Mangiferin induces cell cycle arrest at G2/M phase through ATR-Chk1 pathway in HL-60 leukemia cells
Open accessAbstract
This study aimed to determine the effect of mangiferin on the cell cycle in HL-60 leukemia cells and expression of the cell cycle-regulatory genes Wee1, Chk1 and CDC25C and to further investigate the molecular mechanisms of the antileukemic action of mangiferin. The inhibitory effect of mangiferin on HL-60 leukemia cell proliferation was determined by the MTT assay. The impact of mangiferin on the HL-60 cell cycle was evaluated by flow cytometry. After the cells were treated with different concentrations of mangiferin, the expression levels of Wee1, Chk1 and CDC25C mRNA were determined by RT-PCR, and Western blot was used to evaluate the expression levels of cdc25c, cyclin B1, and Akt proteins. The inhibition of HL-60 cell growth by mangiferin was dose- and time-dependent. After treatment for 24 h, cells in G2/M phase increased, and G2/M phase arrest appeared with increased mRNA expression of Wee1, Chk1 and CDC25C. Mangiferin inhibited Chk1 and cdc25c mRNA expression at high concentrations and induced Wee1 mRNA expression in a dose-dependent manner. It significantly inhibited ATR, Chk1, Wee1, Akt, and ERK1/2 phosphorylation but increased cdc2 and cyclin B1 phosphorylation. Furthermore, mangiferin reduced cdc25c, cyclin B1, and Akt protein levels while inducing Wee1 protein expression. It also antagonized the phosphorylation effect of vanadate on ATR, and the phosphorylation effect of EGF on Wee1. These findings indicated that mangiferin inhibits cell cycle progression through the ATR-Chk1 stress response DNA damage pathway, leading to cell cycle arrest at G2/M phase in leukemia cells.
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Results vary across cell lines and animal strains.
“Notably, the results vary across cell lines and animal strains, and several mechanisms that are frequently cited (for example, NF-κB or MMP-9 modulation, G2/M arrest and AMPK activation) appear to be highly context dependent, with inconsistent replication under different stimuli or dosing conditions (4,13,117,124,186,187).”
From Mangiferin in human disease: Multifaceted mechanisms and applications (Review) (2026) · cites this paper as [186]
The Discussion reports that G2/M arrest in HL-60 cells changes with mangiferin concentration and treatment time, including a possible switch in checkpoint effect at higher concentrations. The study does not compare cell lines or animal strains, or assess whether the mechanism replicates under different stimuli; those parts of the cited claim are unsupported. (LLM, conf=0.82)
Experimental — accuracy not yet measuredSeveral frequently cited mechanisms (NF-κB or MMP-9 modulation, G2/M arrest, AMPK activation) are highly context dependent and inconsistently replicated.
“Notably, the results vary across cell lines and animal strains, and several mechanisms that are frequently cited (for example, NF-κB or MMP-9 modulation, G2/M arrest and AMPK activation) appear to be highly context dependent, with inconsistent replication under different stimuli or dosing conditions (4,13,117,124,186,187).”
From Mangiferin in human disease: Multifaceted mechanisms and applications (Review) (2026) · cites this paper as [186]
The Discussion’s Table 2 reports mangiferin-associated G2/M arrest in HL-60 cells, with the measured proportion varying by dose and treatment time. The paper does not establish inconsistent replication across cell lines, animal strains, or different stimuli, nor does it test NF-κB, MMP-9, or AMPK as part of that claim. (LLM, conf=0.85)
Experimental — accuracy not yet measuredMangiferin triggers G2/M phase cell cycle arrest via regulation of the CDK1-cyclin B1 signaling pathway.
“Notably, mangiferin has been validated to trigger G2/M phase cell cycle arrest via regulation of the CDK1-cyclin B1 signaling pathway (49)(50)(51).”
From Mangiferin: An effective therapeutic agent against several disorders (Review) (2018) · cites this paper as [50]
The Discussion reports G2/M arrest in HL-60 cells, and the protein-expression results show changes in cdc2 (CDK1) and cyclin B1 after mangiferin treatment. But the Discussion describes arrest through the cdc2/cyclin B pathway as a hypothesis, not a validated mechanism; the claim also omits the HL-60 cell context. Our copy provides no page number for these passages. (LLM, conf=0.85)
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Guha, S., Ghosal, S., & Chattopadhyay, U. (2009) · Chemotherapy · doi:10.1159/000239478 · Cited by 275 · cited 3× · see citing works
“Their derivatives such as flavopiridol and genistein have been used safely in human trials (Guha et al., 1996; Huang et al., 2001) to be further applied to experimental evaluation of solid tumors in clinical phaseII (Makare et al., 2001; Garcia et al., 2003).”
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- Muruganandan S, Lal J and Gupta PK (2005). Immunotherapeutic effects of mangiferin mediated by the inhibition of ©FUNPEC-RP www.funpecrp.com.br Genetics and Molecular Research 14 (2): 4989-5002 (2015) oxidative stress to activated lymphocytes, neutrophils and macrophages. Toxicology 215: 57-68.
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Gold-Smith, F., Fernandez, A., & Bishop, K. (2016) · Nutrients · doi:10.3390/nu8070396 · Cited by 158 · see citing works
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Du, S., Liu, H., Lei, T., Xie, X., Wang, H., He, X., Tong, R., & Wang, Y. (2018) · Molecular Medicine Reports · doi:10.3892/mmr.2018.9529 · Cited by 139 · see citing works
“Notably, mangiferin has been validated to trigger G2/M phase cell cycle arrest via regulation of the CDK1-cyclin B1 signaling pathway (49-51).”
Morozkina, S. N., Nhung Vu, T. H., Generalova, Y. E., Snetkov, P. P., & Uspenskaya, M. V. (2021) · Biomolecules · doi:10.3390/biom11010079 · Cited by 82 · see citing works
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Mangiferin in human disease: Multifaceted mechanisms and applications (Review)
Dai, Y., Huang, Q., Tan, M., Wang, Z., Jiang, C., Liu, Z., Zhang, S., & Song, S. (2026) · International Journal of Molecular Medicine · doi:10.3892/ijmm.2026.5736 · Cited by 3 · see citing works
“…without orthogonal validation or causal rescue experiments, and dose‑response and time‑course data are incomplete for several indications (13,186,189). comparative efficacy vs. standard of care is rarely tested, and combination studies seldom include PK or Pd interaction assessments.”
- Authors
- Peng, Z. G., Yao, Y. B., Yang, J., Tang, Y. L., & Huang, X.
- Affiliations
- Guangxi Medical University (CN)
- Venue
- Genetics and Molecular Research
- Publisher
- Genetics and Molecular Research
- Published
- 2015
- Volume
- 14
- Issue
- 2
- Pages
- 4989-5002
- ISSN
- 1676-5680 (ISSN-L)
- OpenAlex
- W268446039
- Cited by
- 41
- References
- 1
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 4 · 2023: 3 · 2022: 5 · 2021: 5 · 2020: 5 · 2019: 1 · 2018: 4 · 2017: 4 · 2016: 3 · 2015: 2
- FWCI
- 8.46
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by
- Locations
- Genetics and Molecular Research (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Complementary and alternative medicine › Mangiferin and Mango Extracts
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
- Keywords
- mangiferin, HL-60 cells, G2/M cell cycle arrest, ATR-Chk1 pathway, WEE1, Chk1, Cdc25C, cdc2, cyclin B1, Akt, ERK1/2 phosphorylation, DNA damage response, antileukemic activity, cell proliferation inhibition
- MeSH terms
- Checkpoint Kinase 1, Humans, Leukemia, Neoplasm Proteins, Protein Kinases, RNA, Messenger, Signal Transduction, Gene Expression Regulation, Leukemic, HL-60 Cells, Xanthones, Cell Cycle Checkpoints, G2 Phase Cell Cycle Checkpoints, Ataxia Telangiectasia Mutated Proteins
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