RESUMO
Radiation enteropathy is a common complication in cancer patients following radiation therapy. Thus, there is a need for agents that can protect the intestinal epithelium against radiation. 12-O-tetradecanoylphorbol-13-acetate (TPA) has been shown to induce differentiation and/or apoptosis in multiple cell lines and primary cells. In the current report, we studied the function of TPA in radiation induced enteropathy in cultured rat intestinal epithelial cell line IEC-6 after ionizing radiation (IR) and in mice after high dose total-body gamma-IR (TBI). In IEC-6 cells, there were reduced apoptosis and cell cycle arrest in TPA treated cells after IR. We detected a four-fold increase in crypt cell survival and a two-fold increase in animal survival post TBI in TPA treated mice. The beneficial effects of TPA were accompanied by upregulation of stem cells markers and higher level of proteins that are involved in PKC signaling pathway. In addition, TPA also decreased the TBI-augmented levels of the DNA damage indicators. The effects were only observed when TPA was given before irradiation. These results suggest that TPA has the ability to modulate intestinal crypt stem cells survival and this may represent a promising countermeasure against radiation induced enteropathy.
Assuntos
Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Mucosa Intestinal/citologia , Células-Tronco/efeitos dos fármacos , Células-Tronco/efeitos da radiação , Acetato de Tetradecanoilforbol/farmacologia , Animais , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos da radiação , Linhagem Celular , Dano ao DNA/efeitos dos fármacos , Dano ao DNA/efeitos da radiação , Modelos Animais de Doenças , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Proteína Quinase C/metabolismo , Lesões por Radiação/genética , Lesões por Radiação/metabolismo , Lesões por Radiação/mortalidade , Lesões por Radiação/patologia , Protetores contra Radiação/farmacologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/efeitos da radiação , Células-Tronco/metabolismoRESUMO
We have demonstrated that 12-0-tetradecanoylphorbol-13-acetate (TPA) combined with vitamin D(3) (VD(3)) and cytosine arabinoside (Ara C) is effective and feasible for chronic myelogenous leukemia (CML) in blastic phase (BP). In the current study, the efficacy of TPA combined with inhibitor imatinib mesylate (imatinib) was investigated in patients with CML in BP that was resistant to standard-dose imatinib (400mg/day). The results suggested that TPA combined with imatinib (400mg/day) might overcome disease-poor response to conventional doses. So this approach deserves further evaluation as frontline therapy for newly diagnosed CML.