS and LPO) and to establish its inhibitory concentration (IC50) on the studied cell line. Subsequently, after determining the optimal cytotoxic concentration of DTX, the protective effects of carvacrol and thymol were investigated in seven groups with varying concentrations (5-200 µg/mL) alongside DTX at its IC50 concentration in all tests, using a pre-treatment approach.
Grouping was performed as follows:
- The negative control group (consisting of A549 cells + DMEM culture medium)
- The positive control group (consisting of DTX at its IC50 concentration)
- Treatment groups (consisting of 7 concentrations of carvacrol [5, 10, 20, 40, 80, 100, and 200 µg/mL] combined with DTX at its IC50 concentration)
- Treatment groups (consisting of 7 concentrations of thymol ([5, 10, 20, 40, 80, 100, and 200 µg/mL] combined with DTX at its IC50 concentration)
- The synergistic effective concentration (consisting of 7 concentrations of thymol and carvacrol [5, 10, 20, 40, 80, 100, and 200 µg/mL] combined with DTX at its IC50 concentration).
Cytotoxicity Assessment: This was performed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay.
Reactive Oxygen Species Level Measurement: Cells were treated with DTX alone and as a pre-treatment with thymol and carvacrol, and then examined.
Lipid Peroxidation Level Measurement: Following cell incubation, LPO levels were measured using the thiobarbituric acid reactive substances (TBARS) assay.
Results
Determination of Docetaxel IC50 Value: DTX, a cytotoxic drug, was used to treat A549 cells across a concentration range of 0-70 µg/mL (from low to high concentrations) to determine the inhibitory concentration (IC50) of DTX on the studied cell line. The IC50 value for A549 cells when treated with DTX was determined to be 8.92 µg/mL.
The Effect of Carvacrol on Cell Function in Docetaxel-Treated A549 Cells: According to the results obtained from the MTT assay, the cell function and viability in DTX-treated cells showed a significant decrease, which was statistically significant compared to the control group (P < 0.001). Carvacrol, at concentrations of 10, 20, 40, 80, 100, and 200 µg/mL, culminated in improved cell function and increased viability in DTX-treated cells. This improvement was statistically significant compared to the DTX-only group (P < 0.01 for 10 µg/mL and P < 0.001 for 20, 40, 80, 100, and 200 µg/mL). However, carvacrol at a concentration of 5 µg/mL did not significantly affect cell function improvement or viability increase in DTX-treated cells.
The Effect of Thymol on Cell Function in Docetaxel-Treated A549 Cells: Thymol, at concentrations of 20, 40, 80, 100, and 200 µg/mL, improved cell function and increased viability in DTX-treated A549 cells compared to the DTX-alone group (P < 0.01 for 20 µg/mL and P < 0.001 for 40, 80, 100, and 200 µg/mL), showing a significant difference. At concentrations of 5 and 10 µg/mL, thymol did not show any significant effect on improving cell function or increasing viability in DTX-treated cells.
The Simultaneous Effects of Carvacrol and Thymol on Cell Function in Docetaxel-Treated A549 Cells: Carvacrol and thymol, at concentrations of 5, 10, 20, 40, 80, 100, and 200 µg/mL, led to an improvement in cell function and viability in DTX-treated A549 cells. This improvement was significantly different compared to the DTX-only group (P < 0.01 for 5 µg/mL, and P < 0.001 for 10, 20, 40, 80, 100, and 200 µg/mL).
The Effects of Carvacrol and Thymol on Reactive Oxygen Species Formation in Docetaxel-Treated A549 Cells: ROS formation was investigated in DTX-treated A549 cells and varying concentrations of carvacrol and thymol after 24 hours of incubation at 37°C. DTX, at a concentration of 8.92 µg/mL, significantly increased ROS levels in normal cells, showing a statistically significant difference compared to the control group (P < 0.001). However, carvacrol and thymol, at concentrations of 5, 10, 20, 40, 80, 100, and 200 μg/mL, significantly reduced ROS formation and oxidative damage in treated cells. This reduction was notably different when compared to the DTX-treated groups (P < 0.01 for 5 μg/mL and P < 0.001 for 10, 20, 40, 80, 100, and 200 μg/mL concentrations). Moreover, carvacrol and thymol, at concentrations of 40, 80, 100, and 200 µg/mL, significantly reduced ROS formation and oxidative damage in the treated cells, with this reduction being statistically significant when compared to the control group (P < 0.01 for 5 µg/mL and P < 0.001 for 10, 20, 40, 80, 100, and 200 µg/mL).
The Effects of Carvacrol and Thymol on Lipid Peroxidation Levels in Docetaxel-Treated A549 Cells: A significant increase in LPO levels was observed in DTX-treated cells so that LPO levels in the DTX-treated groups were significantly different compared to the control group (P < 0.001). In carvacrol- and thymol-treated cells, at concentrations of 5, 10, 20, 40, 80, 100, and 200 µg/mL, the LPO levels were significantly reduced compared to the DTX-treated groups (P < 0.01 for 5 µg/mL and P<0.001 for 10, 20, 40, 80, 100, and 200 µg/mL concentrations).
Conclusion
Based on the findings of our study, DTX significantly increased markers of oxidative stress (ROS) and LPO (malondialdehyde [MDA]), while decreased viability compared to the control group. In contrast, treatment with carvacrol at concentrations of 10, 20, 40, 80, 100, and 200 µg/mL culminated in improved cell function and increased viability in DTX-treated cells, showing a significant difference when compared to the DTX-only group. However, at a concentration of 5 µg/mL of carvacrol, no significant change was observed in viability of treated cells. Regarding thymol, concentrations of 20, 40, 80, 100, and 200 µg/mL led to improved cell function and increased viability in DTX-treated cells, showing a significant difference compared to the DTX-only group. Conversely, regarding carvacrol, at concentrations of 5 and 10 µg/mL, no statistically significant change was observed in the viability of treated cells. Simultaneous incubation with carvacrol and thymol at concentrations of 5, 10, 20, 40, 80, 100, and 200 µg/mL significantly improved cell viability and reduced oxidative stress changes in A549 cells compared to the DTX-treated groups.
Given that the current study was conducted on A549 cells, higher concentrations of thymol and carvacrol were effective in reducing oxidative stress. A greater reduction in oxidative stress was also observed commensurate with increasing concentrations of these compounds. In the present study, thymol and carvacrol exhibited similar therapeutic effects on DTX-treated A549 cells, while carvacrol did not demonstrate significant antioxidant effects at low concentrations. It reduced ROS and LPO at higher concentrations.
Ethical Statement
The study received approval from the Research Ethics Committee at Mazandaran University of Medical Sciences (IR.MAZUMS.REC.1402.375).
Funding
This article has been extracted from doctoral dissertation of Ms. Samaneh Sadat Besharat in Pharmacy from the Faculty of Pharmacy, Mazandaran University of Medical Sciences. This study was funded by the Faculty of Pharmacy, Mazandaran University of Medical Sciences.
Authors' Contributions
Mohammad Shokrzadeh: Project administration and design and approval of the final manuscript.
Mahboube Rahmati Kukandeh: Data analysis and interpretation of the results.
Mohammad Karami: Project administration and design.
Samane Sadat Besharat: Project execution, data collection, and drafting of the initial manuscript.
Conflicts of Interest
No conflicts of interest.
Key Message: Carvacrol and thymol are effective as high-potential compounds in improving cell function and reducing DTX-induced cytotoxicity in A549 cancer cells.
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Shokrzadeh M, Rahmati Kukandeh M, Karami M, Besharat S S. Synergistic Effects of Carvacrol and Thymol on Docetaxel-Induced Cytotoxicity in the A549 Cell Line by Evaluating Cell Viability and Oxidative Stress. J Gorgan Univ Med Sci 2025; 27 (2) :70-82 URL: http://goums.ac.ir/journal/article-1-4510-en.html
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