Combination treatment with arsenic trioxide and irradiation enhances apoptotic effects in U937 cells through increased mitotic arrest and ROS generation.
Arsenic compounds have been used as anti-cancer agents in traditional Chinese medicine. Ionizing radiation (IR) is one of the most effective tools in the clinical treatment of cancer. The induction of apoptotic cell death is a significant mechanism of tumor cells under the influence of radio-/chemotherapy, and resistance to these treatments has been linked to some cancer cell lines with a low propensity for apoptosis. A combination of different anti-tumoral treatment modalities is advantageous in limiting non-specific toxicity often observed by an exceedingly high dose of single regimen. The present study aimed at investigating the enhanced effects and mechanisms in cell cycle distribution and apoptosis of U937 cells, a human pre-monocytic leukemia cell line lacking functional p53 protein, after combination treatment with irradiation and As(2)O(3). Our results indicated that combined treatment led to activation of cdc-2, which is related to the expression of cyclin B. In addition, combined treatment increased apoptotic cell death in U937 cells, which is correlated with the induction of mitotic arrest, the increase in intracellular reactive oxygen species (ROS) generation, the decrease in B-cell leukemia/lymphoma 2 (Bcl-2) and B-cell leukemia/lymphoma XL (Bcl-XL) levels, the loss of mitochondria membrane potential, and the activation of caspase-3. We found that combining radiation and As(2)O(3) may be an effective strategy against p53-deficient leukemia cells.
Ho
Sheng-Yow
SY
Sinlau Christian Hospital, Tainan, Taiwan.
Chen
Wei-Chih
WC
Chiu
Hui-Wen
HW
Lai
Ching-Shu
CS
Guo
How-Ran
HR
Wang
Ying-Jan
YJ
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000528:radiation effects*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects / Q000528:radiation effects; D019925:Cyclin A / Q000096:biosynthesis / Q000187:drug effects / Q000528:radiation effects; D019926:Cyclin B / Q000096:biosynthesis / Q000187:drug effects / Q000528:radiation effects; D045304:Cytochromes c / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D004354:Drug Screening Assays, Antitumor; D016195:G2 Phase / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D051336:Mitochondrial Membranes / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D008938:Mitosis / Q000187:drug effects* / Q000528:radiation effects*; D010087:Oxides / Q000494:pharmacology*; D011839:Radiation, Ionizing; D017382:Reactive Oxygen Species / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000187:drug effects / Q000528:radiation effects; D020298:U937 Cells
D000970:Antineoplastic Agents; D001152:Arsenicals; D019925:Cyclin A; D019926:Cyclin B; D010087:Oxides; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; D045304:Cytochromes c; D020169:Caspases; D000077237:Arsenic Trioxide