Plant-derived extracts P2Et and Anamu-SC affect NO and ROS levels in leukemic cells
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Jun 30, 2023
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Abstract
Leukemic cells often show high nitric oxide (NO) and reactive oxygen species (ROS) levels. These can lead to resistance to apoptosis and therapy and increased proliferation. Plant-derived extracts decrease chemoresistance in cancer cells. In this study, we evaluated the effects of the plant-derived extracts P2Et (Caesalpinia spinosa) and Anamu-SC (Petiveria alliacea) and their combination with chemotherapeutic agents on NO and ROS levels in leukemic cell lines K562 and Reh. NO and ROS were determined using the DAF-FM DA and H2DCFDA probes. The mean fluorescence intensity for each variable was measured by flow cytometry. The extracts showed an antioxidant effect on both cell lines leading to a significant decrease in ROS levels without decreasing cell viability. Anamu-SC also increased NO levels in K562 cells when combined with idarubicin. Both extracts reduced the number of leukemic cells after 12 hours of treatment. Further studies are necessary to evaluate their effect on primary human leukemia cells. These findings suggest the potential of P2Et and Anamu-SC as adjuncts in leukemia treatment.
Keywords
Caesalpinia spinosa; flavonoids; leukemia; nitric oxide; Petiveria alliacea; reactive oxygen species.
References
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doi: 10.1155/2020/8021095
[3] Mijatović S, Savić-Radojević A, Plješa-Ercegovac M, Simić T, Nicoletti F, Maksimović- Ivanić D. The Double-Faced Role of Nitric Oxide and Reactive Oxygen Species in Solid Tumors, Antioxidants. 9(5): 374, 2020.
doi: 10.3390/antiox9050374.
[4] Somasundaram V, Basudhar D, Bharadwaj G, et al. Molecular Mechanisms of Nitric Oxide in Cancer Progression, Signal Transduction, and Metabolism, Antioxidants & Redox Signaling. 30(8): 1124–1143, 2019.
doi: 10.1089/ars.2018.7527
[5] Liou G-Y, Storz P. Reactive oxygen species in cancer. Free Radical Research. 44(5): 479–496, 2010.
doi: 10.3109/10715761003667554
[6] Vivarelli S, Falzone L, Basile MS, Candido S, Libra M. Nitric Oxide in Hematological Cancers: Partner or Rival? Antioxid Redox Signal. 34(5): 383–401, 2021.
doi: 10.1089/ars.2019.7958
[7] Robinson AJ, Davies S, Darley RL, Tonks A. Reactive Oxygen Species Rewires Metabolic Activity in Acute Myeloid Leukemia. Frontiers in Oncology. 11, 2021.
doi: 10.3389/fonc.2021.632623
[8] Weinberg JB. Nitric Oxide and Life or Death of Human Leukemia Cells. In: Bonavida B, ed. Nitric Oxide (NO) and Cancer: Prognosis, Prevention, and Therapy. New York, NY: Springer New York, 2010: 147–67.
doi: 10.1016/j.jep.2014.03.013
[9] Ash D, Subramanian M, Surolia A, Shaha C. Nitric oxide is the key mediator of death induced by fisetin in human acute monocytic leukemia cells. American Journal of Cancer Research. 5(2): 481–497, 2015.
[10] Romo-González M, Ijurko C, Hernández-Hernández Á. Reactive Oxygen Species and Metabolism in Leukemia: A Dangerous Liaison. Frontiers in Immunology. 13, 2022.
doi: 10.3389/fimmu.2022.889875.
[11] Martellet MC, Martins A, Marmitt DJ, Schneider T, Contini V, Goettert MI. Chapter 1 - New opportunities for the application of natural products based on nitric oxide modulation: From research to registered patents. In: Atta ur R, ed. Studies in Natural Products Chemistry: Elsevier: 1–40, 2020.
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[12] Vallejo MJ, Salazar L, Grijalva M. Oxidative Stress Modulation and ROS-Mediated Toxicity in Cancer: A Review on In Vitro Models for Plant-Derived Compounds. Oxidative Medicine and Cellular Longevity. 2017: 1–9, 2017.
doi: 10.1155/2017/4586068
[13] Sandoval TA, Urueña CP, Llano M, et al. Standardized Extract from Caesalpinia spinosa is Cytotoxic Over Cancer Stem Cells and Enhance Anticancer Activity of Doxorubicin. The American Journal of Chinese Medicine. 44(08): 1693–1717, 2016.
doi: 10.1142/s0192415x16500956
[14] Ballesteros-Ramírez R AE, Herrera MV, Urueña C, Rojas L, Echeverri LF, Modesti Costa G, Quijano S, Fiorentino S. Preferential Activity of Petiveria alliacea Extract on Primary Myeloid Leukemic Blast. Evidence-Based Complementary and Alternative Medicine,2020.
doi: 10.1016/j.jep.2014.03.013
[15] Castañeda DM, Pombo LM, Urueña CP, Hernandez JF, Fiorentino S. A gallotannin-rich fraction from Caesalpinia spinosa (Molina) Kuntze displays cytotoxic activity and raises sensitivity to doxorubicin in a leukemia cell line. BMC Complement Altern Med. 12: 38, 2012.
doi: 10.1186/1472-6882-12-38
[16] Cifuentes MC, Castañeda DM, Urueña CP, Fiorentino S. A fraction from Petiveria alliacea induces apoptosis via a mitochondria dependent pathway and regulates HSP70 expression. Universitas Scientiarum. 14(2-3): 125, 2009.
doi: 10.11144/javeriana.sc14-2-3.affp
[17] Hernández JF, Urueña CP, Cifuentes MC, et al. A Petiveria alliacea standardized fraction induces breast adenocarcinoma cell death by modulating glycolytic metabolism. Journal of Ethnopharmacology. 153(3): 641–649, 2014.
doi: 10.1016/j.jep.2014.03.013.
[18] Hernández JF, Urueña CP, Sandoval TA, et al. A cytotoxic Petiveria alliacea dry extract induces ATP depletion and decreases β-F1 ATPase expression in breast cancer cells and promotes survival in tumor-bearing mice. Revista Brasileira de Farmacognosia. 27(3):
306–314, 2017.
doi: 10.1016/j.bjp.2016.09.008
[19] Urueña C, Cifuentes C, Castañeda D, et al. Petiveria alliacea extracts uses multiple mechanisms to inhibit growth of human and mouse tumoral cells. BMC Complement Altern Med. 8: 60, 2008.
doi: 10.1186/1472-6882-8-60
[20] Choudhari SK, Chaudhary M, Bagde S, Gadbail AR, Joshi V. Nitric oxide and cancer: a review. World Journal of Surgical Oncology. 11: 118, 2013.
doi: 10.1186/1477-7819-11-118
[21] Romo-González M, Ijurko C, Hernández-Hernández Á. Reactive Oxygen Species and Metabolism in Leukemia: A Dangerous Liaison. Front Immunol. 13: 889875, 2022.
doi: 10.3389/fimmu.2022.889875
[22] Kellner C, Zunino SJ. Nitric oxide is synthesized in acute leukemia cells after exposure to phenolic antioxidants and initially protects against mitochondrial membrane depolarization. Cancer Letters. 215(1): 43–52, 2004.
doi: 10.1016/j.canlet.2004.06.046
[23] Pan X, Matsumoto M, Nishimoto Y, et al. Cytotoxic and nitric oxide production-inhibitory activities of limonoids and other compounds from the leaves and bark of Melia azedarach. Chemical Biodivers. 11(8): 1121–1139, 2014.
doi: 10.1002/cbdv.201400190
[24] Roman V, Billard C, Kern C, et al. Analysis of resveratrol-induced apoptosis in human B-cell chronic leukaemia. Br J Haematol 117(4): 842–851, 2002.
doi: 10.1046/j.1365-2141.2002.03520.x
[25] Martino R, Arcos ML, Alonso R, Sülsen V, Cremaschi G, Anesini C. Polyphenol-Rich Fraction from Larrea divaricata and its Main Flavonoid Quercetin-3-Methyl Ether Induce Apoptosis in Lymphoma Cells Through Nitrosative Stress. Phytother Res. 30(7): 1128-1136,
2016.
doi: 10.1002/ptr.5615
[26] Hernández JF, Urueña CP, Cifuentes MC, et al. A Petiveria alliacea standardized fraction induces breast adenocarcinoma cell death by modulating glycolytic metabolism. Journal Ethnopharmacol. 153(3): 641–649, 2014.
doi: 10.1016/j.jep.2014.03.013
[27] Su Y, Kondrikov D, Block ER. Cytoskeletal Regulation of Nitric Oxide Synthase. Cell Biochemistry and Biophysics. 43(3): 439–450, 2005.
doi: 10.1385/cbb:43:3:439
[28] Khan T, Ali M, Khan A, et al. Anticancer Plants: A Review of the Active Phytochemicals, Applications in Animal Models, and Regulatory Aspects. Biomolecules. 10(1), 2019.
doi: 10.3390/biom10010047
[29] Kaweme NM, Zhou S, Changwe GJ, Zhou F. The significant role of redox system in myeloid leukemia: from pathogenesis to therapeutic applications. Biomark Res. 8(1): 63, 2020.
doi: 10.1186/s40364-020-00242-z
[30] Renaudin X. Reactive oxygen species and DNA damage response in cancer. Int Rev Cell Mol Biol. 364: 139–161, 2021.
doi: 10.1016/bs.ircmb.2021.04.001
[31] Wang XD, Li CY, Jiang MM, et al. Induction of apoptosis in human leukemia cells through an intrinsic pathway by cathachunine, a unique alkaloid isolated from Catharanthus roseus. Phytomedicine. 23(6): 641–653, 2016.
doi: 10.1016/j.phymed.2016.03.003
[32] El Khoury M, Haykal T, Hodroj MH, et al. Leaf Extract Promotes ROS Induction Leading to Apoptosis in Acute Myeloid Leukemia Cells In Vitro. Cancers (Basel). 12(2), 2020.
doi: 10.3390/cancers12020435
[33] Al-Dabbagh B, Elhaty IA, Al Hrout A, et al. Antioxidant and anticancer activities of Trigonella foenum-graecum, Cassia acutifolia and Rhazya stricta. BMC Complement Altern Med. 18(1): 240, 2018.
doi: 10.1186/s12906-018-2285-7
[34] Jayaprakasha GK JRL, Sakariah K. Antioxidant activities of curcumin, demethoxycurcumin and bisdemethoxycurcumin. Food Chemistry. 98(4): 720–724, 2006.
[35] Larasati YA, Yoneda-Kato N, Nakamae I, Yokoyama T, Meiyanto E, Kato JY. Curcumin targets multiple enzymes involved in the ROS metabolic pathway to suppress tumor cell growth. Sci Rep. 8(1): 2039, 2018.
doi: 10.1038/s41598-018-20179-6
[36] Sun C, Zhang H, Ma XF, et al. Isoliquiritigenin enhances radiosensitivity of HepG2 cells
via disturbance of redox status. Cell Biochem Biophys. 65(3): 433–444, 2013.
doi: 10.1007/s12013-012-9447-x
[37] Sundaram MK, Khan MA, Alalami U, et al. Phytochemicals induce apoptosis by modulation of nitric oxide signaling pathway in cervical cancer cells. Eur Rev Med Pharmacol Sci. 24(22): 11827–11844, 2020.
doi: 10.26355/eurrev_202011_23840
[38] Milanizadeh S, Reza Bigdeli M, Rasoulian B, Amani D. The Effects of Olive Leaf Extract on Antioxidant Enzymes Activity and Tumor Growth in Breast Cancer. Thrita. 3(1): e12914, 2014.
doi: https://doi.org/10.5812/thrita.12914
doi: 10.1182/blood-2021-150930
[2] Ballesteros-Ramírez R, Quijano S, Solano J, et al. Influence of Dose Intensity in Consolida- tion with HIDAC and Other Clinical and Biological Parameters in the Survival of AML, Journal of Cancer Epidemiology. 2020: 8021095.
doi: 10.1155/2020/8021095
[3] Mijatović S, Savić-Radojević A, Plješa-Ercegovac M, Simić T, Nicoletti F, Maksimović- Ivanić D. The Double-Faced Role of Nitric Oxide and Reactive Oxygen Species in Solid Tumors, Antioxidants. 9(5): 374, 2020.
doi: 10.3390/antiox9050374.
[4] Somasundaram V, Basudhar D, Bharadwaj G, et al. Molecular Mechanisms of Nitric Oxide in Cancer Progression, Signal Transduction, and Metabolism, Antioxidants & Redox Signaling. 30(8): 1124–1143, 2019.
doi: 10.1089/ars.2018.7527
[5] Liou G-Y, Storz P. Reactive oxygen species in cancer. Free Radical Research. 44(5): 479–496, 2010.
doi: 10.3109/10715761003667554
[6] Vivarelli S, Falzone L, Basile MS, Candido S, Libra M. Nitric Oxide in Hematological Cancers: Partner or Rival? Antioxid Redox Signal. 34(5): 383–401, 2021.
doi: 10.1089/ars.2019.7958
[7] Robinson AJ, Davies S, Darley RL, Tonks A. Reactive Oxygen Species Rewires Metabolic Activity in Acute Myeloid Leukemia. Frontiers in Oncology. 11, 2021.
doi: 10.3389/fonc.2021.632623
[8] Weinberg JB. Nitric Oxide and Life or Death of Human Leukemia Cells. In: Bonavida B, ed. Nitric Oxide (NO) and Cancer: Prognosis, Prevention, and Therapy. New York, NY: Springer New York, 2010: 147–67.
doi: 10.1016/j.jep.2014.03.013
[9] Ash D, Subramanian M, Surolia A, Shaha C. Nitric oxide is the key mediator of death induced by fisetin in human acute monocytic leukemia cells. American Journal of Cancer Research. 5(2): 481–497, 2015.
[10] Romo-González M, Ijurko C, Hernández-Hernández Á. Reactive Oxygen Species and Metabolism in Leukemia: A Dangerous Liaison. Frontiers in Immunology. 13, 2022.
doi: 10.3389/fimmu.2022.889875.
[11] Martellet MC, Martins A, Marmitt DJ, Schneider T, Contini V, Goettert MI. Chapter 1 - New opportunities for the application of natural products based on nitric oxide modulation: From research to registered patents. In: Atta ur R, ed. Studies in Natural Products Chemistry: Elsevier: 1–40, 2020.
doi:
[12] Vallejo MJ, Salazar L, Grijalva M. Oxidative Stress Modulation and ROS-Mediated Toxicity in Cancer: A Review on In Vitro Models for Plant-Derived Compounds. Oxidative Medicine and Cellular Longevity. 2017: 1–9, 2017.
doi: 10.1155/2017/4586068
[13] Sandoval TA, Urueña CP, Llano M, et al. Standardized Extract from Caesalpinia spinosa is Cytotoxic Over Cancer Stem Cells and Enhance Anticancer Activity of Doxorubicin. The American Journal of Chinese Medicine. 44(08): 1693–1717, 2016.
doi: 10.1142/s0192415x16500956
[14] Ballesteros-Ramírez R AE, Herrera MV, Urueña C, Rojas L, Echeverri LF, Modesti Costa G, Quijano S, Fiorentino S. Preferential Activity of Petiveria alliacea Extract on Primary Myeloid Leukemic Blast. Evidence-Based Complementary and Alternative Medicine,2020.
doi: 10.1016/j.jep.2014.03.013
[15] Castañeda DM, Pombo LM, Urueña CP, Hernandez JF, Fiorentino S. A gallotannin-rich fraction from Caesalpinia spinosa (Molina) Kuntze displays cytotoxic activity and raises sensitivity to doxorubicin in a leukemia cell line. BMC Complement Altern Med. 12: 38, 2012.
doi: 10.1186/1472-6882-12-38
[16] Cifuentes MC, Castañeda DM, Urueña CP, Fiorentino S. A fraction from Petiveria alliacea induces apoptosis via a mitochondria dependent pathway and regulates HSP70 expression. Universitas Scientiarum. 14(2-3): 125, 2009.
doi: 10.11144/javeriana.sc14-2-3.affp
[17] Hernández JF, Urueña CP, Cifuentes MC, et al. A Petiveria alliacea standardized fraction induces breast adenocarcinoma cell death by modulating glycolytic metabolism. Journal of Ethnopharmacology. 153(3): 641–649, 2014.
doi: 10.1016/j.jep.2014.03.013.
[18] Hernández JF, Urueña CP, Sandoval TA, et al. A cytotoxic Petiveria alliacea dry extract induces ATP depletion and decreases β-F1 ATPase expression in breast cancer cells and promotes survival in tumor-bearing mice. Revista Brasileira de Farmacognosia. 27(3):
306–314, 2017.
doi: 10.1016/j.bjp.2016.09.008
[19] Urueña C, Cifuentes C, Castañeda D, et al. Petiveria alliacea extracts uses multiple mechanisms to inhibit growth of human and mouse tumoral cells. BMC Complement Altern Med. 8: 60, 2008.
doi: 10.1186/1472-6882-8-60
[20] Choudhari SK, Chaudhary M, Bagde S, Gadbail AR, Joshi V. Nitric oxide and cancer: a review. World Journal of Surgical Oncology. 11: 118, 2013.
doi: 10.1186/1477-7819-11-118
[21] Romo-González M, Ijurko C, Hernández-Hernández Á. Reactive Oxygen Species and Metabolism in Leukemia: A Dangerous Liaison. Front Immunol. 13: 889875, 2022.
doi: 10.3389/fimmu.2022.889875
[22] Kellner C, Zunino SJ. Nitric oxide is synthesized in acute leukemia cells after exposure to phenolic antioxidants and initially protects against mitochondrial membrane depolarization. Cancer Letters. 215(1): 43–52, 2004.
doi: 10.1016/j.canlet.2004.06.046
[23] Pan X, Matsumoto M, Nishimoto Y, et al. Cytotoxic and nitric oxide production-inhibitory activities of limonoids and other compounds from the leaves and bark of Melia azedarach. Chemical Biodivers. 11(8): 1121–1139, 2014.
doi: 10.1002/cbdv.201400190
[24] Roman V, Billard C, Kern C, et al. Analysis of resveratrol-induced apoptosis in human B-cell chronic leukaemia. Br J Haematol 117(4): 842–851, 2002.
doi: 10.1046/j.1365-2141.2002.03520.x
[25] Martino R, Arcos ML, Alonso R, Sülsen V, Cremaschi G, Anesini C. Polyphenol-Rich Fraction from Larrea divaricata and its Main Flavonoid Quercetin-3-Methyl Ether Induce Apoptosis in Lymphoma Cells Through Nitrosative Stress. Phytother Res. 30(7): 1128-1136,
2016.
doi: 10.1002/ptr.5615
[26] Hernández JF, Urueña CP, Cifuentes MC, et al. A Petiveria alliacea standardized fraction induces breast adenocarcinoma cell death by modulating glycolytic metabolism. Journal Ethnopharmacol. 153(3): 641–649, 2014.
doi: 10.1016/j.jep.2014.03.013
[27] Su Y, Kondrikov D, Block ER. Cytoskeletal Regulation of Nitric Oxide Synthase. Cell Biochemistry and Biophysics. 43(3): 439–450, 2005.
doi: 10.1385/cbb:43:3:439
[28] Khan T, Ali M, Khan A, et al. Anticancer Plants: A Review of the Active Phytochemicals, Applications in Animal Models, and Regulatory Aspects. Biomolecules. 10(1), 2019.
doi: 10.3390/biom10010047
[29] Kaweme NM, Zhou S, Changwe GJ, Zhou F. The significant role of redox system in myeloid leukemia: from pathogenesis to therapeutic applications. Biomark Res. 8(1): 63, 2020.
doi: 10.1186/s40364-020-00242-z
[30] Renaudin X. Reactive oxygen species and DNA damage response in cancer. Int Rev Cell Mol Biol. 364: 139–161, 2021.
doi: 10.1016/bs.ircmb.2021.04.001
[31] Wang XD, Li CY, Jiang MM, et al. Induction of apoptosis in human leukemia cells through an intrinsic pathway by cathachunine, a unique alkaloid isolated from Catharanthus roseus. Phytomedicine. 23(6): 641–653, 2016.
doi: 10.1016/j.phymed.2016.03.003
[32] El Khoury M, Haykal T, Hodroj MH, et al. Leaf Extract Promotes ROS Induction Leading to Apoptosis in Acute Myeloid Leukemia Cells In Vitro. Cancers (Basel). 12(2), 2020.
doi: 10.3390/cancers12020435
[33] Al-Dabbagh B, Elhaty IA, Al Hrout A, et al. Antioxidant and anticancer activities of Trigonella foenum-graecum, Cassia acutifolia and Rhazya stricta. BMC Complement Altern Med. 18(1): 240, 2018.
doi: 10.1186/s12906-018-2285-7
[34] Jayaprakasha GK JRL, Sakariah K. Antioxidant activities of curcumin, demethoxycurcumin and bisdemethoxycurcumin. Food Chemistry. 98(4): 720–724, 2006.
[35] Larasati YA, Yoneda-Kato N, Nakamae I, Yokoyama T, Meiyanto E, Kato JY. Curcumin targets multiple enzymes involved in the ROS metabolic pathway to suppress tumor cell growth. Sci Rep. 8(1): 2039, 2018.
doi: 10.1038/s41598-018-20179-6
[36] Sun C, Zhang H, Ma XF, et al. Isoliquiritigenin enhances radiosensitivity of HepG2 cells
via disturbance of redox status. Cell Biochem Biophys. 65(3): 433–444, 2013.
doi: 10.1007/s12013-012-9447-x
[37] Sundaram MK, Khan MA, Alalami U, et al. Phytochemicals induce apoptosis by modulation of nitric oxide signaling pathway in cervical cancer cells. Eur Rev Med Pharmacol Sci. 24(22): 11827–11844, 2020.
doi: 10.26355/eurrev_202011_23840
[38] Milanizadeh S, Reza Bigdeli M, Rasoulian B, Amani D. The Effects of Olive Leaf Extract on Antioxidant Enzymes Activity and Tumor Growth in Breast Cancer. Thrita. 3(1): e12914, 2014.
doi: https://doi.org/10.5812/thrita.12914
How to Cite
Juan José Arévalo-Ferrin, Jimmy Alejandro García-Ortiz, Cindy Mayerli Arévalo-Olaya, Sandra Milena Quijano-Gómez, Susana Fiorentino-Gómez, & Rodríguez Pardo, V. M. (2023). Plant-derived extracts P2Et and Anamu-SC affect NO and ROS levels in leukemic cells. Universitas Scientiarum, 28(2), 201–216. https://doi.org/10.11144/Javeriana.SC282.pdep
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