Synergistic Effect of Anethole and Platinum Drug Cisplatin against Oral Cancer Cell Growth and Migration by Inhibiting MAPKase, Beta-Catenin, and NF-κB Pathways.
Abdelhabib SemlaliIkram AjalaSarra BejiMohammed Mousa Al-ZharaniMahmoud RouabhiaPublished in: Pharmaceuticals (Basel, Switzerland) (2023)
Cisplatin is a common drug used to treat patients with oral squamous cell carcinoma. However, cisplatin-induced chemoresistance poses a major challenge to its clinical application. Our recent study has shown that anethole possesses an anti-oral cancer effect. In this study, we examined the combined effect of anethole and cisplatin on oral cancer therapy. Gingival cancer cells Ca9-22 were cultured in the presence of various concentrations of cisplatin with or without anethole. The cell viability/proliferation and cytotoxicity were evaluated, respectively, by MTT, Hoechst staining, and LDH assay, while colony formation was measured by crystal violet. Oral cancer cell migration was evaluated by the scratch method. Apoptosis, caspase activity, oxidative stress, MitoSOX, and mitochondrial membrane potential (ΔΨm) levels were evaluated by flow cytometry, and the inhibition of signaling pathways was investigated by Western blot. Our results show that anethole (3 µM) potentiates cisplatin-induced inhibition of cell proliferation and decreases the ΔΨm on Ca9-22 cells. Furthermore, drug combination was found to inhibit cell migration and enhanced cisplatin cytotoxicity. The combination of anethole and cisplatin potentiates cisplatin-induced oral cancer cell apoptosis through the activation of caspase, while we also found anethole and cisplatin to enhance the cisplatin-induced generation of reactive oxygen species (ROS) and mitochondrial stress. In addition, major cancer signaling pathways were inhibited by the combination of anethole and cisplatin such as MAPKase, beta-catenin, and NF-κB pathways. This study reports that the combination of anethole and cisplatin might provide a beneficial effect in enhancing the cisplatin cancer cell-killing effect, thus lowering the associated side effects.
Keyphrases
- oxidative stress
- signaling pathway
- cell proliferation
- induced apoptosis
- cell migration
- cell death
- flow cytometry
- cell cycle arrest
- pi k akt
- reactive oxygen species
- epithelial mesenchymal transition
- dna damage
- cancer therapy
- endoplasmic reticulum stress
- endothelial cells
- adverse drug
- high resolution
- lps induced
- toll like receptor
- risk assessment
- immune response
- high throughput
- single molecule
- papillary thyroid