Effects of Sorafenib and Arsenic Trioxide on U937 and KG-1 Cell Lines: Apoptosis or Autophagy?

(Pages: 253-262)
Atousa Haghi, M.Sc, 1,2,#Mahdieh Salami, M.Sc, 1,3,#Mahnaz Mohammadi Kian, M.Sc, 1,3Mohsen Nikbakht, Ph.D, 1,3,*Saeed Mohammadi, Ph.D., 1,3,*Bahram Chahardouli, Ph.D., 1,3Shaharbano Rostami, Ph.D., 1,3Kianoosh Malekzadeh, Ph.D., 4
Hematology, Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran
Young Researchers and Elite Club, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
Hematologic Malignancies Research Center, Tehran University of Medical Sciences, 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
Young Researchers and Elite Club, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
Hematologic Malignancies Research Center, Tehran University of Medical Sciences, Tehran, Iran
Molecular Medicine Research Center (MMRC), Hormozgan University of Medical Science (HUMS), Bandar Abbass, Iran
*Corresponding Address: P.O.Box: 1411713135 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

The first two authors equally contributed to this work.

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Haghi A, Salami M, Mohammadi Kian M, Nikbakht M, Mohammadi S, Chahardouli B, Rostami Sh, Malekzadeh K. Effects of sorafenib and arsenic
trioxide on U937 and KG-1 cell lines: apoptosis or autophagy? Cell J. 2020; 22(3): 253-262. doi: 10.22074/cellj.2020.6728.

Abstract

Objective

Acute myeloid leukemia (AML) is a clonal disorder of hemopoietic progenitor cells. The Raf serine/threonine (Ser/Thr) protein kinase isoforms including B-Raf and RAF1, are the upstream in the MAPK cascade that play essential functions in regulating cellular proliferation and survival. Activated autophagy-related genes have a dual role in both cell death and cell survival in cancer cells. The cytotoxic activities of arsenic trioxide (ATO) were widely assessed in many cancers. Sorafenib is known as a multikinase inhibitor which acts through suppression of Ser/Thr kinase Raf that was reported to have a key role in tumor cell signaling, proliferation, and angiogenesis. In this study, we examined the combination effect of ATO and sorafenib in AML cell lines.

Materials and Methods

In this experimental study, we studied in vitro effects of ATO and sorafenib on human leukemia cell lines. The effective concentrations of compounds were determined by MTT assay in both single and combination treatments. Apoptosis was evaluated by annexin-V FITC staining. Finally, mRNA levels of apoptotic and autophagy genes were evaluated using real-time polymerase chain reaction (PCR).

Results

Data demonstrated that sorafenib, ATO, and their combination significantly increase the number of apoptotic cells. We found that the combination of ATO and sorafenib significantly reduces the viability of U937 and KG-1 cells. The expression level of selective autophagy genes, ULK1 and Beclin1 decreased but LC3-II increased in U937.

Conclusion

The expression levels of apoptotic and autophagy activator genes were increased in response to treatment. The crosstalk between apoptosis and autophagy is a complicated mechanism and further investigations seem to be necessary.