TY - JOUR
T1 - Combination treatment with arsenic trioxide and irradiation enhances cell-killing effects in human fibrosarcoma cells in vitro and in vivo through induction of both autophagy and apoptosis
AU - Chiu, Hui Wen
AU - Lin, Jing Hua
AU - Chen, Yi An
AU - Ho, Sheng Yow
AU - Wang, Ying Jan
N1 - Funding Information:
This study was supported by the National Science Council, Taiwan (NSC-95-2314-B-006-095-MY3).
Funding Information:
RNA interference (RNAi). We used the MicroPorator, a pipette-type electroporation system (Digital Bio Tech. Co., KOREA) to transfect cells. The RNAi reagents were obtained from the National RNAi Core Facility located at the Institute of Molecular Biology/Genomic Research Center, Academia Sinica, supported by the National Research Program for Genomic Medicine Grants of NSC (NSC 97-3112-B-001-016). The human library is referred to as TRC-Hs 1.0. Individual clones are identified as shRNA TRCN0000033550 and shRNA TRCN0000072184.
PY - 2010/4/1
Y1 - 2010/4/1
N2 - The traditional treatments for fibrosarcoma have limited efficacy. Therefore, new therapeutic strategies and/or new adjuvant drugs still need to be explored. Accumulating evidence indicates that programmed cell death (PCD) is closely related to anticancer therapy. Many studies have shown that tumor cells treated with anticancer drugs experience the induction of type I PCD, apoptosis, and type II PCD, autophagy. In the present study, we investigated the anticancer effects of ionizing radiation (IR) combined with arsenic trioxide (ATO) in human fibrosarcoma cells in vitro and in xenograft tumors in SCID mice in vivo. We found that IR increased the population of HT1080 cells in the G 2/M phase in a time-dependent manner within 9 h. IR treatment combined with ATO at this time point induced a significantly prolonged G 2/M arrest and consequently enhanced cell death. Furthermore, damage of mitochondria membrane potential could be involved in the underlying mechanisms. The enhanced cytotoxic effect of combined treatment occurred due to the increased induction of more autophagy and apoptosis through the inhibition of Akt and the activation of ERK1/2 signaling pathways in HT1080 cells. The combined treatment of HT1080 cells pretreated with Z-VAD or 3-MA resulted in a significant reduction in AO-positive cells, apoptotic cells and cytotoxicity. In in vivo studies, the combination of IR and ATO significantly reduced the tumor volume in SCID mice that had received a subcutaneous injection of HT1080 cells. The data suggest that a combination of IR and ATO could be a new potential therapeutic strategy for the treatment of fibrosarcoma.
AB - The traditional treatments for fibrosarcoma have limited efficacy. Therefore, new therapeutic strategies and/or new adjuvant drugs still need to be explored. Accumulating evidence indicates that programmed cell death (PCD) is closely related to anticancer therapy. Many studies have shown that tumor cells treated with anticancer drugs experience the induction of type I PCD, apoptosis, and type II PCD, autophagy. In the present study, we investigated the anticancer effects of ionizing radiation (IR) combined with arsenic trioxide (ATO) in human fibrosarcoma cells in vitro and in xenograft tumors in SCID mice in vivo. We found that IR increased the population of HT1080 cells in the G 2/M phase in a time-dependent manner within 9 h. IR treatment combined with ATO at this time point induced a significantly prolonged G 2/M arrest and consequently enhanced cell death. Furthermore, damage of mitochondria membrane potential could be involved in the underlying mechanisms. The enhanced cytotoxic effect of combined treatment occurred due to the increased induction of more autophagy and apoptosis through the inhibition of Akt and the activation of ERK1/2 signaling pathways in HT1080 cells. The combined treatment of HT1080 cells pretreated with Z-VAD or 3-MA resulted in a significant reduction in AO-positive cells, apoptotic cells and cytotoxicity. In in vivo studies, the combination of IR and ATO significantly reduced the tumor volume in SCID mice that had received a subcutaneous injection of HT1080 cells. The data suggest that a combination of IR and ATO could be a new potential therapeutic strategy for the treatment of fibrosarcoma.
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U2 - 10.4161/auto.6.3.11229
DO - 10.4161/auto.6.3.11229
M3 - Review article
C2 - 20200477
AN - SCOPUS:77953712305
VL - 6
SP - 353
EP - 365
JO - Autophagy
JF - Autophagy
SN - 1554-8627
IS - 3
ER -