The Citrus Flavanone Hesperetin Induces Apoptosis in CTCL Cells via STAT3/Notch1/NFκB-Mediated Signaling Axis

Author(s): Amuthavalli Kottaiswamy*, Atish Kizhakeyil, Abirami M. Padmanaban, Fathima B. Mirza, Venkatesh R. Vijay, Pin S. Lee, Navin K. Verma, Parkavi Kalaiselvan, Shila Samuel*

Journal Name: Anti-Cancer Agents in Medicinal Chemistry
(Formerly Current Medicinal Chemistry - Anti-Cancer Agents)

Volume 20 , Issue 12 , 2020


Become EABM
Become Reviewer
Call for Editor

Graphical Abstract:


Abstract:

Background: Hesperetin is a natural compound known for its cholesterol-lowering effect and a wide range of pharmacological activities.

Objectives: Investigating the potential anticancer activities of Hesperetin in malignant hematolymphoid cell lines HuT78 and MJ, derived from patients with Cutaneous T-Cell Lymphomas (CTCL).

Methods: The cytotoxic effect of Hesperetin on two different CTCL cell lines, HuT78 and MJ, was assessed by MTS-based colorimetric assay. Apoptosis, cell cycle, ROS (Reactive Oxygen Species) and molecular analysis were performed using flow-cytometry and immunoblotting.

Results: Hesperetin-treated CTCL cells were arrested at the sub-G1 phase of cell cycle with the concomitant decrease in the expression of the cell cycle regulator protein cyclin B. In addition, the study found that the cellular treatment with Hesperetin caused an induction of apoptosis, which was independent of ROS generation. Hesperetin caused a significant decrease in the expression level of anti-apoptotic protein Bcl-xL and an increase in cleaved caspase-3 and PARP proteins in CTCL cells. Furthermore, Hesperetin treatment in CTCL cells down-regulated the expression of Notch1 and phosphorylation of STAT3 (Tyr705) and inhibited NFκBp65.

Conclusion: This study highlights the anticancer properties of Hesperetin. Which induces apoptosis in CTCL cells via STAT3/Notch1/NFκB mediated signaling pathway, suggesting that further development of this novel class of flavonoid may contribute to new drug discovery for certain hematolymphoid malignancies.

Keywords: Apoptosis, CTCL, ROS, Notch1, STAT3, NFκB.

[1]
Miranda-Filho, A.; Piñeros, M.; Ferlay, J.; Soerjomataram, I.; Monnereau, A.; Bray, F. Epidemiological patterns of leukaemia in 184 countries: A population-based study. Lancet Haematol., 2018, 5(1), e14-e24.
[http://dx.doi.org/10.1016/S2352-3026(17)30232-6]] [PMID: 29304322]
[2]
Siegel, R.L.; Miller, K.D.; Jemal, A. Cancer statistics, 2016. CA Cancer J. Clin., 2016, 66(1), 7-30.
[http://dx.doi.org/10.3322/caac.21332] [PMID: 26742998]
[3]
Verma, N.K.; Sadeer, A.; Kizhakeyil, A.; Pang, J.H.; Chiu, Q.Y.A.; Tay, S.W.; Kumar, P.; Pullarkat, S.A. Screening of ferrocenyl–phosphines identifies a gold-coordinated derivative as a novel anticancer agent for hematological malignancies. RSC Advances, 2018, 8(51), 28960-28968.
[http://dx.doi.org/10.1039/C8RA05224G]
[4]
Raffa, D.; Maggio, B.; Raimondi, M.V.; Plescia, F.; Daidone, G. Recent discoveries of anticancer flavonoids. Eur. J. Med. Chem., 2017, 142, 213-228.
[http://dx.doi.org/10.1016/j.ejmech.2017.07.034] [PMID: 28793973]
[5]
Cencic, A.; Chingwaru, W. The role of functional foods, nutraceuticals, and food supplements in intestinal health. Nutrients, 2010, 2(6), 611-625.
[http://dx.doi.org/10.3390/nu2060611] [PMID: 22254045]
[6]
Muscatello, M.R.A.; Zoccali, R.A.; Bruno, A. Citrus Fruit polyphenols and flavonoids: Applications to psychiatric disorders. In: Polyphenols: Mechanisms of Action in Human Health and Disease; Elsevier, 2018; pp. 119-131.
[http://dx.doi.org/10.1016/B978-0-12-813006-3.00011-8]
[7]
Benavente-García, O.; Castillo, J. Update on uses and properties of citrus flavonoids: New findings in anticancer, cardiovascular, and anti-inflammatory activity. J. Agric. Food Chem., 2008, 56(15), 6185-6205.
[http://dx.doi.org/10.1021/jf8006568]] [PMID: 18593176]
[8]
Adan, A.; Baran, Y. Fisetin and hesperetin induced apoptosis and cell cycle arrest in chronic myeloid leukemia cells accompanied by modulation of cellular signaling. Tumour Biol., 2016, 37(5), 5781-5795.
[http://dx.doi.org/10.1007/s13277-015-4118-3] [PMID: 26408178]
[9]
Sivagami, G.; Vinothkumar, R.; Bernini, R.; Preethy, C.P.; Riyasdeen, A.; Akbarsha, M.A.; Menon, V.P.; Nalini, N. Role of hesperetin (a natural flavonoid) and its analogue on apoptosis in HT-29 human colon adenocarcinoma cell line--a comparative study. Food Chem. Toxicol., 2012, 50(3-4), 660-671.
[http://dx.doi.org/10.1016/j.fct.2011.11.038] [PMID: 22142698]
[10]
Alshatwi, A.A.; Ramesh, E.; Periasamy, V.S.; Subash-Babu, P. The apoptotic effect of hesperetin on human cervical cancer cells is mediated through cell cycle arrest, death receptor, and mitochondrial pathways. Fundam. Clin. Pharmacol., 2013, 27(6), 581-592.
[http://dx.doi.org/10.1111/j.1472-8206.2012.01061.x] [PMID: 22913657]
[11]
Palit, S.; Kar, S.; Sharma, G.; Das, P.K. Hesperetin induces apoptosis in breast carcinoma by triggering accumulation of ROS and activation of ASK1/JNK pathway. J. Cell. Physiol., 2015, 230(8), 1729-1739.
[http://dx.doi.org/10.1002/jcp.24818] [PMID: 25204891]
[12]
Ranjan, A.; Iwakuma, T. Non-canonical cell death induced by p53. Int. J. Mol. Sci., 2016, 17(12), 2068.
[http://dx.doi.org/10.3390/ijms17122068] [PMID: 27941671]
[13]
Johnson, D.G.; Walker, C.L. Cyclins and cell cycle checkpoints. Annu. Rev. Pharmacol. Toxicol., 1999, 39(1), 295-312.
[http://dx.doi.org/10.1146/annurev.pharmtox.39.1.295] [PMID: 10331086]
[14]
Barnum, K.J.; O’Connell, M.J. Cell cycle regulation by checkpoints. In: Cell Cycle Control; Springer, 2014; pp. 29-40.
[15]
Bononi, A.; Agnoletto, C.; De Marchi, E.; Marchi, S.; Patergnani, S.; Bonora, M.; Giorgi, C.; Missiroli, S.; Poletti, F.; Rimessi, A. Protein kinases and phosphatases in the control of cell fate. Enzyme Res., 2011, 2011, Article ID 329098.
[http://dx.doi.org/10.4061/2011/329098]
[16]
Bertrand, F.E.; McCubrey, J.A.; Angus, C.W.; Nutter, J.M.; Sigounas, G. NOTCH and PTEN in prostate cancer. Adv. Biol. Regul., 2014, 56, 51-65.
[http://dx.doi.org/10.1016/j.jbior.2014.05.002] [PMID: 24933481]
[17]
Al-Yacoub, N.; Fecker, L.F.; Möbs, M.; Plötz, M.; Braun, F.K.; Sterry, W.; Eberle, J. Apoptosis induction by SAHA in cutaneous T-cell lymphoma cells is related to downregulation of c-FLIP and enhanced TRAIL signaling. J. Invest. Dermatol., 2012, 132(9), 2263-2274.
[http://dx.doi.org/10.1038/jid.2012.125] [PMID: 22551975]
[18]
Olsen, E.A.; Hodak, E.; Anderson, T.; Carter, J.B.; Henderson, M.; Cooper, K.; Lim, H.W. Guidelines for phototherapy of mycosis fungoides and Sézary syndrome: A consensus statement of the United States Cutaneous Lymphoma Consortium. J. Am. Acad. Dermatol., 2016, 74(1), 27-58.
[http://dx.doi.org/10.1016/j.jaad.2015.09.033] [PMID: 26547257]
[19]
Zic, J.A. Photopheresis in the treatment of cutaneous T-cell lymphoma: Current status. Curr. Opin. Oncol., 2012, 24(Suppl. 1), S1-S10.
[http://dx.doi.org/10.1097/01.cco.0000410158.56500.c4]] [PMID: 22157241]
[20]
Duvic, M. Histone deacetylase inhibitors for cutaneous T-cell lymphoma. Dermatol. Clin., 2015, 33(4), 757-764.
[http://dx.doi.org/10.1016/j.det.2015.05.010] [PMID: 26433847]
[21]
Wang, Y.; Yu, H.; Zhang, J.; Gao, J.; Ge, X.; Lou, G. Hesperidin inhibits HeLa cell proliferation through apoptosis mediated by endoplasmic reticulum stress pathways and cell cycle arrest. BMC Cancer, 2015, 15(1), 682.
[http://dx.doi.org/10.1186/s12885-015-1706-y] [PMID: 26459308]
[22]
Porter, A.G.; Jänicke, R.U. Emerging roles of caspase-3 in apoptosis. Cell Death Differ., 1999, 6(2), 99-104.
[http://dx.doi.org/10.1038/sj.cdd.4400476] [PMID: 10200555]
[23]
Hata, A.N.; Engelman, J.A.; Faber, A.C. The BCL2 family: Key mediators of the apoptotic response to targeted anticancer therapeutics. Cancer Discov., 2015, 5(5), 475-487.
[http://dx.doi.org/10.1158/2159-8290.CD-15-0011] [PMID: 25895919]
[24]
Wilcox, R.A. Cutaneous T-cell lymphoma: 2016 update on diagnosis, risk-stratification, and management. Am. J. Hematol., 2016, 91(1), 151-165.
[http://dx.doi.org/10.1002/ajh.24233] [PMID: 26607183]
[25]
Sambantham, S.; Radha, M.; Paramasivam, A.; Anandan, B.; Malathi, R.; Chandra, S.R.; Jayaraman, G. Molecular mechanism underlying hesperetin-induced apoptosis by in silico analysis and in prostate cancer PC-3 cells. Asian Pac. J. Cancer Prev., 2013, 14(7), 4347-4352.
[http://dx.doi.org/10.7314/APJCP.2013.14.7.4347] [PMID: 23992001]
[26]
Cardoso, B.A.; Gírio, A.; Henriques, C.; Martins, L.R.; Santos, C.; Silva, A.; Barata, J.T. Aberrant signaling in T-cell acute lymphoblastic leukemia: biological and therapeutic implications. Braz. J. Med. Biol. Res., 2008, 41(5), 344-350.
[http://dx.doi.org/10.1590/S0100-879X2008005000016] [PMID: 18488097]
[27]
Sors, A.; Jean-Louis, F.; Pellet, C.; Laroche, L.; Dubertret, L.; Courtois, G.; Bachelez, H.; Michel, L. Down-regulating constitutive activation of the NF-kappaB canonical pathway overcomes the resistance of cutaneous T-cell lymphoma to apoptosis. Blood, 2006, 107(6), 2354-2363.
[http://dx.doi.org/10.1182/blood-2005-06-2536] [PMID: 16219794]
[28]
Patel, P.N.; Yu, X-M.; Jaskula-Sztul, R.; Chen, H. Hesperetin activates the Notch1 signaling cascade, causes apoptosis, and induces cellular differentiation in anaplastic thyroid cancer. Ann. Surg. Oncol., 2014, 21(4)(Suppl. 4), S497-S504.
[http://dx.doi.org/10.1245/s10434-013-3459-7] [PMID: 24419754]
[29]
Kamstrup, M.R.; Gjerdrum, L.M.R.; Biskup, E.; Lauenborg, B.T.; Ralfkiaer, E.; Woetmann, A.; Ødum, N.; Gniadecki, R. Notch1 as a potential therapeutic target in cutaneous T-cell lymphoma. Blood, 2010, 116(14), 2504-2512.
[http://dx.doi.org/10.1182/blood-2009-12-260216] [PMID: 20538790]
[30]
Hsu, K-W.; Hsieh, R-H.; Huang, K-H.; Fen-Yau Li, A.; Chi, C-W.; Wang, T-Y.; Tseng, M-J.; Wu, K-J.; Yeh, T-S. Activation of the Notch1/STAT3/Twist signaling axis promotes gastric cancer progression. Carcinogenesis, 2012, 33(8), 1459-1467.
[http://dx.doi.org/10.1093/carcin/bgs165] [PMID: 22581828]
[31]
Wen, Z.; Zhong, Z.; Darnell, J.E., Jr Maximal activation of transcription by Stat1 and Stat3 requires both tyrosine and serine phosphorylation. Cell, 1995, 82(2), 241-250.
[http://dx.doi.org/10.1016/0092-8674(95)90311-9] [PMID: 7543024]
[32]
Krishnan, G.; Subramaniyan, J.; Subramani, P.C.; Thiruvengadam, D. Nanochemopreventive effect of polymer functionalized gold nanoparticles containing hesperetin drug inhibited proliferation and induced apoptosis in Hep3B cells. J. Appl. Pharm. Sci., 2016, 6(12), 114-123.
[http://dx.doi.org/10.7324/JAPS.2016.601216]
[33]
Hildebrand, D.; Uhle, F.; Sahin, D.; Krauser, U.; Weigand, M.A.; Heeg, K. The interplay of Notch signaling and STAT3 in TLR-activated human primary monocytes. Front. Cell. Infect. Microbiol., 2018, 8, 241.
[http://dx.doi.org/10.3389/fcimb.2018.00241] [PMID: 30042932]
[34]
Grivennikov, S.I.; Karin, M. Dangerous liaisons: STAT3 and NF-kappaB collaboration and crosstalk in cancer. Cytokine Growth Factor Rev., 2010, 21(1), 11-19.
[http://dx.doi.org/10.1016/j.cytogfr.2009.11.005] [PMID: 20018552]
[35]
Shin, H.M.; Minter, L.M.; Cho, O.H.; Gottipati, S.; Fauq, A.H.; Golde, T.E.; Sonenshein, G.E.; Osborne, B.A. Notch1 augments NF-kappaB activity by facilitating its nuclear retention. EMBO J., 2006, 25(1), 129-138.
[http://dx.doi.org/10.1038/sj.emboj.7600902] [PMID: 16319921]
[36]
Krejsgaard, T.; Vetter-Kauczok, C.S.; Woetmann, A.; Kneitz, H.; Eriksen, K.W.; Lovato, P.; Zhang, Q.; Wasik, M.A.; Geisler, C.; Ralfkiaer, E.; Becker, J.C.; Ødum, N. Ectopic expression of B-lymphoid kinase in cutaneous T-cell lymphoma. Blood, 2009, 113(23), 5896-5904.
[http://dx.doi.org/10.1182/blood-2008-09-181024] [PMID: 19351960]


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 20
ISSUE: 12
Year: 2020
Published on: 06 September, 2020
Page: [1459 - 1468]
Pages: 10
DOI: 10.2174/1871521409666200324110031
Price: $65

Article Metrics

PDF: 35
HTML: 2
EPUB: 1
PRC: 1