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Melatonin Enhances the Effect of ABT-737 in Acute Monocytic Leukemia THP-1 Cells

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Abstract

Melatonin (N-acetyl-5-methoxytryptamine, MEL) is a hormone synthesized by the pineal gland. Due to its oncostatic effect, it can be considered as an antitumor agent and used for combination therapy. ABT-737, a Bcl-2 inhibitor, promotes cell death after treatment with agents that induce pro-apoptotic signals. In the present study, the combined effect of MEL and ABT-737 on changes in proliferative and mitotic activity, mitochondrial membrane potential, intracellular production of reactive oxygen species (ROS), and cytosolic Ca2+ was studied. Moreover, changes in the expression of anti- and pro-apoptotic proteins (Bcl-2 and Bax), autophagy markers (LC3A/B (I, II)), endoplasmic reticulum stress markers (chaperones BIP and PDI, CHOP) were studied under these conditions. The effect of MEL together with ABT-737 led to an increase in the level of cytosolic Ca2+, intracellular production of ROS and a decrease in the membrane potential of mitochondria. The content of Bcl-2 increased, while the level of Bax decreased. Activation of CHOP stimulated autophagy and led to a decrease in the synthesis of chaperones BIP and PDI. It is assumed that melatonin can enhance the effect of other chemotherapeutic agents and can be used in the treatment of tumors.

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REFERENCES

  1. De Kouchkovsky I., Abdul-Hay M. 2016. Acute myeloid leukemia: A comprehensive review and 2016 update. Blood Cancer J. 6, e441.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Fernandez H.F., Sun Z., Yao X., Litzow M.R., Luger S.M., Paietta E.M., Racevskis J., Dewald G.W., Ketterling R.P., Bennett J.M., Rowe J.M., Lazarus H.M., Tallman M.S. 2009. Anthracycline dose intensification in acute myeloid leukemia. N. Engl. J. Med. 361, 1249‒1259.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Coombs C.C., Tavakkoli M., Tallman M.S. 2015. Acute promyelocytic leukemia: Where did we start, where are we now, and the future. Blood Cancer J. 5, e304.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Guerra V.A., DiNardo C., Konopleva M. 2019. Venetoclax-based therapies for acute myeloid leukemia. Best Pract. Res. Clin. Haematol. 32, 145‒153.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Oltersdorf T., Elmore S.W., Shoemaker A.R., Armstrong R.C., Augeri D.J., Belli B.A., Bruncko M., Deckwerth T.L., Dinges J., Hajduk P.J., Joseph M.K., Kitada S., Korsmeyer S.J., Kunzer A.R., Letai A., Li C., Mitten M.J., Nettesheim D.G., Ng S., Nimmer P.M., O’Connor J.M., Oleksijew A., Petros A.M., Reed J.C., Shen W., Tahir S.K., Thompson C.B., Tomaselli K.J., Wang B., Wendt M.D., Zhang H., Fesik S.W., Rosenberg S.H. 2005. An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature. 435, 677‒681.

    Article  ADS  CAS  PubMed  Google Scholar 

  6. Matthews J.P., Bishop J.F., Young G.A., Juneja S.K., Lowenthal R.M., Garson O.M., Cobcroft R.G., Dodds A.J., Enno A., Gillett E.A., Hermann R.P., Joshua D.E., Ma D.D., Szer J., Taylor K.M., Wolf M., Bradstock K.F., Australian Leukemia Study G. 2001. Patterns of failure with increasing intensification of induction chemotherapy for acute myeloid leukaemia. Br. J. Haematol. 113, 727‒736.

    Article  CAS  PubMed  Google Scholar 

  7. Menendez-Pelaez A., Reiter R.J. 1993. Distribution of melatonin in mammalian tissues: The relative importance of nuclear versus cytosolic localization. J. Pineal Res. 15, 59‒69.

    Article  CAS  PubMed  Google Scholar 

  8. Pourhanifeh M.H., Mahdavinia M., Reiter R.J., Asemi Z. 2019. Potential use of melatonin in skin cancer treatment: A review of current biological evidence. J. Cell. Physiol. 234, 12142‒12148.

    Article  CAS  PubMed  Google Scholar 

  9. Pourhanifeh M.H., Mehrzadi S., Kamali M., Hosseinzadeh A. 2020. Melatonin and gastrointestinal cancers: Current evidence based on underlying signaling pathways. Eur. J. Pharmacol. 886, 173471.

    Article  CAS  PubMed  Google Scholar 

  10. Wang J., Xiao X., Zhang Y., Shi D., Chen W., Fu L., Liu L., Xie F., Kang T., Huang W., Deng W. 2012. Simultaneous modulation of COX-2, p300, Akt, and Apaf-1 signaling by melatonin to inhibit proliferation and induce apoptosis in breast cancer cells. J. Pineal Res. 53, 77‒90.

    Article  CAS  PubMed  Google Scholar 

  11. Anderson G. 2020. The effects of melatonin on signaling pathways and molecules involved in glioma: Melatonin and glioblastoma: Pathophysiology and treatment. Fundam. Clin. Pharmacol. 34, 189‒191.

    Article  CAS  PubMed  Google Scholar 

  12. Buyukavci M., Ozdemir O., Buck S., Stout M., Ravindranath Y., Savasan S. 2006. Melatonin cytotoxicity in human leukemia cells: Relation with its pro-oxidant effect. Fundam. Clin. Pharmacol. 20, 73‒79.

    Article  CAS  PubMed  Google Scholar 

  13. Bejarano I., Redondo P.C., Espino J., Rosado J.A., Paredes S.D., Barriga C., Reiter R.J., Pariente J.A., Rodriguez A.B. 2009. Melatonin induces mitochondrial-mediated apoptosis in human myeloid HL-60 cells. J. Pineal Res. 46, 392‒400.

    Article  CAS  PubMed  Google Scholar 

  14. Shafabakhsh R., Mirzaei H., Asemi Z. 2020. Melatonin: A promising agent targeting leukemia. J. Cell Biochem. 121, 2730‒2738.

    Article  CAS  PubMed  Google Scholar 

  15. Plaimee P., Weerapreeyakul N., Barusrux S., Johns N.P. 2015. Melatonin potentiates cisplatin-induced apoptosis and cell cycle arrest in human lung adenocarcinoma cells. Cell Proliferation. 48, 67‒77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Yi C., Zhang Y., Yu Z., Xiao Y., Wang J., Qiu H., Yu W., Tang R., Yuan Y., Guo W., Deng W. 2014. Melatonin enhances the anti-tumor effect of fisetin by inhibiting COX-2/iNOS and NF-kappaB/p300 signaling pathways. PLoS One. 9, e99943.

    Article  ADS  PubMed  PubMed Central  Google Scholar 

  17. Shen Y.Q., Guerra-Librero A., Fernandez-Gil B.I., Florido J., Garcia-Lopez S., Martinez-Ruiz L., Mendivil-Perez M., Soto-Mercado V., Acuna-Castroviejo D., Ortega-Arellano H., Carriel V., Diaz-Casado M.E., Reiter R.J., Rusanova I., Nieto A., Lopez L.C., Escames G. 2018. Combination of melatonin and rapamycin for head and neck cancer therapy: Suppression of AKT/mTOR pathway activation, and activation of mitophagy and apoptosis via mitochondrial function regulation. J. Pineal Res. 64 (3), e12461. https://doi.org/10.1111/jpi.12461

  18. Gao Y., Xiao X., Zhang C., Yu W., Guo W., Zhang Z., Li Z., Feng X., Hao J., Zhang K., Xiao B., Chen M., Huang W., Xiong S., Wu X., Deng W. 2017. Melatonin synergizes the chemotherapeutic effect of 5-fluorouracil in colon cancer by suppressing PI3K/AKT and NF-κB/iNOS signaling pathways. J. Pineal Res. 62 (2), e12380. https://doi.org/10.1111/jpi.12380

  19. Baburina Y., Lomovsky A., Krestinina O. 2021. Melatonin as a potential multitherapeutic agent. J. Pers. Med. 11 (4), 274.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Krestinina O., Fadeev R., Lomovsky A., Baburina Y., Kobyakova M., Akatov V. 2018. Melatonin can strengthen the effect of retinoic acid in HL-60 cells. Int. J. Mol. Sci. 19, 2873.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Lomovsky A., Baburina Y., Odinokova I., Kobyakova M., Evstratova Y., Sotnikova L., Krestinin R., Krestinina O. 2020. Melatonin can modulate the effect of navitoclax (ABT-737) in HL-60 cells. Antioxidants (Basel). 9 (11), 1143.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Lomovsky A.I., Baburina Y.L., Fadeev R.S., Lomovskaya Y.V., Kobyakova M.I., Krestinin R.R., Sotnikova L.D., Krestinina O.V. 2023. Melatonin can enhance the effect of drugs used in the treatment of leukemia. Biochemistry (Moscow). 88, 73‒85.

    CAS  PubMed  Google Scholar 

  23. Lomovsky A.I., Baburina Y.L., Kobyakova M.I., Fadeev R.S., Akatov V.S., Krestinina O.V. 2020. Melatonin enhances the chemotherapeutic effect of cytarabin in HL-60 cells Biochemistry (Moscow), Suppl. Ser. A. 14 (2), 140‒145.

    Google Scholar 

  24. Zeeshan H.M., Lee G.H., Kim H.R., Chae H.J. 2016. Endoplasmic reticulum stress and associated ROS. Int. J. Mol. Sci. 17, 327.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Huber T.B., Walz G., Kuehn E.W. 2011. mTOR and rapamycin in the kidney: Signaling and therapeutic implications beyond immunosuppression. Kidney Int. 79, 502‒511.

    Article  CAS  PubMed  Google Scholar 

  26. Cybulsky A.V. 2013. The intersecting roles of endoplasmic reticulum stress, ubiquitin−proteasome system, and autophagy in the pathogenesis of proteinuric kidney disease. Kidney Int. 84, 25‒33.

    Article  CAS  PubMed  Google Scholar 

  27. Yuzefovych L.V., LeDoux S.P., Wilson G.L., Rachek L.I. 2013. Mitochondrial DNA damage via augmented oxidative stress regulates endoplasmic reticulum stress and autophagy: Crosstalk, links and signaling. PLoS One. 8, e83349.

    Article  ADS  PubMed  PubMed Central  Google Scholar 

  28. Tsuchiya S., Yamabe M., Yamaguchi Y., Kobayashi Y., Konno T., Tada K. 1980. Establishment and characterization of a human acute monocytic leukemia cell line (THP-1). Int. J. Cancer. 26, 171‒176.

    Article  CAS  PubMed  Google Scholar 

  29. Schwende H., Fitzke E., Ambs P., Dieter P. 1996. Differences in the state of differentiation of THP-1 cells induced by phorbol ester and 1,25-dihydroxyvitamin D3. J. Leukoc. Biol. 59, 555‒561.

    Article  CAS  PubMed  Google Scholar 

  30. Daigneault M., Preston J.A., Marriott H.M., Whyte M.K., Dockrell D.H. 2010. The identification of markers of macrophage differentiation in PMA-stimulated THP-1 cells and monocyte-derived macrophages. PLoS One. 5, e8668.

    Article  ADS  PubMed  PubMed Central  Google Scholar 

  31. Mediavilla M.D., Cos S., Sanchez-Barcelo E.J. 1999. Melatonin increases p53 and p21WAF1 expression in MCF-7 human breast cancer cells in vitro. Life Sci. 65, 415‒420.

    Article  CAS  PubMed  Google Scholar 

  32. Fornas O., Mato M.E., Webb S.M. 2000. Antiproliferative effect and cell cycle modulation by melatonin on GH(3) cells. Horm. Res. 53, 251‒255.

    CAS  PubMed  Google Scholar 

  33. Bejarano I., Espino J., Marchena A.M., Barriga C., Paredes S.D., Rodriguez A.B., Pariente J.A. 2011. Melatonin enhances hydrogen peroxide-induced apoptosis in human promyelocytic leukaemia HL-60 cells. Mol. Cell. Biochem. 353, 167‒176.

    Article  CAS  PubMed  Google Scholar 

  34. Czabotar P.E., Lessene G., Strasser A., Adams J.M. 2014. Control of apoptosis by the BCL-2 protein family: Implications for physiology and therapy. Nat. Rev. Mol. Cell. Biol. 15, 49‒63.

    Article  CAS  PubMed  Google Scholar 

  35. Bonora M., Pinton P. 2014. The mitochondrial permeability transition pore and cancer: Molecular mechanisms involved in cell death. Front. Oncol. 4, 302.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Boga J.A., Caballero B., Potes Y., Perez-Martinez Z., Reiter R.J., Vega-Naredo I., Coto-Montes A. 2019. Therapeutic potential of melatonin related to its role as an autophagy regulator: A review. J. Pineal Res. 66, e12534.

    Article  PubMed  Google Scholar 

  37. Kato H., Nishitoh H. 2015. Stress responses from the endoplasmic reticulum in cancer. Front. Oncol. 5, 93.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Yorimitsu T., Nair U., Yang Z., Klionsky D.J. 2006. Endoplasmic reticulum stress triggers autophagy. J. Bio-l. Chem. 281, 30299‒30304.

    Article  CAS  Google Scholar 

  39. Akbarzadeh M., Movassaghpour A.A., Ghanbari H., Kheirandish M., Fathi Maroufi N., Rahbarghazi R., Nouri M., Samadi N. 2017. The potential therapeutic effect of melatonin on human ovarian cancer by inhibition of invasion and migration of cancer stem cells. Sci. Rep. 7, 17062.

    Article  ADS  PubMed  PubMed Central  Google Scholar 

  40. Sonehara N.M., Lacerda J.Z., Jardim-Perassi B.V., de Paula R., Jr., Moschetta-Pinheiro M.G., Souza Y.S.T., de Andrade J.C.J., De Campos Zuccari D.A.P. 2019. Melatonin regulates tumor aggressiveness under acidosis condition in breast cancer cell lines. Oncol. Lett. 17, 1635‒1645.

    CAS  PubMed  Google Scholar 

  41. Liu L., Xu Y., Reiter R.J. 2013. Melatonin inhibits the proliferation of human osteosarcoma cell line MG-63. Bone. 55, 432‒438.

    Article  CAS  PubMed  Google Scholar 

  42. Wang L., Wang C., Choi W.S. 2022. Use of melatonin in cancer treatment: Where are we? Int. J. Mol. Sci. 23 (7), 3779.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Wang X., Wang B., Zhan W., Kang L., Zhang S., Chen C., Hou D., You R., Huang H. 2019. Melatonin inhibits lung metastasis of gastric cancer in vivo. Biomed. Pharmacother. 117, 109018.

    Article  CAS  PubMed  Google Scholar 

  44. Tsukano H., Gotoh T., Endo M., Miyata K., Tazume H., Kadomatsu T., Yano M., Iwawaki T., Kohno K., Araki K., Mizuta H., Oike Y. 2010. The endoplasmic reticulum stress-C/EBP homologous protein pathway-mediated apoptosis in macrophages contributes to the instability of atherosclerotic plaques. Arterioscler., Thromb., Vasc. Biol. 30, 1925‒1932.

    Article  CAS  PubMed  Google Scholar 

  45. Iurlaro R., Munoz-Pinedo C. 2016. Cell death induced by endoplasmic reticulum stress. FEBS J. 283, 2640‒2652.

    Article  CAS  PubMed  Google Scholar 

  46. Dhillon S. 2018. Ivosidenib: First global approval. Drugs. 78, 1509‒1516.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Li G., Mongillo M., Chin K.T., Harding H., Ron D., Marks A.R., Tabas I. 2009. Role of ERO1-alpha-mediated stimulation of inositol 1,4,5-triphosphate receptor activity in endoplasmic reticulum stress-induced apoptosis. J. Cell Biol. 186, 783‒792.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Giorgi C., Romagnoli A., Pinton P., Rizzuto R. 2008. Ca2+ signaling, mitochondria and cell death. Curr. Mol. Med. 8, 119‒130.

    Article  CAS  PubMed  Google Scholar 

  49. Pinton P., Giorgi C., Siviero R., Zecchini E., Rizzuto R. 2008. Calcium and apoptosis: ER-mitochondria Ca2+ transfer in the control of apoptosis. Oncogene. 27, 6407‒6418.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Kruman I., Guo Q., Mattson M.P. 1998. Calcium and reactive oxygen species mediate staurosporine-induced mitochondrial dysfunction and apoptosis in PC12 cells. J. Neurosci. Res. 51, 293‒308.

    Article  CAS  PubMed  Google Scholar 

  51. Kowaltowski A.J., de Souza-Pinto N.C., Castilho R.F., Vercesi A.E. 2009. Mitochondria and reactive oxygen species. Free Radicals Biol. Med. 47, 333‒343.

    Article  CAS  Google Scholar 

  52. Maciel E.N., Vercesi A.E., Castilho R.F. 2001. Oxidative stress in Ca2+-induced membrane permeability transition in brain mitochondria. J. Neurochem. 79, 1237‒1245.

    Article  CAS  PubMed  Google Scholar 

  53. Kim K.W., Moretti L., Mitchell L.R., Jung D.K., Lu B. 2010. Endoplasmic reticulum stress mediates radiation-induced autophagy by Perk-eIF2alpha in caspase-3/7-deficient cells. Oncogene. 29, 3241‒3251.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Rouschop K.M., van den Beucken T., Dubois L., Niessen H., Bussink J., Savelkouls K., Keulers T., Mujcic H., Landuyt W., Voncken J.W., Lambin P., van der Kogel A.J., Koritzinsky M., Wouters B.G. 2010. The unfolded protein response protects human tumor cells during hypoxia through regulation of the autophagy genes MAP1LC3B and ATG5. J. Clin. Invest. 120, 127‒141.

    Article  CAS  PubMed  Google Scholar 

  55. Ubeda M., Wang X.Z., Zinszner H., Wu I., Habener J.F., Ron D. 1996. Stress-induced binding of the transcriptional factor CHOP to a novel DNA control element. Mol. Cell Biol. 1, 1479‒1489.

    Article  Google Scholar 

  56. Kosakowska-Cholody T., Lin J., Srideshikan S.M., Scheffer L., Tarasova N.I., Acharya J.K. 2014. HKH40A downregulates GRP78/BiP expression in cancer cells. Cell Death Dis. 5, e1240.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Lee E., Lee D.H. 2017. Emerging roles of protein disulfide isomerase in cancer. BMB Rep. 50, 401‒410.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Nishitoh H. 2012. CHOP is a multifunctional transcription factor in the ER stress response. J. Biochem. 151, 217‒219.

    Article  CAS  PubMed  Google Scholar 

  59. Fernandez A., Ordonez R., Reiter R.J., Gonzalez-Gallego J., Mauriz J.L. 2015. Melatonin and endoplasmic reticulum stress: Relation to autophagy and apoptosis. J. Pineal Res. 59, 292‒307.

    Article  CAS  PubMed  Google Scholar 

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Funding

The work was carried out within the framework of the State Assignment of the Institute of Theoretical and Experimental Biophysics of the Russian Academy of Sciences no.  075-01025-23-00.

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Authors and Affiliations

  1. Institute of Theoretical and Experimental Biophysics, 142290, Pushchino, Moscow oblast, Russia

    A. I. Lomovsky, Y. L. Baburina, R. S. Fadeev, M. I. Kobyakova, Ya. V. Lomovskaya, R. R. Krestinin, L. D. Sotnikova & O. V. Krestinina

  2. Research Institute of Clinical and Experimental Lymphology—Branch of Institute of Cytology and Genetics, Siberian Branch, Russian Academy of Sciences, 630117, Novosibirsk, Russia

    M. I. Kobyakova

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  1. A. I. Lomovsky
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  2. Y. L. Baburina
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Lomovsky, A.I., Baburina, Y.L., Fadeev, R.S. et al. Melatonin Enhances the Effect of ABT-737 in Acute Monocytic Leukemia THP-1 Cells. Mol Biol 58, 112–122 (2024). https://doi.org/10.1134/S002689332401014X

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