RESUMEN
BACKGROUND AND PURPOSE: The primary cannabinoids, Delta(9)-tetrahydrocannabinol (Delta(9)-THC) and Delta(8)-tetrahydrocannabinol (Delta(8)-THC) are known to disturb the mitochondrial function and possess antitumor activities. These observations prompted us to investigate their effects on the mitochondrial O(2) consumption in human oral cancer cells (Tu183). This epithelial cell line overexpresses bcl-2 and is highly resistant to anticancer drugs. EXPERIMENTAL APPROACH: A phosphorescence analyzer that measures the time-dependence of O(2) concentration in cellular or mitochondrial suspensions was used for this purpose. KEY RESULTS: A rapid decline in the rate of respiration was observed when Delta(9)-THC or Delta(8)-THC was added to the cells. The inhibition was concentration-dependent, and Delta(9)-THC was the more potent of the two compounds. Anandamide (an endocannabinoid) was ineffective; suggesting the effects of Delta(9)-THC and Delta(8)-THC were not mediated by the cannabinoidreceptors. Inhibition of O(2) consumption by cyanide confirmed the oxidations occurred in the mitochondrial respiratory chain. Delta(9)-THC inhibited the respiration of isolated mitochondria from beef heart. CONCLUSIONS AND IMPLICATIONS: These results show the cannabinoids are potent inhibitors of Tu183 cellular respiration and are toxic to this highly malignant tumor.
Asunto(s)
Respiración de la Célula/efectos de los fármacos , Dronabinol/análogos & derivados , Dronabinol/farmacología , Neoplasias de la Boca/metabolismo , Adenosina Trifosfato/metabolismo , Línea Celular Tumoral , Humanos , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Consumo de Oxígeno/efectos de los fármacosRESUMEN
OBJECTIVE: To investigate the effects of the psychotropic compounds Delta(9)-tetrahydrocannabinol (Delta(9)-THC) and Delta(8)-tetrahydrocannabinol (Delta(8)-THC) on sperm mitochondrial O(2) consumption (respiration). SETTING: State University of New York Upstate Medical University, Syracuse, New York. PATIENT(S): Forty-one men who visited the andrology laboratory for fertility evaluation. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): A phosphorescence analyzer that measures O(2) concentration in sperm suspensions as a function of time was used to measure respiration. RESULT(S): An immediate decline in the rate of respiration was observed when Delta(9)-THC or Delta(8)-THC was added to washed sperm. The inhibition was concentration dependent, and Delta(9)-THC was the more potent of the two compounds. Respiration was much less affected when Delta(9)-THC or Delta(8)-THC was added to neat semen, suggesting the presence of protective factors in seminal plasma. Both compounds inhibited the respiration of isolated mitochondria, illustrating that direct mitochondrial damage is likely the primary mechanism of action. CONCLUSION(S): The two main active cannabinoids of the marijuana plant, Delta(9)- and Delta(8)-THC, are potent inhibitors of mitochondrial O(2) consumption in human sperm. These findings emphasize the adverse effects of these toxins on male fertility. The cytoprotective capacity of seminal plasma deserves further investigation.
Asunto(s)
Cannabinoides/farmacología , Consumo de Oxígeno/efectos de los fármacos , Espermatozoides/fisiología , Cromatografía Líquida de Alta Presión , Dronabinol/farmacología , Etanol/farmacología , Humanos , Cinética , Masculino , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Oxígeno/análisis , Espermatozoides/efectos de los fármacosRESUMEN
In normal oral epithelium the cells divide, mature, differentiate, and die. This sequence is not normally followed in oral cancer. Instead, the death of the cells is somehow prevented, although the pathways toward cell death in normal oral epithelium and the defects in oral cancer are not well defined. However, several components in the system have been identified, and information on their interactions is becoming available. This review summarizes the evidence for cell death being due to apoptosis and the central role of the p53 gene product in its regulation. Areas for future research are also identified.