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

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.

Nitensidine B affects proteins of the glycolytic pathway and induces apoptosis in cervical carcinoma cells immortalized by HPV16.

BACKGROUND: Cervical cancer, the fourth most common type of cancer among women worldwide, accounts for approximately 12% of all types of malignancies that affect women. Natural products have contributed significantly to the development of modern therapies; approximately 70% of the drugs available for chemotherapy are naturally based products. PURPOSE: The purpose of this study was to examine the biological activities of nitensidine B (NTB), a guanidinic alkaloid isolated from the leaves of Pterogyne nitens Tul. (Fabaceae) in a cervical cancer cell line. METHODS: In vitro experiments were performed using cervical carcinoma cells immortalized by human papillomavirus type 16 (HPV16, SiHa cells), since epidemiological and molecular studies have demonstrated robust associations between the etiologies of cervical cancer and HPV infection. Cytotoxicity as well as the effect of NTB treatment on intracellular signals of apoptosis, fragmentation of internucleosomal DNA via terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), and levels of apoptosis effectors (Caspase 3/7) were evaluated. In addition, differential proteomic analysis (iTRAQ) and protein validation using western blot were performed. RESULTS: The cytotoxicity of NTB treatment in the SiHa cell line was concentration-dependent, with the minimum inhibitory concentration of 50% of the cells of 40.98 µM. In the TUNEL assay, SiHa cell apoptosis with 3/7 caspase activation was reported at 12 h following treatment. Differential proteomic analysis by iTRAQ demonstrated that proteins of the glycolytic pathway, aldolase A, alpha-enolase, pyruvate kinase, and glyceraldehyde 3-phosphate dehydrogenase were underexpressed. CONCLUSION: These results indicated that NTB could play a role in decreasing glycolysis . Since tumor cells prefer the glycolytic pathway to generate energy, these findings suggest that NTB may be a reliable model for the study of human cervical cancer cell lines immortalized by HPV16, however more experiments can be performed.

Emodin, Physcion, and Crude Extract of Rhamnus sphaerosperma var. pubescens Induce Mixed Cell Death, Increase in Oxidative Stress, DNA Damage, and Inhibition of AKT in Cervical and Oral Squamous Carcinoma Cell Lines.

There have been few studies on the pharmacological properties of Rhamnus sphaerosperma var. pubescens, a native Brazilian species popularly known as "fruto-de-pombo." The aim of this study was to investigate the scavenging capacity of emodin, physcion, and the ethanolic crude extract of Rhamnus sphaerosperma var. pubescens against reactive oxygen and nitrogen species, as well as their role and plausible mechanisms in prompting cell death and changes in AKT phosphorylation after cervical (SiHa and C33A) and oral (HSC-3) squamous cell carcinoma treatments. Emodin was shown to be the best scavenger of NO• and O2•-, while all samples were equally effective in HOCl/OCl- capture. Emodin, physcion, and the ethanolic extract all exhibited cytotoxic effects on SiHa, C33A, HSC-3, and HaCaT (immortalized human keratinocytes, nontumorigenic cell line), involving mixed cell death (apoptosis and necrosis) independent of the caspase activation pathway. Emodin, physcion, and the ethanolic extract increased intracellular oxidative stress and DNA damage. Emodin decreased the activation of AKT in all tumor cells, physcion in HSC-3 and HaCaT cells, and the ethanolic extract in C33A and HaCaT cells, respectively. The induction of cancer cell death by emodin, physcion, and the ethanolic crude extract of Rhamnus sphaerosperma var. pubescens was related to an increase in intracellular oxidative stress and DNA damage and a decrease in AKT activation. These molecules are therefore emerging as interesting candidates for further study as novel options to treat cervical and oral carcinomas.