Jin Liu1, Long Liang2, Xin Li1, Yuan Liang Peng1, Ji Zhang3, Xiao Long Wang4, Jing Liu1, Ling Nie5. 1. Hunan Province Key Laboratory of Basic and Applied Hematology, School of Life Sciences, Molecular Biology Research Center, Central South University, Changsha, 410078, Hunan, China. 2. Xiangya Hospital, Central South University, No. 87 Xiangya Road, Changsha, 410078, Hunan, China. 3. Department of Clinical Laboratory, The First Affiliated Hospital of South China University, Hengyang, 421000, Hunan, China. 4. School of Life Sciences, Central South University, Changsha, 410078, Hunan, China. 5. Xiangya Hospital, Central South University, No. 87 Xiangya Road, Changsha, 410078, Hunan, China. nielingcsu@outlook.com.
Abstract
OBJECTIVE: To investigate the efficacy and safety of the AMPK activator AICAR alone or in combination with decitabine on myelodysplastic syndromes (MDS). RESULTS: p-AMPK (Thr172) expression was lower in MDS samples than in healthy donors. AMPK agonist AICAR inhibited the proliferation of MDS cell lines (SKM1 and MDS-L) (P < 0.05). The results from flow cytometry suggested that AICAR induced G0/G1 phase arrest and apoptosis through inducing DNA damage, as confirmed by immunofluorescence analysis in MDS cell lines. AICAR alone or in combination with decitabine was applied to the two MDS cell lines, and the combination index values at all concentrations were significantly < 1. This strong synergistic effect was also corroborated in the primary MDS patient samples and in an MDS cell line xenograft mouse model. Furthermore, immunohistochemical staining showed that there was more DNA damage accumulation in the combination group than that in any other groups. CONCLUSION: This is the first report on how the AICAR suppresses MDS cell proliferation and synergizes with decitabine via DNA damage induction. AICAR in combination with decitabine may be a promising therapeutic strategy in MDS.
OBJECTIVE: To investigate the efficacy and safety of the AMPK activator AICAR alone or in combination with decitabine on myelodysplastic syndromes (MDS). RESULTS: p-AMPK (Thr172) expression was lower in MDS samples than in healthy donors. AMPK agonist AICAR inhibited the proliferation of MDS cell lines (SKM1 and MDS-L) (P < 0.05). The results from flow cytometry suggested that AICAR induced G0/G1 phase arrest and apoptosis through inducing DNA damage, as confirmed by immunofluorescence analysis in MDS cell lines. AICAR alone or in combination with decitabine was applied to the two MDS cell lines, and the combination index values at all concentrations were significantly < 1. This strong synergistic effect was also corroborated in the primary MDS patient samples and in an MDS cell line xenograft mouse model. Furthermore, immunohistochemical staining showed that there was more DNA damage accumulation in the combination group than that in any other groups. CONCLUSION: This is the first report on how the AICAR suppresses MDS cell proliferation and synergizes with decitabine via DNA damage induction. AICAR in combination with decitabine may be a promising therapeutic strategy in MDS.
Entities:
Keywords:
AICAR; AMPK; DNA damage; Decitabine; Myelodysplastic syndromes