Disminución de la toxicidad y del efecto terapéutico del ácido zoledrónico en el tratamiento combinado con diferentes extractos antioxidantes / Decrease in toxicity and therapeutic effect of zoledronic acid in combination therapy with different antioxidant extracts

Antecedentes. El ácido zoledrónico se utiliza en el tratamiento de diversas enfermedades, tumorales o no, aunque su uso se asocia con necrosis avascular ósea. Objetivo. Determinar un posible efecto protector de diferentes sustancias antioxidantes frente a la inhibición del crecimiento de células epiteliales de próstata humana (PNT2) y en células tumorales de adenocarcinoma transgénico de próstata murina (TRAMP-C1), en tratamientos combinados de ácido zoledrónico junto con radiación ionizante (IR). Material y métodos. Mediante un ensayo de viabilidad celular (MTT) se estudia la supervivencia celular de 2 líneas celulares en tratamientos aislados y combinados con ácido zoledrónico y con IR, así como, el efecto de la adición de diferentes sustancias antioxidantes. Resultados. El ácido zoledrónico muestra un efecto citotóxico significativo sobre las células PNT2 y TRAMP-C1 (p<0,001). La administración de diferentes sustancias antioxidantes en el tratamiento con ácido zoledrónico presenta un efecto protector sobre las células PNT2 (p<0,001), pero no sobre las células tumorales. Sin embargo, la administración de ácido rosmarínico y apigenina en el tratamiento combinado con ácido zoledrónico junto con IR presenta un efecto protector no solo sobre las células PNT2 (p<0,001), sino también sobre las células TRAMP-C1 (p<0,001). Conclusión. El uso de sustancias antioxidantes produce una disminución del efecto citotóxico del ácido zoledrónico sobre las células no tumorales, por lo que podrían ser utilizadas en enfermedades benignas no tumorales. Sin embargo, en un tratamiento combinado con IR, también pueden proporcionar protección a las células tumorales, y reducir de este modo el efecto terapéutico deseado (AU)

Background. Zoledronic acid is used in the treatment of cancer-related diseases, although its use has been associated with avascular osteonecrosis. Aims. To determine the possible protective effect of a range of antioxidant substances against the inhibition of human prostate epithelial cell growth (PNT2) and transgenic adenocarcinoma mouse prostate tumour cells (TRAMP-C1), in treatments combining zoledronic acid and ionising radiation (IR). Material and method. Cell survival is studied via cell viability assays (MTT) for 2 cell lines in isolated and combined treatments with zoledronic acid and/or IR, as well as the effect of adding 3 antioxidant substances. Results. Zoledronic acid displays a significant cytotoxic effect over PNT2 and TRAMP-C1 cells (P<.001). The administration of antioxidants together with the zoledronic acid shows a protective effect for normal prostate cells, yet not so for prostate tumour cells. However, the administration of rosmarinic acid and apigenin in treatments combined with zoledronic acid provides a protective effect from the harmful effects of applying ionizing radiation, not only for normal PNT2 cells, but also for tumour cells. Conclusion. The use of antioxidant substances decreases the cytotoxic effect of zoledronic acid over non-tumour cells, and as such could be used in benign diseases. Furthermore, in the combined treatment using ionising radiation, these antioxidants also produced a protective effect in tumour cells, thus reducing the therapeutic effect sought by combining the treatment with radiation (AU)

[Decrease in toxicity and therapeutic effect of zoledronic acid in combination therapy with different antioxidant extracts]. / Disminución de la toxicidad y del efecto terapéutico del ácido zoledrónico en el tratamiento combinado con diferentes extractos antioxidantes.

BACKGROUND: Zoledronic acid is used in the treatment of cancer-related diseases, although its use has been associated with avascular osteonecrosis. AIMS: To determine the possible protective effect of a range of antioxidant substances against the inhibition of human prostate epithelial cell growth (PNT2) and transgenic adenocarcinoma mouse prostate tumour cells (TRAMP-C1), in treatments combining zoledronic acid and ionising radiation (IR). MATERIAL AND METHOD: Cell survival is studied via cell viability assays (MTT) for 2 cell lines in isolated and combined treatments with zoledronic acid and/or IR, as well as the effect of adding 3 antioxidant substances. RESULTS: Zoledronic acid displays a significant cytotoxic effect over PNT2 and TRAMP-C1 cells (P<.001). The administration of antioxidants together with the zoledronic acid shows a protective effect for normal prostate cells, yet not so for prostate tumour cells. However, the administration of rosmarinic acid and apigenin in treatments combined with zoledronic acid provides a protective effect from the harmful effects of applying ionizing radiation, not only for normal PNT2 cells, but also for tumour cells. CONCLUSION: The use of antioxidant substances decreases the cytotoxic effect of zoledronic acid over non-tumour cells, and as such could be used in benign diseases. Furthermore, in the combined treatment using ionising radiation, these antioxidants also produced a protective effect in tumour cells, thus reducing the therapeutic effect sought by combining the treatment with radiation.

Radiosensitizing effect of rosmarinic acid in metastatic melanoma B16F10 cells.

BACKGROUND: Rosmarinic acid is an ester of caffeic acid with interesting biological activities including antioxidant effects and scavenging of oxygen-free radicals. AIM: To determine the potentially paradoxical effect of rosmarinic acid, typically being radioprotective when applied to non-tumorous cells, yet conversely displaying a sensitizing action when applied to metastatic B16F10 melanoma cells. MATERIALS AND METHODS: The genoprotective effect was studied by means of micronucleus tests for anti-mutagenic activity in which the reduction in the frequency of micronuclei was evaluated using cytokinesis-blocked human lymphocytes. The radioprotective effect was studied via a cell viability test in PNT2 (human prostate epithelium) and B16F10 melanoma cells. RESULTS: Rosmarinic acid exhibits a significant genoprotective capacity (p<0.001) against X-rays with a protection factor of 58%, and a dose reduction factor of 7.2. Cell survival obtained after exposure to 10 Gy of X-rays showed a protection factor of 47.5%, thus eliminating 29.1% of radiation-induced cell death in normal prostate epithelial cells (p<0.001). However, in metastatic B16F10 melanoma cells, rosmarinic acid acted not as a radioprotector, but as a sensitizing agent, increasing cellular death by 42% (p<0.001), with an enhancement ratio of 2.36. CONCLUSION: Rosmarinic acid has an increased capacity for producing radio-induced damage, and thus a paradoxical damaging effect in melanoma cells. Potentially, research into substances such as rosmarinic acid could help clarify mechanisms that provide protection on healthy normal cells, while exclusively damaging neoplastic cells, thus presenting a new strategy for patients undergoing radiotherapy for cancer.