Hatah et al Tropical Journal of Pharmaceutical Research December 2019; 18 (12): 2653-2668 ISSN: 1596-5996 (print); 1596-9827 (electronic) © Pharmacotherapy Group, Faculty of Pharmacy, University of Benin, Benin City, 300001 Nigeria. Available online at http://www.tjpr.org http://dx.doi.org/10.4314/tjpr.v18i12.26 Original Research Article Annexin A1 and leukemia: A systematic review Ernieda Hatah1, Phylicia Gan Yin Hui2, Endang Kumolosasi2* 1Centre of Quality Management of Medicines, 2Drug and Herbal Research Centre, Faculty of Pharmacy, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia *For correspondence: Email: [email protected]; Tel: +603-9289 8054 Sent for review: 31 May 2019 Revised accepted: 17 November 2019 Abstract Purpose: To review systematically the involvement of Annexin A1 (ANXA1) in various leukemia cells in order to advance the understanding of ANXA1 role in leukemia. Methods: The systematic review was carried out via a comprehensive search of electronic databases for all relevant articles published up to September 2017. Specific key words were used to retrieve the articles. All articles were imported into EndNote software while duplicates were removed from the list. The retrieved articles were selected using inclusion and exclusion criteria. Results: FK228, a novel HDACi and FR235222, increased expression of ANXA1 in Kasumi-1, SKNO-1 and U937 cells, respectively, and induced apoptosis. The study also neutralized ANXA1 in the same cells, which caused a complete blockage of the FK228-induced apoptosis. Resveratrol was reported to markedly increase ANXA1 levels which led to caspase 3-mediated apoptosis on HL-60 cells. Dexamethasone, 17β-estradiol (E2β), all-trans retinoic acid and okadaic acid enhanced ANXA1 mRNA expression in U937, human CCRF-CEM, ATRA-NB4 and HL-60 cell lines. Rp-8-Br-cAMPs prevented dexamethasone-, E2β- and dBcAMP-induced ANXA1 synthesis via the activation of cAMP-respond- element binding protein (CREB). ANXA1 levels were reduced dramatically in K562/ADR cells as compared to K562 cells. When ANXA1 was upregulated by transfection in these cells, the cells exhibited a decrease in resistance to ADR and vincristine. Conclusion: ANXA1 expression is induced by different drugs which leads to apoptosis in different types of cell. ANXA1 plays a role in the drug resistance of leukemic cells. Keyword: Annexin A1, ANXA1, Lipocortin-1, Renocortin, Leukemia This is an Open Access article that uses a fund-ing model which does not charge readers or their institutions for access and distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0) and the Budapest Open Access Initiative (http://www.budapestopenaccessinitiative.org/read), which permit unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. Tropical Journal of Pharmaceutical Research is indexed by Science Citation Index (SciSearch), Scopus, International Pharmaceutical Abstract, Chemical Abstracts, Embase, Index Copernicus, EBSCO, African Index Medicus, JournalSeek, Journal Citation Reports/Science Edition, Directory of Open Access Journals (DOAJ), African Journal Online, Bioline International, Open-J-Gate and Pharmacy Abstracts INTRODUCTION of leukemia such as acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic Leukemia is the sixth most common cancer in leukemia, and chronic myeloid leukemia [2]. Malaysia, and contributes to 4.4 % of all cancer cases with 4,573 cases from the year of 2007 to Annexin A1 (ANXA1) is reported to involve in 2011. Lymphoid leukemia occurs more often at various biological processes such as cellular younger age and its incidence increases with age transduction, proliferation, differentiation, [1]. Leukemia is a cancer of the early blood- apoptosis, inflammation and phagocytosis and forming cells, there are generally four main types these processes can relate to cancer [3]. The ----------------------------------------------------------------------------------------------------------------------------------------------------- © 2019 The authors. This work is licensed under the Creative CommonsTrop J Pharm Attribution Res, December 4.0 International 2019; 18(12):License 2653 Hatah et al ANXA1 is a 37 kDA protein and is the first annexin A1, annexin 1, anxa1, annexins, characterized member of the annexin lipocortin 1, calpactin II, renocortin, chromobindin superfamily. This protein was previously 9, leukemia, lymphoma, and blood cancer. Then recognised as renocortin, lipomodulin, lipocortin- articles were imported to EndNote software while 1 and phospholipase A2 (PLA2) inhibitor [4]. It is duplicates were removed from the list. widely distributed in the body, which includes biological fluids, lymphocytes, monocytes and Selection of articles granulocytes, whereby T cells and neutrophils are the predominant in the lymphocyte and During preliminary screening titles and abstracts granulocyte subgroups, respectively [5-7]. It were evaluated. Articles that could not be possesses anti-inflammatory effects and also categorized based on title and abstract were mimics the effects of glucocorticoids on retrieved as full texts. The inclusion and leukocytes such as the inhibition of superoxide exclusion criteria were used to screen full text generation, chemotaxis and eicosanoids articles. The inclusion criteria were for articles production [8]. ANXA1 is able to protect cancer that reported the roles of ANXA1 in leukemia cell cells when they are exposed to stress and lines and available in English language, including cytotoxic agents, and thus it is said to contribute those with clear description of the methodology to chemotherapeutic drug resistance [9]. A study used and results presentation. Meanwhile, by Yu et al reported that ANXA1 possibly plays a review articles, editorial letters and case studies role as a promising marker to predict drug were excluded from the study (Figure 1). resistance in bladder cancer [10]. This review reports the relationship between ANXA1 Data extraction and synthesis expression towards apoptosis and its contribution to drug resistance in leukemia cell lines. Data extracted included information on authors, year of study, cell line used, study findings and Lim and Pervaiz, 2007 reported that the ANXA1 data of significant statistical value. A summary of may have important regulatory roles in tumor the findings was presented in table form. development and progression. [4]. The protein was found to act as endogenous inhibitor of NF- Bias assessment κB in human cancer cells. The finding provided a novel molecular mechanism for the action of anti- The articles included were subjected to bias inflammatory drugs and may guide for a future assessment by using Office of Health mechanism-driven drug to inhibit cancer assessment and Translation (OHAT) risk of bias development [11]. tool [14]. Recently, many studies that related to annexin A1 in cancer were conducted. Decreased in ANXA1 expression of ANXA1 was found to correlate with breast cancer development and progression [12]. Besides, ANXA1 was also reported to contribute to the cancer progression of oral squamous cell carcinoma and may be as a potential biomarker for the pathologic differentiation grade of this cancer [13]. This study systematically reviews the involvement of ANXA1 in various leukemia cells in order to increase the understanding of ANXA1 role in leukemia. METHODS Search for relevant studies The study was conducted by using a systematic review of previous literature on ANXA1 in Figure 1: Flow diagram of the selection process and search strategy for systematic review of Annexin A1 leukemia cell lines. The study was conducted by (ANXA1) and Leukemia a comprehensive search of electronic databases namely Medline, PubMed and Scopus for all The bias assessment included the following relevant articles published until September 2017. evaluations: attrition or exclusion bias, detection The following keywords were used for retrieval: bias, selection of reporting bias that may cause Trop J Pharm Res, December 2019; 18(12): 2654 Hatah et al potential threats to the internal validity of the increased. However, the levels did not change study. Based on the assessment, the study was with longer incubation time. This study also classified into bias of low risk, high risk and showed that the level of intracellular ANXA1 unclear risk. A summary of the bias assessment protein, upon incubation for 30 min, was risk is presented in table form. significantly reduced to the base level. These results indicated that induced de novo RESULTS synthesis of ANXA1 and stimulated its secretion in CCRF-CEM cells [20]. ANXA1 and apoptosis A study of Solito et al demonstrated that A study by Tabe et al investigated the effects of dexamethasone induced the expression of FK228, a novel histone deacetylase inhibitor ANXA1 mRNA and ANXA1 protein in (HDACi), in AML-eight-twenty-one oncoprotein differentiated U-937 cells [21]. A study by Castro- (AML-ETO) positive cell lines, which included Caldas et al. in 2002 investigated the effect of Kasumi-1 and SKNO-1 cells and found an dexamethasone in CCRF-CEM cells and it was upregulated ANXA1 mRNA expression. This shown that dexamethasone at 1 μM decreased study also showed that FK228 and SAHA, which levels of intracellular ANXA1 protein and was another type of HDACi, promoted histone increased the levels of extracellular ANXA1 acetylation in ANXA1 promoter of both types of protein in these cells.