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Anti-Cancer Agents in Medicinal Chemistry


ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

Research Article

Curcumin Suppresses M2 Macrophage-derived Paclitaxel Chemoresistance through Inhibition of PI3K-AKT/STAT3 Signaling

Author(s): Bhawna Deswal, Urmi Bagchi and Sonia Kapoor*

Volume 24, Issue 2, 2024

Published on: 08 November, 2023

Page: [146 - 156] Pages: 11

DOI: 10.2174/0118715206275259231105184959

Price: $65


Background: Breast cancer is the leading cancer in women worldwide. The development of chemoresistance that leads to recurrence and mortality remains a major concern. M2-type tumor-associated macrophages (TAMs), present in the breast tumor microenvironment, secrete various cytokines and growth factors that induce chemoresistance. Curcumin, isolated from Curcuma longa, is known to sensitize cancer cells and increase the efficacy of standard chemotherapeutic agents. However, the effect of curcumin on the chemoresistancegenerating ability of M2 TAMs is not known.

Objective: The study aimed to determine whether curcumin could modulate M2 macrophages and suppress their ability to induce resistance to paclitaxel in breast cancer cells.

Methods: THP-1 cells were differentiated to M2 macrophages using PMA and IL-4/IL-13 in the presence or absence of curcumin in vitro. The effect of the conditioned medium of M2 macrophages on inducing resistance towards paclitaxel in MCF-7 or MDA-MB-231 cells was analyzed by cell proliferation assay, cell cycle analysis, wound healing and transwell migration assays. RT-PCR analysis was used to determine the mRNA expression of anti-inflammatory cytokines in M2 macrophages. The effect of curcumin on TGF-β, pAKT, and pSTAT3 in M2 macrophages was analyzed by western blotting.

Results: Our data revealed that the M2 macrophages polarized in the presence of curcumin lacked the ability to generate chemoresistance to paclitaxel in breast cancer cell lines. Transcriptomic analysis revealed the expression of TGF-β to be highest amongst M2 macrophage-secreted cytokines. We observed that purified recombinant TGF-β generated chemoresistance in breast cancer cells. We found that curcumin treatment abrogated the expression of TGF-β in M2 macrophages and suppressed their ability to induce chemoresistance in breast cancer cells. STITCH analysis showed strong interaction between curcumin and AKT/STAT3 pathway. Mechanistically, curcumin inhibited PI3K/AKT/STAT3 signaling in M2 macrophages. Western blot analysis revealed that M2 TAM CM, but not curcumin-treated macrophage CM, activated COX2/NF-κB in breast cancer cells.

Conclusion: Our results showed that curcumin reduced the chemoresistance-generating ability of M2 TAMs. The study has revealed a non-cancer cell-autonomous mechanism by which curcumin partly overcomes the chemoresistance of paclitaxel in breast cancer.

Keywords: Tumor-associated macrophages, breast cancer, curcumin, chemoresistance, TGF-β, paclitaxel chemoresistance.

Graphical Abstract
Jagetia, G.C.; Aggarwal, B.B. “Spicing up” of the immune system by curcumin. J. Clin. Immunol., 2007, 27(1), 19-35.
[] [PMID: 17211725]
Jiang, H.; Wei, H.; Wang, H. Zeb1-induced metabolic reprogramming of glycolysis is essential for macrophage polarization in breast cancer. Cell Death Dis., 2022, 13(3), 206.
Mentoor, I.; Engelbrecht, A.M.; van Jaarsveld, P.J.; Nell, T. Chemoresistance: Intricate interplay between breast tumor cells and adipocytes in the tumor microenvironment. Front. Endocrinol., 2018, 9, 758.
Sica, A.; Mantovani, A. Macrophage plasticity and polarization: in vivo veritas. J. Clin. Invest., 2012, 122(3), 787-795.
[] [PMID: 22378047]
Cassetta, L.; Pollard, J.W. Tumor-associated macrophages. Curr. Biol., 2020, 30(6), R246-R248.
[] [PMID: 32208142]
Biswas, S.K.; Mantovani, A. Macrophage plasticity and interaction with lymphocyte subsets: Cancer as a paradigm. Nat. Immunol., 2010, 11(10), 889-896.
[] [PMID: 20856220]
Nelson, K.M.; Dahlin, J.L.; Bisson, J.; Graham, J.; Pauli, G.F.; Walters, M.A. The essential medicinal chemistry of curcumin. J. Med. Chem., 2017, 60(5), 1620-1637.
[] [PMID: 28074653]
Peng, Y.; Ao, M.; Dong, B. Anti-inflammatory effects of curcumin in the inflammatory diseases: Status, limitations and countermeasures. Drug Des. Devel. Ther., 2021, 15, 4503-4525.
Pricci, M.; Girardi, B.; Giorgio, F.; Losurdo, G.; Ierardi, E.; Di Leo, A. Curcumin and colorectal cancer: From basic to clinical evidences. Int. J. Mol. Sci., 2020, 21(7), 2364.
[] [PMID: 32235371]
Wang, L.; Wang, C.; Tao, Z.; Zhao, L.; Zhu, Z.; Wu, W.; He, Y.; Chen, H.; Zheng, B.; Huang, X.; Yu, Y.; Yang, L.; Liang, G.; Cui, R.; Chen, T. Curcumin derivative WZ35 inhibits tumor cell growth via ROS-YAP-JNK signaling pathway in breast cancer. J. Exp. Clin. Cancer Res., 2019, 38(1), 460.
[] [PMID: 31703744]
Ohnishi, Y.; Sakamoto, T.; Zhengguang, L.; Yasui, H.; Hamada, H.; Kubo, H.; Nakajima, M. Curcumin inhibits epithelial mesenchymal transition in oral cancer cells via c Met blockade. Oncol. Lett., 2020, 19(6), 4177-4182.
[] [PMID: 32391111]
Ghasemi, F.; Shafiee, M.; Banikazemi, Z.; Pourhanifeh, M.H.; Khanbabaei, H.; Shamshirian, A.; Moghadam, S. Curcumin inhibits NF-kB and Wnt/β-catenin pathways in cervical cancer cells. Pathol. Res. Pract., 2019, 215(10), 152556.
Tang, X.; Ding, H.; Liang, M.; Chen, X.; Yan, Y.; Wan, N.; Chen, Q.; Zhang, J.; Cao, J. Curcumin induces ferroptosis in non‐small‐cell lung cancer via activating autophagy. Thorac. Cancer, 2021, 12(8), 1219-1230.
[] [PMID: 33656766]
Kotha, R.R.; Luthria, D.L. Curcumin: Biological, pharmaceutical, nutraceutical, and analytical aspects. Molecules, 2019, 24(16), 2930.
[] [PMID: 31412624]
Giordano, A.; Tommonaro, G. Curcumin and cancer. Nutrients, 2019, 11(10), 2376.
[] [PMID: 31590362]
Chu, Y.W.; Liu, S.T.; Cheng, H.C.; Huang, S.M.; Chang, Y.L.; Chiang, C.P.; Liu, Y.C.; Wang, W.M. Opposing effects of zac1 and curcumin on AP-1-Regulated expressions of S100A7. PLoS One, 2015, 10(12), e0144175.
[] [PMID: 26633653]
Nakamae, I.; Morimoto, T.; Shima, H.; Shionyu, M.; Fujiki, H.; Yoneda-Kato, N.; Yokoyama, T.; Kanaya, S.; Kakiuchi, K.; Shirai, T.; Meiyanto, E.; Kato, J. Curcumin derivatives verify the essentiality of ros upregulation in tumor suppression. Molecules, 2019, 24(22), 4067.
[] [PMID: 31717651]
Cheng, C.; Jiao, J.T.; Qian, Y.; Guo, X.Y.; Huang, J.; Dai, M.C.; Zhang, L.; Ding, X.P.; Zong, D.; Shao, J.F. Curcumin induces G2/M arrest and triggers apoptosis via FoxO1 signaling in U87 human glioma cells. Mol. Med. Rep., 2016, 13(5), 3763-3770.
[] [PMID: 27035875]
Khan, A.Q.; Ahmed, E.I.; Elareer, N.; Fathima, H.; Prabhu, K.S.; Siveen, K.S.; Kulinski, M.; Azizi, F.; Dermime, S.; Ahmad, A.; Steinhoff, M.; Uddin, S. Curcumin-mediated apoptotic cell death in papillary thyroid cancer and cancer stem-like cells through targeting of the JAK/STAT3 signaling pathway. Int. J. Mol. Sci., 2020, 21(2), 438.
[] [PMID: 31936675]
Senthebane, D.A.; Rowe, A.; Thomford, N.E.; Shipanga, H.; Munro, D.; Mazeedi, M.A.M.A.; Almazyadi, H.A.M.; Kallmeyer, K.; Dandara, C.; Pepper, M.S.; Parker, M.I.; Dzobo, K. The role of tumor microenvironment in chemoresistance: To survive, keep your enemies closer. Int. J. Mol. Sci., 2017, 18(7), 1586.
[] [PMID: 28754000]
Farghadani, R.; Naidu, R. Curcumin as an enhancer of therapeutic efficiency of chemotherapy drugs in breast cancer. Int. J. Mol. Sci., 2022, 23(4), 2144.
[] [PMID: 35216255]
Ham, I.H.; Wang, L.; Lee, D.; Woo, J.; Kim, T.; Jeong, H.; Oh, H.; Choi, K.; Kim, T.M.; Hur, H. Curcumin inhibits the cancer associated fibroblast derived chemoresistance of gastric cancer through the suppression of the JAK/STAT3 signaling pathway. Int. J. Oncol., 2022, 61(1), 85.
[] [PMID: 35621145]
Mukherjee, S.; Hussaini, R.; White, R.; Atwi, D.; Fried, A.; Sampat, S.; Piao, L.; Pan, Q.; Banerjee, P. TriCurin, a synergistic formulation of curcumin, resveratrol, and epicatechin gallate, repolarizes tumor-associated macrophages and triggers an immune response to cause suppression of HPV+ tumors. Cancer Immunol. Immunother., 2018, 67(5), 761-774.
[] [PMID: 29453519]
Gao, J.; Liang, Y.; Wang, L. Shaping polarization of tumor-associated macrophages in cancer immunotherapy. Front. Immunol., 2022, 13, 888713.
[] [PMID: 35844605]
Soni, V.K.; Mehta, A.; Ratre, Y.K. Counteracting action of curcumin on high glucose-induced chemoresistance in hepatic carcinoma cells. Front. Oncol., 2021, 11, 738961.
Wu, M.F.; Huang, Y.H.; Chiu, L.Y.; Cherng, S.H.; Sheu, G.T.; Yang, T.Y. Curcumin induces apoptosis of chemoresistant lung cancer cells via ROS-Regulated p38 MAPK phosphorylation. Int. J. Mol. Sci., 2022, 23(15), 8248.
Sung, B.; Kunnumakkara, A.B.; Sethi, G.; Anand, P.; Guha, S.; Aggarwal, B.B. Curcumin circumvents chemoresistance in vitro and potentiates the effect of thalidomide and bortezomib against human multiple myeloma in nude mice model. Mol. Cancer Ther., 2009, 8(4), 959-970.
[] [PMID: 19372569]
Paciello, F.; Fetoni, A.R.; Mezzogori, D. The dual role of curcumin and ferulic acid in counteracting chemoresistance and cisplatin-induced ototoxicity. Sci. Rep., 2020, 10(1), 1063.
Tian, N.; Shangguan, W.; Zhou, Z.; Yao, Y.; Fan, C.; Cai, L. Lin28b is involved in curcumin-reversed paclitaxel chemoresistance and associated with poor prognosis in hepatocellular carcinoma. J. Cancer, 2019, 10(24), 6074-6087.
Farghadani, R.; Naidu, R. Curcumin as an enhancer of therapeutic efficiency of chemotherapy drugs in breast cancer. Int. J. Mol. Sci., 2022, 23(4), 2144.
Kapoor, S.; Srivastava, S.; Panda, D. Indibulin dampens microtubule dynamics and produces synergistic antiproliferative effect with vinblastine in MCF-7 cells: Implications in cancer chemotherapy. Sci. Rep., 2018, 8(1), 12363.
[] [PMID: 30120268]
Rai, A.; Kapoor, S.; Naaz, A.; Kumar, S.M.; Panda, D. Enhanced stability of microtubules contributes in the development of colchicine resistance in MCF-7 cells. Biochem. Pharmacol., 2017, 132, 38-47.
[] [PMID: 28242250]
Kapoor, S.; Panda, D. Kinetic stabilization of microtubule dynamics by indanocine perturbs EB1 localization, induces defects in cell polarity and inhibits migration of MDA-MB-231 cells. Biochem. Pharmacol., 2012, 83(11), 1495-1506.
[] [PMID: 22387536]
Rai, A.; Kapoor, S.; Singh, S.; Chatterji, B.P.; Panda, D. Transcription factor NF-κB associates with microtubules and stimulates apoptosis in response to suppression of microtubule dynamics in MCF-7 cells. Biochem. Pharmacol., 2015, 93(3), 277-289.
[] [PMID: 25536174]
Genin, M.; Clement, F.; Fattaccioli, A.; Raes, M.; Michiels, C. M1 and M2 macrophages derived from THP-1 cells differentially modulate the response of cancer cells to etoposide. BMC Cancer, 2015, 15(1), 577.
[] [PMID: 26253167]
Wang, T.H.; Wang, H.S.; Soong, Y.K. Paclitaxel-induced cell death. Cancer, 2000, 88(11), 2619-2628.
[<2619:AID-CNCR26>3.0.CO;2-J] [PMID: 10861441]
Liu, K.; Cang, S.; Ma, Y.; Chiao, J.W. Synergistic effect of paclitaxel and epigenetic agent phenethyl isothiocyanate on growth inhibition, cell cycle arrest and apoptosis in breast cancer cells. Cancer Cell Int., 2013, 13(1), 10.
[] [PMID: 23388416]
Hao, Y.; Baker, D.; ten Dijke, P. TGF-β-Mediated epithelial-mesenchymal transition and cancer metastasis. Int. J. Mol. Sci., 2019, 20(11), 2767.
[] [PMID: 31195692]
Borges, G.A.; Elias, S.T.; Amorim, B.; de Lima, C.L.; Coletta, R.D.; Castilho, R.M.; Squarize, C.H.; Guerra, E.N.S. Curcumin downregulates the PI3K–AKT–MTOR pathway and inhibits growth and progression in head and neck cancer cells. Phytother. Res., 2020, 34(12), 3311-3324.
[] [PMID: 32628350]
Hart, J.R.; Liao, L.; Yates, J.R., III; Vogt, P.K. Essential role of Stat3 in PI3K-induced oncogenic transformation. Proc. Natl. Acad. Sci. USA, 2011, 108(32), 13247-13252.
[] [PMID: 21788516]
Wang, W.; Nag, S.; Zhang, R. Targeting the NFκB signaling pathways for breast cancer prevention and therapy. Curr. Med. Chem., 2014, 22(2), 264-289.
[] [PMID: 25386819]
Lim, J.W.; Kim, H.; Kim, K.H. Nuclear factor-kappaB regulates cyclooxygenase-2 expression and cell proliferation in human gastric cancer cells. Lab. Invest., 2001, 81(3), 349-360.
[] [PMID: 11310828]
Nowak, M.; Klink, M. The role of tumor-associated macrophages in the progression and chemoresistance of ovarian cancer. Cells, 2020, 9(5), 1299.
Li, H.; Yang, P.; Wang, J. HLF regulates ferroptosis, development and chemoresistance of triple-negative breast cancer by activating tumor cell-macrophage crosstalk. J. Hematol. Oncol., 2022, 15(1), 2.
Song, M.; Yeku, O.O. Rafiq, S Tumor derived UBR5 promotes ovarian cancer growth and metastasis through inducing immunosuppressive macrophages. Nat. Commun., 2020, 11(1), 6298.
Wang, N.; Wang, S.; Wang, X.; Zheng, Y.; Yang, B.; Zhang, J.; Pan, B.; Gao, J.; Wang, Z. Research trends in pharmacological modulation of tumor‐associated macrophages. Clin. Transl. Med., 2021, 11(1), e288.
[] [PMID: 33463063]
Li, H.; Luo, F.; Jiang, X.; Zhang, W.; Xiang, T.; Pan, Q.; Cai, L.; Zhao, J.; Weng, D.; Li, Y.; Dai, Y.; Sun, F.; Yang, C.; Huang, Y.; Yang, J.; Tang, Y.; Han, Y.; He, M.; Zhang, Y.; Song, L.; Xia, J.C. CircITGB6 promotes ovarian cancer cisplatin resistance by resetting tumor-associated macrophage polarization toward the M2 phenotype. J. Immunother. Cancer, 2022, 10(3), e004029.
[] [PMID: 35277458]
Larionova, I.; Cherdyntseva, N.; Liu, T.; Patysheva, M.; Rakina, M.; Kzhyshkowska, J. Interaction of tumor-associated macrophages and cancer chemotherapy. OncoImmunology, 2019, 8(7), 1596004.
Zhang, G.; Tao, X.; Ji, B.; Gong, J. Hypoxia-driven m2-polarized macrophages facilitate cancer aggressiveness and temozolomide resistance in glioblastoma. Oxid. Med. Cell. Longev., 2022, 1614336.
Oelschlaegel, D.; Weiss Sadan, T.; Salpeter, S. Cathepsin inhibition modulates metabolism and polarization of tumor-associated macrophages. Cancers, 2020, 12(9), 2579.
Olson, O.C.; Kim, H.; Quail, D.F.; Foley, E.A.; Joyce, J.A. Tumor-associated macrophages suppress the cytotoxic activity of antimitotic agents. Cell Rep., 2017, 19(1), 101-113.
[] [PMID: 28380350]
Mantovani, A.; Allavena, P. The interaction of anticancer therapies with tumor-associated macrophages. J. Exp. Med., 2015, 212(4), 435-445.
[] [PMID: 25753580]
Peng, D.; Fu, M.; Wang, M.; Wei, Y.; Wei, X. Targeting TGF-β signal transduction for fibrosis and cancer therapy. Mol. Cancer, 2022, 21(1), 104.
Xie, F.; Ling, L.; Van Dam, H.; Zhou, F.; Zhang, L. TGF-β signaling in cancer metastasis. Acta Biochim. Biophys. Sin. (Shanghai), 2018, 50(1), 121-132.
[] [PMID: 29190313]
Derynck, R.; Turley, S.J.; Akhurst, R.J. TGFβ biology in cancer progression and immunotherapy. Nat. Rev. Clin. Oncol., 2021, 18(1), 9-34.
[] [PMID: 32710082]
Zhao, M.; Mishra, L.; Deng, C.X. The role of TGF-β/SMAD4 signaling in cancer. Int. J. Biol. Sci., 2018, 14(2), 111-123.
Hata, A.; Chen, Y.G. TGF-β signaling from receptors to smads. Cold Spring Harb. Perspect. Biol., 2016, 8(9), a022061.
Tzavlaki, K.; Moustakas, A. TGF-β Signaling. Biomolecules, 2020, 10(3), 487.
[] [PMID: 32210029]
Gabrilovich, D.I.; Ostrand-Rosenberg, S.; Bronte, V. Coordinated regulation of myeloid cells by tumours. Nat. Rev. Immunol., 2012, 12(4), 253-268.
[] [PMID: 22437938]
Su, Y.L.; Banerjee, S.; White, S.; Kortylewski, M. STAT3 in tumor-associated myeloid cells: multitasking to disrupt immunity. Int. J. Mol. Sci., 2018, 19(6), 1803.
[] [PMID: 29921770]
Peng, P.; Zhu, H.; Liu, D. TGFBI secreted by tumor-associated macrophages promotes glioblastoma stem cell-driven tumor growth via integrin αvβ5-Src-Stat3 signaling. Theranostics, 2022, 12(9), 4221-4236.
Nadella, V.; Garg, M.; Kapoor, S.; Barwal, T.S.; Jain, A.; Prakash, H. Emerging neo adjuvants for harnessing therapeutic potential of M1 tumor associated macrophages (TAM) against solid tumors: Enusage of plasticity. Ann. Transl. Med., 2020, 8(16), 1029.
[] [PMID: 32953829]
Li, H. Chen, A.; Yuan, Q.; Chen, W.; Zhong, H.; Teng, M.; Xu, C.; Qiu, Y.; Cao, J. NF-κB/Twist axis is involved in chysin inhibition of ovarian cancer stem cell features induced by co-treatment of TNF-α and TGF-β. Int. J. Clin. Exp. Pathol., 2019, 12(1), 101-112.
[PMID: 31933724]
Vergani, E.; Dugo, M.; Cossa, M.; Frigerio, S.; Di Guardo, L.; Gallino, G.; Mattavelli, I.; Vergani, B.; Lalli, L.; Tamborini, E.; Valeri, B.; Gargiuli, C.; Shahaj, E.; Ferrarini, M.; Ferrero, E.; Gomez Lira, M.; Huber, V.; Del Vecchio, M.; Sensi, M.; Leone, B.E.; Santinami, M.; Rivoltini, L.; Rodolfo, M.; Vallacchi, V. miR-146a-5p impairs melanoma resistance to kinase inhibitors by targeting COX2 and regulating NFkB-mediated inflammatory mediators. Cell Commun. Signal., 2020, 18(1), 156.
[] [PMID: 32967672]
Allegra, A.; Mirabile, G.; Ettari, R.; Pioggia, G.; Gangemi, S. The impact of curcumin on immune response: An Immunomodulatory strategy to treat sepsis. Int. J. Mol. Sci., 2022, 23(23), 14710.
Bose, S.; Panda, A.K.; Mukherjee, S.; Sa, G. Curcumin and tumor immune-editing: Resurrecting the immune system. Cell Div., 2015, 10, 6.
Paul, S.; Sa, G. Curcumin as an adjuvant to cancer immunotherapy. Front. Oncol., 2021, 11, 675923.
Jiang, M.; Qi, Y.; Huang, W.; Lin, Y.; Li, B. Curcumin Reprograms TAMs from a protumor phenotype towards an antitumor phenotype via inhibiting MAO-A/STAT6 Pathway. Cells, 2022, 11(21), 3473.
[] [PMID: 36359867]
Oh, J.G.; Hwang, D.J.; Heo, T.H. Direct regulation of IL-2 by curcumin. Biochem. Biophys. Res. Commun., 2018, 495(1), 300-305.
[] [PMID: 29127008]
Zhang, X.; Tian, W.; Cai, X.; Wang, X.; Dang, W.; Tang, H.; Cao, H.; Wang, L.; Chen, T. Hydrazinocurcumin Encapsuled nanoparticles “re-educate” tumor-associated macrophages and exhibit anti-tumor effects on breast cancer following STAT3 suppression. PLoS One, 2013, 8(6), e65896.
[] [PMID: 23825527]
Shiri, S.; Alizadeh, A.M.; Baradaran, B.; Farhanghi, B.; Shanehbandi, D.; Khodayari, S.; Khodayari, H.; Tavassoli, A. Dendrosomal curcumin suppresses metastatic breast cancer in mice by changing m1/m2 macrophage balance in the tumor microenvironment. Asian Pac. J. Cancer Prev., 2015, 16(9), 3917-3922.
[] [PMID: 25987060]
Xu, L.; Wang, X.; Wang, X.Y.; Yao, Q.H. Chen, YB signaling pathway to repair intestinal mucosal injury induced by 5-FU chemotherapy for colon. Zhongguo Zhongyao Zazhi, 2021, 46(3), 670-677.
Weir, N.M.; Selvendiran, K.; Kutala, V.K.; Tong, L.; Vishwanath, S.; Rajaram, M.; Tridandapani, S.; Anant, S.; Kuppusamy, P. Curcumin induces G2/M arrest and apoptosis in cisplatin-resistant human ovarian cancer cells by modulating akt and p38 mAPK. Cancer Biol. Ther., 2007, 6(2), 178-184.
[] [PMID: 17218783]
Zhao, H.Y.; Zhang, Y.Y.; Xing, T. M2 macrophages, but not M1 macrophages, support megakaryopoiesis by upregulating PI3K-AKT pathway activity. Signal Transduct. Target. Ther., 2021, 6(1), 234.
Zhao, S.J.; Kong, F.Q.; Jie, J. Macrophage MSR1 promotes BMSC osteogenic differentiation and M2-like polarization by activating PI3K/AKT/GSK3β/β-catenin pathway. Theranostics, 2020, 10(1), 17-35.
Yu, L.L.; Wu, J.G.; Dai, N.; Yu, H.G.; Si, J.M. Curcumin reverses chemoresistance of human gastric cancer cells by downregulating the NF-κB transcription factor. Oncol. Rep., 2011, 26(5), 1197-1203.
[] [PMID: 21811763]

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