Arsenic Trioxide and Thalidomide Combination Induces Autophagy Along with Apoptosis in Acute Myeloid Cell Lines

(Pages: 193-202)
Mahnaz Mohammadi Kian, M.Sc, 1,2Atousa Haghi, M.Sc, 1,3Mahdieh Salami, M.Sc, 1,2Bahram Chahardouli, Ph.D., 1,2Shahrbanoo Rostami, Ph.D., 1,2Kianoosh Malekzadeh, Ph.D., 4Hosein Kamranzadeh Foumani, M.D., 1,2Saeed Mohammadi, Ph.D., 1,2,*Mohsen Nikbakht, Ph.D., 1,2,*
Hematology, Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran
Hematologic Malignancies Research Center, Tehran University of Medical Sciences, Tehran, Iran
Young Researchers and Elite Club, Pharmaceutical Sciences Branch, Islamic Azad University, Tehran, Iran
Molecular Medicine Research Center (MMRC), Hormozgan University of Medical Science (HUMS), Bandar Abbass, Iran
Hematology, Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran
Hematologic Malignancies Research Center, Tehran University of Medical Sciences, Tehran, Iran
Young Researchers and Elite Club, Pharmaceutical Sciences Branch, Islamic Azad University, Tehran, Iran
Molecular Medicine Research Center (MMRC), Hormozgan University of Medical Science (HUMS), Bandar Abbass, Iran
*Corresponding Address: P.O.Box: 1411713131 Hematology Oncology and Stem Cell Transplantation Research Center Tehran University of Medical Sciences Tehran Iran Emails:m-nikbakht@sina.tums.ac.ir,smohammadi@sina.tums.ac.ir
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Mohammadi Kian M, Haghi A, Salami M, Chahardouli B, Rostami Sh, Malekzadeh K, Kamranzadeh Foumani H, Mohammadi S, Nikbakht M. Arsenic trioxide and thalidomide combination induces autophagy along with apoptosis in acute myeloid cell lines. Cell J. 2020; 22(2): 193-202. doi: 10.22074/ cellj.2020.6469.

Abstract

Objective

Autophagy and apoptosis play key roles in cancer survival and pathogenesis and are governed by specific genes which have a dual role in both cell death and survival. Arsenic trioxide (ATO) and thalidomide (THAL) are used for treatment of many types of hematologic malignancies. ATO prevents the proliferation of cells and induces apoptosis in some cancer cells. Moreover, THAL has immunomodulatory and antiangiogenic effects in malignant cells. The aim of present study was to examine the effects of ATO and THAL on U937 and KG-1 cells, and evaluation of mRNA expression level of VEGFs genes, PI3K genes and some of autophagy genes.

Materials and Methods

In this in vitro experimental study, U937 and KG-1 cells were treated by ATO (0.4-5 µM) and THAL (5-100 µM) for 24, 48 and 72 hours. Cell viability was measured by MTT assay. The apoptosis rate and cell cycle arrest were evaluated by flow cytometry (Annexin/PI) and cell cycle flow cytometry analysis, respectively. The effect of ATO/THAL on mRNAs expression was evaluated by real-time polymerase chain reaction (PCR).

Results

ATO/THAL combination enhanced cell apoptosis in a dose-dependent manner. Also, ATO/THAL induced SubG1/ G1 phase arrest. mRNA expression levels of VEGFC (contrary to other VEGFs isoform), PI3K, AKT, mTOR, MEK1, PTEN, IL6, LC3 and P62 genes were upregulated in acute myeloid leukemia (AML) cells following treatment with ATO/THAL.

Conclusion

Combined treatment with ATO and THAL can inhibit proliferation and invasion of AML cells by down-regulating ULK1 and BECLIN1 and up-regulating PTEN and IL6, and this effect was more marked than the effects of ATO and THAL alone.