Skip to main content
Top
Published in: BMC Complementary Medicine and Therapies 1/2020

Open Access 01-12-2020 | Leukemia | Research article

Distinct anti-proliferative effects of herbal melanin on human acute monocytic leukemia THP-1 cells and embryonic kidney HEK293 cells

Authors: Adila El-Obeid, Hala Alajmi, Mashael Harbi, Wesam Bin Yahya, Hamad Al-Eidi, Monira Alaujan, Adil Haseeb, Thadeo Trivilegio, Alshaimaa Alhallaj, Saleh Alghamdi, Abdul-Wali Ajlouni, Sabine Matou-Nasri

Published in: BMC Complementary Medicine and Therapies | Issue 1/2020

Login to get access

Abstract

Background

Herbal melanin (HM) is a dark pigment extracted from the seed coat of Nigella sativa L. and known to exert biological effects via toll-like receptor 4 (TLR4). Recently, TLR4 was described as involved in natural programmed cell death (apoptosis). Tumor and embryonic cells are used as in vitro cellular models for drug and anti-cancer agent screening. To date, no cytotoxic studies have been reported of HM in TLR4-positive acute monocytic leukemia THP-1 cells compared to TLR4-negative human embryonic kidney HEK293 cells.

Methods

We studied the anti-proliferative effects of several HM concentrations on THP-1 and HEK293 cells by evaluating cell viability using the CellTiter-Glo® luminescent assay, assessing the TLR4 expression level, determining the apoptotic status, and analyzing the cell cycle distribution using flow cytometry. Apoptotic pathways were investigated using mitochondrial transition pore opening, caspase activity assays and immunoblot technology.

Results

Low HM concentrations did not affect THP-1 cell viability, but high HM concentrations (62.5–500 μg/mL) did decrease THP-1 cell viability and induced G0/G1 phase cell cycle arrest. Only at the highest concentration (500 μg/mL), HM slightly increased the TLR4 expression on the THP-1 cell surface, concomitantly upregulated TLR4 whole protein and gene expression, and induced apoptosis in THP-1 cells via activation of the extrinsic and intrinsic pathways. No change of apoptotic status was noticed in TLR4-negative HEK293 cells, although HM decreased HEK293 cell viability and induced cell growth arrest in the G2 phase.

Conclusion

HM exerts distinct anti-proliferative effects on human acute monocytic leukemia and embryonic kidney cells mainly through cell cycle interference in a TLR4-independent manner and through apoptosis induction in a TLR4-dependent manner, as observed in only the THP-1 cells.
Literature
1.
go back to reference ElObeid AS, Kamal-Eldin A, Abdelhalim MAK, Haseeb AM. Pharmacological properties of melanin and its function in health. Basic Clin Pharmacol Toxicol. 2017;120(6):515–22.PubMedCrossRef ElObeid AS, Kamal-Eldin A, Abdelhalim MAK, Haseeb AM. Pharmacological properties of melanin and its function in health. Basic Clin Pharmacol Toxicol. 2017;120(6):515–22.PubMedCrossRef
2.
go back to reference Lampel A, McPhee SA, Park HA, Scott GG, Humagain S, et al. Polymeric peptide pigments with sequence-encoded properties. Science. 2017;356(6342):1064–8.PubMedCrossRef Lampel A, McPhee SA, Park HA, Scott GG, Humagain S, et al. Polymeric peptide pigments with sequence-encoded properties. Science. 2017;356(6342):1064–8.PubMedCrossRef
4.
go back to reference Ahmad A, Husain A, Mujeeb M, Khan SA, Najmi AK, et al. A review on therapeutic potential of Nigella sativa: a miracle herb. Asian Pac J Trop Biomed. 2013;3(5):337–52.PubMedPubMedCentralCrossRef Ahmad A, Husain A, Mujeeb M, Khan SA, Najmi AK, et al. A review on therapeutic potential of Nigella sativa: a miracle herb. Asian Pac J Trop Biomed. 2013;3(5):337–52.PubMedPubMedCentralCrossRef
5.
go back to reference Abdelhalim MAK, Moussa SAA, Qaid HA, Al-Ayed MS. Effect of melanin on gold nanoparticle-induced hepatotoxicity and lipid peroxidation in rats. Int J Nanomedicine. 2018;13:5207–13.PubMedPubMedCentralCrossRef Abdelhalim MAK, Moussa SAA, Qaid HA, Al-Ayed MS. Effect of melanin on gold nanoparticle-induced hepatotoxicity and lipid peroxidation in rats. Int J Nanomedicine. 2018;13:5207–13.PubMedPubMedCentralCrossRef
6.
go back to reference Christensen BM, Li J, Chen CC, Nappi AJ. Melanization immune responses in mosquito vectors. Trends Parasitol. 2005;21(4):192–9.PubMedCrossRef Christensen BM, Li J, Chen CC, Nappi AJ. Melanization immune responses in mosquito vectors. Trends Parasitol. 2005;21(4):192–9.PubMedCrossRef
8.
go back to reference Tapia CV, Falconer M, Tempio F, Falcón F, López M, et al. Melanocytes and melanin represent a first line of innate immunity against Candida albicans. Med Mycol. 2014;52(5):445–52.PubMedCrossRef Tapia CV, Falconer M, Tempio F, Falcón F, López M, et al. Melanocytes and melanin represent a first line of innate immunity against Candida albicans. Med Mycol. 2014;52(5):445–52.PubMedCrossRef
12.
go back to reference Mulé JJ, McIntosh JK, Jablons DM, Rosenberg SA. Antitumor activity of recombinant interleukin 6 in mice. J Exp Med. 1990;171(3):629–36.PubMedCrossRef Mulé JJ, McIntosh JK, Jablons DM, Rosenberg SA. Antitumor activity of recombinant interleukin 6 in mice. J Exp Med. 1990;171(3):629–36.PubMedCrossRef
13.
go back to reference Kircheis R, Ostermann E, Wolscheck MF, Lichtenberger C, Magin-Lachmann C, et al. Tumor-targeted gene delivery of tumor necrosis factor-alpha induces tumor necrosis and tumor regression without systemic toxicity. Cancer Gene Ther. 2002;9(8):673–80.PubMedCrossRef Kircheis R, Ostermann E, Wolscheck MF, Lichtenberger C, Magin-Lachmann C, et al. Tumor-targeted gene delivery of tumor necrosis factor-alpha induces tumor necrosis and tumor regression without systemic toxicity. Cancer Gene Ther. 2002;9(8):673–80.PubMedCrossRef
14.
go back to reference El-Obeid A, Al-Harbi S, Al-Jomah N, Hassib A. Herbal melanin modulates tumor necrosis factor alpha (TNF-alpha), interleukin 6 (IL-6) and vascular endothelial growth factor (VEGF) production. Phytomedicine. 2006;13(5):324–33.PubMedCrossRef El-Obeid A, Al-Harbi S, Al-Jomah N, Hassib A. Herbal melanin modulates tumor necrosis factor alpha (TNF-alpha), interleukin 6 (IL-6) and vascular endothelial growth factor (VEGF) production. Phytomedicine. 2006;13(5):324–33.PubMedCrossRef
15.
go back to reference Öberg F, Haseeb A, Ahnfelt M, El-Obeid A. Herbal melanin activates TLR4/NF-kappaB signaling pathway. Phytomedicine. 2009;16(5):477–84.PubMedCrossRef Öberg F, Haseeb A, Ahnfelt M, El-Obeid A. Herbal melanin activates TLR4/NF-kappaB signaling pathway. Phytomedicine. 2009;16(5):477–84.PubMedCrossRef
16.
go back to reference Ricci-Azevedo R, Roque-Barreira MC, Gay NJ. Targeting and recognition of toll-like receptors by plant and pathogen lectins. Front Immunol. 2017;8:1820.PubMedPubMedCentralCrossRef Ricci-Azevedo R, Roque-Barreira MC, Gay NJ. Targeting and recognition of toll-like receptors by plant and pathogen lectins. Front Immunol. 2017;8:1820.PubMedPubMedCentralCrossRef
17.
go back to reference Liu B, Sun R, Luo H, Liu X, Jiang M, et al. Both intrinsic and extrinsic apoptotic pathways are involved in toll-like receptor 4 (TLR4)-induced cell death in monocytic THP-1 cells. Immunobiology. 2017;222(2):198–205.PubMedCrossRef Liu B, Sun R, Luo H, Liu X, Jiang M, et al. Both intrinsic and extrinsic apoptotic pathways are involved in toll-like receptor 4 (TLR4)-induced cell death in monocytic THP-1 cells. Immunobiology. 2017;222(2):198–205.PubMedCrossRef
18.
go back to reference Sharma J, Boyd T, Alvarado C, Gunn E, Adams J, et al. Reporter cell assessment of TLR4-induced NF-kB responses to cell-free hemoglobin and the influence of biliverdin. Biomedicines. 2019;7:41.PubMedCentralCrossRef Sharma J, Boyd T, Alvarado C, Gunn E, Adams J, et al. Reporter cell assessment of TLR4-induced NF-kB responses to cell-free hemoglobin and the influence of biliverdin. Biomedicines. 2019;7:41.PubMedCentralCrossRef
19.
21.
go back to reference Peyret V, Nazar M, Martín M, Quintar AA, Fernandez EA, et al. Functional toll-like receptor 4 overexpression in papillary thyroid cancer by MAPK/ERK-induced ETS1 transcriptional activity. Mol Cancer Res. 2018;16(5):833–45.PubMedCrossRef Peyret V, Nazar M, Martín M, Quintar AA, Fernandez EA, et al. Functional toll-like receptor 4 overexpression in papillary thyroid cancer by MAPK/ERK-induced ETS1 transcriptional activity. Mol Cancer Res. 2018;16(5):833–45.PubMedCrossRef
22.
go back to reference Hsu HY, Lin TY, Lu MK, Leng PJ, Tsao SM, Wu YC. Fucoidan induced toll-like receptor 4-regulated reactive oxygen species and promotes endoplasmic reticulum stress-mediated apoptosis in lung cancer. Sci Rep. 2017;7:44990.PubMedPubMedCentralCrossRef Hsu HY, Lin TY, Lu MK, Leng PJ, Tsao SM, Wu YC. Fucoidan induced toll-like receptor 4-regulated reactive oxygen species and promotes endoplasmic reticulum stress-mediated apoptosis in lung cancer. Sci Rep. 2017;7:44990.PubMedPubMedCentralCrossRef
23.
go back to reference Li C, Che LH, Ji TF, Shi L, Yu JL. Effects of the TLR4 signaling pathway on apoptosis of neuronal cells in diabetes mellitus complicated with cerebral infarction in a rat model. Sci Rep. 2017;7:43834.PubMedPubMedCentralCrossRef Li C, Che LH, Ji TF, Shi L, Yu JL. Effects of the TLR4 signaling pathway on apoptosis of neuronal cells in diabetes mellitus complicated with cerebral infarction in a rat model. Sci Rep. 2017;7:43834.PubMedPubMedCentralCrossRef
25.
go back to reference Haase R, Kirschning CJ, Sing A, Schröttner P, Fukase K, et al. A dominant role of toll-like receptor 4 on the signaling of apoptosis in bacteria-faced macrophages. J Immunol. 2003;171(8):4294–303.PubMedCrossRef Haase R, Kirschning CJ, Sing A, Schröttner P, Fukase K, et al. A dominant role of toll-like receptor 4 on the signaling of apoptosis in bacteria-faced macrophages. J Immunol. 2003;171(8):4294–303.PubMedCrossRef
26.
go back to reference Cai C, Chen W, Miao D, Cheng L, Yang G, et al. Toll-like receptor 4 (TLR4) is required for the cytotoxicity of cytokine-induced killer cells. Acta Haematol. 2014;132(1):5–9.PubMedCrossRef Cai C, Chen W, Miao D, Cheng L, Yang G, et al. Toll-like receptor 4 (TLR4) is required for the cytotoxicity of cytokine-induced killer cells. Acta Haematol. 2014;132(1):5–9.PubMedCrossRef
27.
go back to reference Bhatia S, Miller NJ, Lu H, Longino NV, Ibrani D, et al. Intratumoral G100, a TLR4 agonist, induces anti-tumor immune responses and tumor regression in patients with Merkel cell carcinoma. Clin Cancer Res. 2019;25(4):1185–95.PubMedCrossRef Bhatia S, Miller NJ, Lu H, Longino NV, Ibrani D, et al. Intratumoral G100, a TLR4 agonist, induces anti-tumor immune responses and tumor regression in patients with Merkel cell carcinoma. Clin Cancer Res. 2019;25(4):1185–95.PubMedCrossRef
28.
go back to reference Hu J, Han J, Li H, Zhang X, Liu LL, et al. Human embryonic kidney 293 cells: a vehicle for biopharmaceutical manufacturing, structural biology, and electrophysiology. Cells Tissues Organs. 2019;205(1):1–8.CrossRef Hu J, Han J, Li H, Zhang X, Liu LL, et al. Human embryonic kidney 293 cells: a vehicle for biopharmaceutical manufacturing, structural biology, and electrophysiology. Cells Tissues Organs. 2019;205(1):1–8.CrossRef
31.
go back to reference Zeise L. Analytical methods for characterization and identification of melanins. In: Zeise L, Chedekel M, Fitzpatrick T, editors. Melanin: Its Role in Human Photoprotection. Over- land Park, Kansas: Valdenmar Publishing Company; 1995. p. 65–7. Zeise L. Analytical methods for characterization and identification of melanins. In: Zeise L, Chedekel M, Fitzpatrick T, editors. Melanin: Its Role in Human Photoprotection. Over- land Park, Kansas: Valdenmar Publishing Company; 1995. p. 65–7.
32.
go back to reference Matou-Nasri S, Rhaban Z, Albuyaijan H, Al-Eidi H, Yahya WB, et al. CD95-mediated apoptosis in Burkitt’s lymphoma B-cells is associated with Pim-1 down-regulation. Biochim Biophys Acta Mol basis Dis. 2017;1863(1):239–52.PubMedCrossRef Matou-Nasri S, Rhaban Z, Albuyaijan H, Al-Eidi H, Yahya WB, et al. CD95-mediated apoptosis in Burkitt’s lymphoma B-cells is associated with Pim-1 down-regulation. Biochim Biophys Acta Mol basis Dis. 2017;1863(1):239–52.PubMedCrossRef
33.
go back to reference Yoon YK, Woo HJ, Kim Y. Orostachys japonicus inhibits expression of the TLR4, NOD2, iNOS, and COX2 genes in LPS-stimulated human PMA-differentiated THP-1 cells by inhibiting NF-kB and MAPK activation. Evid Based Complement Alternat Med. 2015;2015:682019.PubMedPubMedCentralCrossRef Yoon YK, Woo HJ, Kim Y. Orostachys japonicus inhibits expression of the TLR4, NOD2, iNOS, and COX2 genes in LPS-stimulated human PMA-differentiated THP-1 cells by inhibiting NF-kB and MAPK activation. Evid Based Complement Alternat Med. 2015;2015:682019.PubMedPubMedCentralCrossRef
34.
go back to reference Samadi AK, Bilsland A, Georgakilas AG, Amedei A, Amin A, Bishayee A, et al. A multi-targeted approach to suppress tumor-promoting inflammation. Semin Cancer Biol. 2015;35(Suppl):S151–84.PubMedCrossRef Samadi AK, Bilsland A, Georgakilas AG, Amedei A, Amin A, Bishayee A, et al. A multi-targeted approach to suppress tumor-promoting inflammation. Semin Cancer Biol. 2015;35(Suppl):S151–84.PubMedCrossRef
39.
go back to reference Blinova MI, Yudintseva NM, Kalmykova NV, Kuzminykh EV, Yurlova NA, et al. Effect of melanins from black yeast fungi on proliferation and differentiation of cultivated human keratinocytes and fibroblasts. Cell Biol Int. 2003;27(2):135–46.PubMedCrossRef Blinova MI, Yudintseva NM, Kalmykova NV, Kuzminykh EV, Yurlova NA, et al. Effect of melanins from black yeast fungi on proliferation and differentiation of cultivated human keratinocytes and fibroblasts. Cell Biol Int. 2003;27(2):135–46.PubMedCrossRef
40.
go back to reference El-Naggar NE, El-Ewasy SM. Bioproduction, characterization, anticancer and antioxidant activities of extracellular melanin pigment produced by newly isolated microbial cell factories Streptomyces glaucescens NEAE-H. Sci Rep. 2017;7:42129.PubMedPubMedCentralCrossRef El-Naggar NE, El-Ewasy SM. Bioproduction, characterization, anticancer and antioxidant activities of extracellular melanin pigment produced by newly isolated microbial cell factories Streptomyces glaucescens NEAE-H. Sci Rep. 2017;7:42129.PubMedPubMedCentralCrossRef
41.
go back to reference Yoo HS, Chung KH, Lee KJ, Dim DH, An JH. Melanin extract from Gallus gallus domesticus promotes proliferation and differentiation of osteoblastic MG-63 cells via bone morphogenetic protein-2 signaling. Nutr Res Pract. 2017;11(3):190–7.PubMedPubMedCentralCrossRef Yoo HS, Chung KH, Lee KJ, Dim DH, An JH. Melanin extract from Gallus gallus domesticus promotes proliferation and differentiation of osteoblastic MG-63 cells via bone morphogenetic protein-2 signaling. Nutr Res Pract. 2017;11(3):190–7.PubMedPubMedCentralCrossRef
42.
go back to reference Yan X, Wang T, Ming Y, Yey Y, Chen T, et al. Melanin uptake reduces cell proliferation of human epidermal keratinocytes. J Cosm Dermatol Sci Appl. 2015;5(4):300–10. Yan X, Wang T, Ming Y, Yey Y, Chen T, et al. Melanin uptake reduces cell proliferation of human epidermal keratinocytes. J Cosm Dermatol Sci Appl. 2015;5(4):300–10.
43.
go back to reference Zhang Y, Chen X, Gueydan C, Han J. Plasma membrane changes during programmed cell deaths. Cell Res. 2018;28(1):9–21.PubMedCrossRef Zhang Y, Chen X, Gueydan C, Han J. Plasma membrane changes during programmed cell deaths. Cell Res. 2018;28(1):9–21.PubMedCrossRef
45.
go back to reference Naoi M, Maruyama W, Yi H, Yamaoka Y, Shamoto-Nagai M, et al. Neuromelanin selectively induces apoptosis in dopaminergic SH-SY5Y cells by deglutathionylation in mitochondria: involvement of the protein and melanin component. J Neurochem. 2008;105(6):2489–500.PubMedCrossRef Naoi M, Maruyama W, Yi H, Yamaoka Y, Shamoto-Nagai M, et al. Neuromelanin selectively induces apoptosis in dopaminergic SH-SY5Y cells by deglutathionylation in mitochondria: involvement of the protein and melanin component. J Neurochem. 2008;105(6):2489–500.PubMedCrossRef
Metadata
Title
Distinct anti-proliferative effects of herbal melanin on human acute monocytic leukemia THP-1 cells and embryonic kidney HEK293 cells
Authors
Adila El-Obeid
Hala Alajmi
Mashael Harbi
Wesam Bin Yahya
Hamad Al-Eidi
Monira Alaujan
Adil Haseeb
Thadeo Trivilegio
Alshaimaa Alhallaj
Saleh Alghamdi
Abdul-Wali Ajlouni
Sabine Matou-Nasri
Publication date
01-12-2020
Publisher
BioMed Central
Keyword
Leukemia
Published in
BMC Complementary Medicine and Therapies / Issue 1/2020
Electronic ISSN: 2662-7671
DOI
https://doi.org/10.1186/s12906-020-02944-1

Other articles of this Issue 1/2020

BMC Complementary Medicine and Therapies 1/2020 Go to the issue