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Updated: Sep 2, 2025
Modeling Oral-Esophageal Squamous Cell Carcinoma in 3D Organoids
Published on: December 23, 2022
Negative terpinen-4-ol modulate potentially malignant and malignant lingual lesions induced by
José Nunes Carneiro Neto1, Juliana Maria Sorbo2, Carlos Alberto Arcaro Filho2
1Bucco-Maxillo-Facial Surgery and Traumatology Service, Walter Cantídio University Hospital, UFC - Federal University of Ceará, Fortaleza, Ceará, Brazil.
Abstract:
Our aim was to verify the modulative TP-4-ol capacity in 4-nitroquinoline-1-oxide induced oral rat cancer. The stereoisomers of TP-4-ol were used against the human tongue squamous cell line and the negative stereoisomer showed lower IC50. Thirty-one Holtzman rats (120-130 g) were cancer-induced by 4-nitroquinoline-1-oxide (4-NQO/8 weeks/25 ppm) and 32 Holtzman rats (120-130 g) were used to healthy and TP-4-ol toxicity experiments. Six groups were used, healthy, 0.1nL/g of TP-4-ol, 8nL/g of TP-4-ol, 4-NQO, 4-NQO + 0.1nL/g of TP-4-ol, and 4-NQO + 8nL/g of TP-4-ol. We performed the toxicity analysis by biochemical and histopathological analysis. The biochemistry analysis includes alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate transaminase (AST), urea, and creatinine and the histopathology analysis includes the liver, kidney, lung, and spleen. Specifically, for malign modulation, we performed a macroscopic and microscopic analysis. The group exposed to 0.1nL/g of TP-4-ol demonstrated a reduced risk of malignancy in dysplasia considering the criteria of architecture and cytology. Similarly, a drop of percentual rats with SCC diagnosis was observed in 4-NQO + 0.1nL/g (41.6%) when compared to 4-NQO (87.5%). Moreover, the 4-NQO group presented a median of 2.62 SCC/rat and the 4-NQO + 0.1nL/g demonstrated a median of 0.75 SCC/rat. For toxicity analysis, 4-NQO + 0.1nL/g showed focal necrosis in the kidney and 4-NQO showed lung hemorrhagic areas. The concentration of 0.1nL/g was more effective in reducing the tongue induction of potentially malignant and malignant lesions by 4-NQO. A kidney toxicity was observed in healthy animals exposed to 0.1nL/g of TP-4-ol. The negative isoform of terpinen-4-ol negatively modulates the development of potentially malignant and malignant lesions in rats (Rattus nonverdicts albinos, Holtzman) exposed to 4-NQO. (-)-Terpinen-4-ol reduced the mice percentual with squamous cell carcinoma, 87.5 to 41.6%, and decreased the cancer/rat ratio of 2.62 in 4-NQO to 0.75 in 4-NQO + 0.1nL/g. This represents 52.4% by group and 71.3% in the cancer/rat ratio.
Insights
The negative stereoisomer of terpinen-4-ol (TP-4-ol) significantly reduced oral cancer development in rats exposed to 4-nitroquinoline-1-oxide (4-NQO). This terpinen-4-ol compound decreased squamous cell carcinoma incidence and cancer burden, showing therapeutic potential.
Area of Science:
- Oncology
- Pharmacology
- Toxicology
Background:
- Oral cancer remains a significant global health challenge.
- 4-nitroquinoline-1-oxide (4-NQO) is a chemical carcinogen used to induce oral cancer in animal models.
- Terpinen-4-ol (TP-4-ol) is a monoterpenoid alcohol with potential biological activities.
Purpose of the Study:
- To evaluate the modulative capacity of terpinen-4-ol (TP-4-ol) stereoisomers in 4-nitroquinoline-1-oxide (4-NQO) induced oral cancer in rats.
- To assess the anti-cancer effects and toxicity of TP-4-ol.
Main Methods:
- Oral cancer was induced in rats using 4-NQO.
- Rats were treated with different doses of TP-4-ol (0.1nL/g and 8nL/g).
- Biochemical (liver and kidney function markers) and histopathological analyses (liver, kidney, lung, spleen) were performed to assess toxicity and anti-cancer effects.
Main Results:
- The negative stereoisomer of TP-4-ol demonstrated a lower IC50 against a human tongue squamous cell line.
- Treatment with 0.1nL/g TP-4-ol significantly reduced the incidence of potentially malignant and malignant lesions in 4-NQO-exposed rats.
- The percentage of rats with squamous cell carcinoma (SCC) decreased from 87.5% in the 4-NQO group to 41.6% in the 4-NQO + 0.1nL/g TP-4-ol group.
- The cancer/rat ratio decreased from 2.62 to 0.75 with the same treatment.
Conclusions:
- The negative stereoisomer of terpinen-4-ol (TP-4-ol) effectively modulates the development of potentially malignant and malignant oral lesions induced by 4-NQO in rats.
- A dose of 0.1nL/g TP-4-ol showed significant anti-cancer effects with manageable toxicity, including focal kidney necrosis.
- (-)-Terpinen-4-ol represents a promising agent for oral cancer prevention or treatment.
