Inhibitory Effects of Arsenic Trioxide and Thalidomide on Angiogenesis and Vascular Endothelial Growth Factor Expression in Leukemia Cells

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Abstract

Acute myeloid leukemia (AML) is a blood disorder characterized by uncontrolled proliferation of myeloid progenitors and decrease in the apoptosis rate. The vascular endothelial growth factor (VEGF) promotes blood vessel regeneration which might play important roles in development and progression of neoplasia. Our previous studies focused on cytotoxicity and anticancer effects of arsenic trioxide (ATO) and thalidomide (THAL) as an anti-VEGF compound in the AML cell model. ATO also affects regulatory genes involved in cell proliferation and apoptosis. The aim of present study was to examine the effects of ATO and THAL alone and in combination on U937 and KG-1 cells, with attention to mRNA expression for VEGF isoforms. Growth inhibitory effects was assessed by MTT assay and apoptosis induction was determined by Annexin/PI staining. mRNA expression levels were evaluated by real-time PCR. Our data indicated that ATO (1.618μM and 1μM in KG-1 and U937 cell lines respectively), THAL (80μM and 60μM) and their combination inhibited proliferation and induced apoptosis in our cell lines. mRNA expression of VEGF (A, B) decreased while C and D isoforms did not show any significant changes. Taken together, according to the obtained results, the VEGF autocrine loop could be a target as a therapeutic strategy for cases of AML.

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Most cited references 35

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Vascular endothelial growth factor (VEGF) is an apparently endothelial cell-specific mitogen that is structurally related to platelet-derived growth factor. By Northern blot and protein analyses, we show that VEGF is produced by cultured vascular smooth muscle cells. Analysis of VEGF transcripts in these cells by polymerase chain reaction and cDNA cloning revealed three different forms of the VEGF coding region, as had been reported in HL60 cells. The three forms of the human VEGF protein chain predicted from these coding regions are 189, 165, and 121 amino acids in length. Comparison of cDNA nucleotide sequences with sequences derived from human VEGF genomic clones indicates that the VEGF gene is split among eight exons and that the various VEGF coding region forms arise from this gene by alternative splicing: the 165-amino-acid form of the protein is missing the residues encoded by exon 6, whereas the 121-amino-acid form is missing the residues encoded by exons 6 and 7. Analysis of the VEGF gene promoter region revealed a single major transcription start, which lies near a cluster of potential Sp1 factor binding sites. The promoter region also contains several potential binding sites for the transcription factors AP-1 and AP-2; consistent with the presence of these sites, Northern blot analysis demonstrated that the level of VEGF transcripts is elevated in cultured vascular smooth muscle cells after treatment with the phorbol ester 12-O-tetradecanoyl-phorbol-13-acetate.

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Arsenic trioxide has shown substantial efficacy in treating both newly diagnosed and relapsed patients with acute promyelocytic leukemia (APL). As a single agent, it induces complete remissions, causing few adverse effects and only minimal myelosuppression. These successes have prompted investigations to elucidate the mechanisms of action underlying these clinical responses. Substantial data show that arsenic trioxide produces remissions in patients with APL at least in part through a mechanism that results in the degradation of the aberrant PML-retinoic acid receptor alpha fusion protein. Studies have also investigated concerns about the toxicity and potential carcinogenicity of long-term exposure to environmental arsenic. Arsenic apparently affects numerous intracellular signal transduction pathways and causes many alterations in cellular function. These actions of arsenic may result in the induction of apoptosis, the inhibition of growth and angiogenesis, and the promotion of differentiation. Such effects have been observed in cultured cell lines and animal models, as well as clinical studies. Because arsenic affects so many cellular and physiological pathways, a wide variety of malignancies, including both hematologic cancer and solid tumors derived from several tissue types, may be susceptible to therapy with arsenic trioxide. These multiple actions of arsenic trioxide also highlight the need for additional mechanistic studies to determine which actions mediate the diverse biological effects of this agent. This information will be critical to realizing the potential for synergy between arsenic trioxide and other chemotherapeutic agents, thus providing enhanced benefit in cancer therapy.

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Author and article information

Journal

Journal ID (nlm-ta): Asian Pac J Cancer Prev

Journal ID (iso-abbrev): Asian Pac. J. Cancer Prev

Title: Asian Pacific Journal of Cancer Prevention : APJCP

Publisher: West Asia Organization for Cancer Prevention (Iran )

ISSN (Print): 1513-7368

ISSN (Electronic): 2476-762X

Publication date (Print): 2018

Volume: 19

Issue: 4

Pages: 1127-1134

Affiliations

[1 ] Hematology Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran

[2 ] Hematologic Malignancies Research Center, Tehran University of Medical Sciences, Tehran

[3 ] Human Genetics Research Center, Baqiyatallah University of Medical Sciences, Tehran

[4 ] Department of Medical Laboratory Sciences, Faculty of Allied Medicine, Qazvin University of Medical Sciences, Qazvin, Iran

Author notes

[* ] For Correspondence: m-nikbakht@ 123456sina.tums.ac.ir , smohammadi@ 123456sina.tums.ac.ir

Article

Publisher ID: APJCP-19-1127

DOI: 10.22034/APJCP.2018.19.4.1127

PMC ID: 6031772

PubMed ID: 29699374

SO-VID: bc56974a-7797-4a82-9d59-109c8b3e4b26

License:

This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License

History

Date received : 04 January 2018

Date accepted : 20 March 2018

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