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Negative terpinen-4-ol modulate potentially malignant and malignant lingual lesions induced by 4-nitroquinoline-1-oxide in rat model

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.

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Data availability

Data archiving is not mandated but data will be made available on reasonable request.

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The authors declare that all data were generated in-house and that no paper mill was used. JNCN and CLRA conceived research, designed research, acquired data, analyzed data, interpreted data, drafting the article, revised the article, and approved the final version. AM and BB conducted experiments. GR contributed new reagents or analytical tools. CAAF conceived research, acquired data, analyzed data, and approved the final version. TFMS conceived research, designed research, acquired data, revised the article, and approved the final version. DAR conceived research, designed research, interpreted data, revised the article, and approved the final version. ILB conceived research, designed research, acquired data, analyzed data, revised the article, and approved the final version. CRLA wrote the manuscript.

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This project was approved by the Animal Use Ethics Commission (CEUA) at the Araraquara School of Dentistry with protocol nº 8/2015 according to the rules established by the National Council for Animal Experimentation Control (CONCEA) and Normative Instruction No. 04 of June 18, 2014, of the Brazilian National Health Surveillance Agency (ANVISA) on non-clinical studies of toxicology and pharmacological safety necessary for the development and registration of herbal medicines. The ARRIVE guidelines (Animal Research: Reporting of In Vivo Experiments) were used to write this article.

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Neto, J.N.C., Sorbo, J.M., Filho, C.A.A. et al. Negative terpinen-4-ol modulate potentially malignant and malignant lingual lesions induced by 4-nitroquinoline-1-oxide in rat model. Naunyn-Schmiedeberg's Arch Pharmacol (2022). https://doi.org/10.1007/s00210-022-02275-7

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Keywords

  • Oral cancer modulation
  • 4-Nitroquinoline-1-oxide
  • Terpinen-4-ol
  • Toxicity