Mechanism of Preventing Recurrence of Stage II-III Colorectal Cancer Metastasis with Immuno-inflammatory and Hypoxic Microenvironment by a Four Ingredients Chinese Herbal Formula: A Bioinformatics and Network Pharmacology Analysis


Cite item

Full Text

Abstract

Background:Colorectal Cancer (CRC) is one of the top three malignancies with the highest incidence and mortality.

Objective:The study aimed to identify the effect of Traditional Chinese Medicine (TCM) on postoperative patients with stage II-III CRC and explore the core herb combination and its mechanism.

Methods:An observational cohort study was conducted on patients diagnosed with stage II-III CRC from January 2016 to January 2021. The primary outcome was disease-free survival, which was compared between the patients who received TCM or not, and the secondary outcome was the hazard ratio. The relevance principle was used to obtain the candidate herb combinations, and the core combination was evaluated through an assessment of efficacy and representativeness. Then, biological processes and signaling pathways associated with CRC were obtained by Gene Ontology function, Kyoto Encyclopedia of Gene and Genomes pathway, and Wikipathway. Furthermore, hub genes were screened by the Kaplan-Meier estimator, and molecular docking was employed to predict the binding sites of key ingredients to hub genes. The correlation analysis was employed for the correlations between the hub genes and tumor-infiltrating immune cells and hypoxiarelated genes. Ultimately, a quantitative polymerase chain reaction was performed to verify the regulation of hub genes by their major ingredients.

Results:A total of 707 patients were included. TCM could decrease the metastatic recurrence associated with stage II-III CRC (HR: 0.61, log-rank p < 0.05). Among those patients in the TCM group, the core combination was Baizhu → Yinchen, Chenpi, and Fuling (C combination), and its antitumor mechanism was most likely related to the regulation of BCL2L1, XIAP, and TOP1 by its key ingredients, quercetin and tangeretin. The expression of these genes was significantly correlated with both tumor-infiltrating immune cells and hypoxia- related genes. In addition, quercetin and tangeretin down-regulated the mRNA levels of BCL2L1, XIAP, and TOP1, thereby inhibiting the growth of HCT116 cells.

Conclusion:Overall, a combination of four herbs, Baizhu → Yinchen, Chenpi, and Fuling, could reduce metastatic recurrence in postoperative patients with stage II-III CRC. The mechanism may be related to the regulation of BCL2L1, XIAP, and TOP1 by its key ingredients quercetin and tangeretin.

About the authors

Chuan Shi

Oncology Department III, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine

Email: info@benthamscience.net

Xing Liu

Department of Central Laboratory Medicine, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine

Email: info@benthamscience.net

Su-Su Han

Oncology Department III, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine

Email: info@benthamscience.net

Yu-Fei Tang

Oncology Department III, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine

Email: info@benthamscience.net

Hai-Lun Zeng

Oncology Department III, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine

Email: info@benthamscience.net

Mei-Lu Du

Oncology Department III, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine

Email: info@benthamscience.net

Yi Yang

Oncology Department III, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine

Email: info@benthamscience.net

Jia-Ning Jia

Oncology Department III, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine

Email: info@benthamscience.net

Qi Shi

Oncology Department III, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine

Author for correspondence.
Email: info@benthamscience.net

Feng-Gang Hou

Oncology Department III, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine

Author for correspondence.
Email: info@benthamscience.net

References

  1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin 2020; 70(1): 7-30. doi: 10.3322/caac.21590 PMID: 31912902
  2. Wilhelmsen M, Kring T, Jorgensen LN, et al. Determinants of recurrence after intended curative resection for colorectal cancer. Scand J Gastroenterol 2014; 49(12): 1399-408. doi: 10.3109/00365521.2014.926981 PMID: 25370351
  3. Chen WQ, Li H, Sun KX, et al. Report of cancer incidence and mortality in China, 2014. Zhonghua Zhong Liu Za Zhi 2018; 40(1): 5-13. PMID: 29365411
  4. Feng RM, Zong YN, Cao SM, Xu RH. Current cancer situation in China: Good or bad news from the 2018 Global Cancer Statistics? Cancer Commun (Lond) 2019; 39(1): 1-12. doi: 10.1186/s40880-019-0368-6 PMID: 31030667
  5. Song L, Zhu S, Liu C, Zhang Q, Liang X. Baicalin triggers apoptosis, inhibits migration, and enhances anti-tumor immunity in colorectal cancer via TLR4/NF-κB signaling pathway. J Food Biochem 2022; 46(3): e13703. doi: 10.1111/jfbc.13703 PMID: 33742464
  6. Wang C, Yang S, Gao L, Wang L, Cao L. Carboxymethyl pachyman (CMP) reduces intestinal mucositis and regulates the intestinal microflora in 5-fluorouracil-treated CT26 tumour-bearing mice. Food Funct 2018; 9(5): 2695-704. doi: 10.1039/C7FO01886J PMID: 29756138
  7. Shi Q, Liu S, Li W, et al. Exploring the medication duration based on the effect of traditional Chinese medicine on postoperative stage I-III colorec-tal patients: A retrospective cohort study. Oncotarget 2017; 8(8): 13488-95. doi: 10.18632/oncotarget.14567 PMID: 28086238
  8. Gray R, Barnwell J, McConkey C, Hills RK, Williams NS, Kerr DJ. Adjuvant chemotherapy versus observation in patients with colorectal cancer: A randomised study. Lancet 2007; 370(9604): 2020-9. doi: 10.1016/S0140-6736(07)61866-2 PMID: 18083404
  9. Böckelman C, Engelmann BE, Kaprio T, Hansen TF, Glimelius B. Risk of recurrence in patients with colon cancer stage II and III: A systematic review and meta-analysis of recent literature. Acta Oncol 2015; 54(1): 5-16. doi: 10.3109/0284186X.2014.975839 PMID: 25430983
  10. Kaelin WG Jr, Ratcliffe PJ, Semenza GL. Pathways for oxygen regulation and homeostasis. JAMA 2016; 316(12): 1252-3. doi: 10.1001/jama.2016.12386 PMID: 27622845
  11. Mo Z, Liu D, Rong D, Zhang S. Hypoxic characteristic in the immunosuppressive microenvironment of hepatocellular carcinoma. Front Immunol 2021; 12: 611058. doi: 10.3389/fimmu.2021.611058 PMID: 33679749
  12. Yang Y, Sun M, Yao W, et al. Compound kushen injection relieves tumor-associated macrophage-mediated immunosuppression through TNFR1 and sensitizes hepatocellular carcinoma to sorafenib. J Immunother Cancer 2020; 8(1): e000317. doi: 10.1136/jitc-2019-000317 PMID: 32179631
  13. Chen F, Li J, Wang H, Ba Q. Anti-tumor effects of Chinese medicine compounds by regulating immune cells in microenvironment. Front Oncol 2021; 11: 746917. doi: 10.3389/fonc.2021.746917 PMID: 34722304
  14. Wang Y, Zhang Q, Chen Y, et al. Antitumor effects of immunity-enhancing traditional Chinese medicine. Biomed Pharmacother 2020; 121: 109570. doi: 10.1016/j.biopha.2019.109570 PMID: 31710893
  15. Zhang Y, Lou Y, Wang J, Yu C, Shen W. Research status and molecular mechanism of the traditional Chinese medicine and antitumor therapy combined strategy based on tumor microenvironment. Front Immunol 2021; 11: 609705. doi: 10.3389/fimmu.2020.609705 PMID: 33552068
  16. Shang L. Mechanism of Sijunzi decoction in the treatment of colorectal cancer based on network pharmacology and experimental validation. J Ethnopharmacol 2023; 302(Pt A): 115876. doi: 10.1016/j.jep.2022.115876
  17. Hopkins AL. Network pharmacology: The next paradigm in drug discovery. Nat Chem Biol 2008; 4(11): 682-90. doi: 10.1038/nchembio.118 PMID: 18936753
  18. Zhao L, Zhang H, Li N, et al. Network pharmacology, a promising approach to reveal the pharmacology mechanism of Chinese medicine formula. J Ethnopharmacol 2023; 309: 116306. doi: 10.1016/j.jep.2023.116306 PMID: 36858276
  19. Li X, Liu Z, Liao J, Chen Q, Lu X, Fan X. Network pharmacology approaches for research of traditional Chinese medicines. Chin J Nat Med 2023; 21(5): 323-32. doi: 10.1016/S1875-5364(23)60429-7 PMID: 37245871
  20. Ru J, Li P, Wang J, et al. TCMSP: A database of systems pharmacology for drug discovery from herbal medicines. J Cheminform 2014; 6(1): 13. doi: 10.1186/1758-2946-6-13 PMID: 24735618
  21. Fang S, Dong L, Liu L, et al. HERB: A high-throughput experiment- and reference-guided database of traditional Chinese medicine. Nucleic Acids Res 2021; 49(D1): D1197-206. doi: 10.1093/nar/gkaa1063 PMID: 33264402
  22. Bateman A, Martin M-J, Orchard S, et al. UniProt: The universal protein knowledgebase in 2021. Nucleic Acids Res 2021; 49(D1): D480-9. doi: 10.1093/nar/gkaa1100 PMID: 33237286
  23. Shannon P, Markiel A, Ozier O, et al. Cytoscape: A software environment for integrated models of biomolecular interaction networks. Genome Res 2003; 13(11): 2498-504. doi: 10.1101/gr.1239303 PMID: 14597658
  24. Ardlie KG, Deluca DS, Segrè AV, et al. The Genotype-Tissue Expression (GTEx) pilot analysis: Multitissue gene regulation in humans. Science 2015; 348(6235): 648-60. doi: 10.1126/science.1262110 PMID: 25954001
  25. Ritchie ME, Phipson B, Wu D, et al. Limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res 2015; 43(7): e47. doi: 10.1093/nar/gkv007 PMID: 25605792
  26. Chen H, Boutros PC. VennDiagram: A package for the generation of highly-customizable Venn and Euler diagrams in R. BMC Bioinformatics 2011; 12(1): 35. doi: 10.1186/1471-2105-12-35 PMID: 21269502
  27. Szklarczyk D, Gable AL, Nastou KC, et al. The STRING database in 2021: Customizable protein–protein networks, and functional characterization of user-uploaded gene/measurement sets. Nucleic Acids Res 2021; 49(D1): D605-12. doi: 10.1093/nar/gkaa1074 PMID: 33237311
  28. Chin CH. cytoHubba: Identifying hub objects and sub-networks from complex interactome. BMC Syst Biol 2014; 4 (Suppl. 4): S11.
  29. Conway JR, Lex A, Gehlenborg N. UpSetR: An R package for the visualization of intersecting sets and their properties. Bioinformatics 2017; 33(18): 2938-40. doi: 10.1093/bioinformatics/btx364 PMID: 28645171
  30. Kanehisa M, Goto S. KEGG: Kyoto encyclopedia of genes and genomes. Nucleic Acids Res 2000; 28(1): 27-30. doi: 10.1093/nar/28.1.27 PMID: 10592173
  31. Harris MA, Clark J, Ireland A, et al. The Gene Ontology (GO) database and informatics resource. Nucleic Acids Res 2004; 32(Database issue): D258-61. PMID: 14681407
  32. Martens M, Ammar A, Riutta A, et al. WikiPathways: Connecting communities. Nucleic Acids Res 2021; 49(D1): D613-21. doi: 10.1093/nar/gkaa1024 PMID: 33211851
  33. Yu G, Wang LG, Han Y, He QY. clusterProfiler: An R package for comparing biological themes among gene clusters. OMICS 2012; 16(5): 284-7. doi: 10.1089/omi.2011.0118 PMID: 22455463
  34. Wickham H. Ggplot2: Elegant Graphics for Data Analysis Midtown Manhattan. New York City: Springer Link 2009. doi: 10.1007/978-0-387-98141-3
  35. Walter W, Sánchez-Cabo F, Ricote M. GOplot: An R package for visually combining expression data with functional analysis. Bioinformatics 2015; 31(17): 2912-4. doi: 10.1093/bioinformatics/btv300 PMID: 25964631
  36. Chandrashekar DS, Bashel B, Balasubramanya SAH, et al. UALCAN: A portal for facilitating tumor subgroup gene expression and survival anal-yses. Neoplasia 2017; 19(8): 649-58. doi: 10.1016/j.neo.2017.05.002 PMID: 28732212
  37. Uhlen M, Zhang C, Lee S, et al. A pathology atlas of the human cancer transcriptome. Science 2017; 357(6352): eaan2507. doi: 10.1126/science.aan2507 PMID: 28818916
  38. Sturm G, Finotello F, List M. Immunedeconv: An R package for unified access to computational methods for estimating immune cell fractions from bulk RNA-sequencing data. Methods Mol Biol 2020; 2120: 223-32. doi: 10.1007/978-1-0716-0327-7_16 PMID: 32124323
  39. Sturm G, Finotello F, Petitprez F, et al. Comprehensive evaluation of transcriptome-based cell-type quantification methods for immuno-oncology. Bioinformatics 2019; 35(14): i436-45. doi: 10.1093/bioinformatics/btz363 PMID: 31510660
  40. Finotello F, Mayer C, Plattner C, et al. Molecular and pharmacological modulators of the tumor immune contexture revealed by deconvolution of RNA-seq data. Genome Med 2019; 11(1): 34. doi: 10.1186/s13073-019-0638-6 PMID: 31126321
  41. Buffa FM, Harris AL, West CM, Miller CJ. Large meta-analysis of multiple cancers reveals a common, compact and highly prognostic hypoxia metagene. Br J Cancer 2010; 102(2): 428-35. doi: 10.1038/sj.bjc.6605450 PMID: 20087356
  42. Thienpont B, Steinbacher J, Zhao H, et al. Tumour hypoxia causes DNA hypermethylation by reducing TET activity. Nature 2016; 537(7618): 63-8. doi: 10.1038/nature19081 PMID: 27533040
  43. Wei J, Huang K, Chen Z, et al. Characterization of glycolysis-associated molecules in the tumor microenvironment revealed by pan-cancer tissues and lung cancer single cell data. Cancers (Basel) 2020; 12(7): 1788. doi: 10.3390/cancers12071788 PMID: 32635458
  44. Jumper J, Evans R, Pritzel A, et al. Highly accurate protein structure prediction with AlphaFold. Nature 2021; 596(7873): 583-9. doi: 10.1038/s41586-021-03819-2 PMID: 34265844
  45. Varadi M, Anyango S, Deshpande M, et al. Alpha fold protein structure database: Massively expanding the structural coverage of protein-sequence space with high-accuracy models. Nucleic Acids Res 2022; 50(D1): D439-44. doi: 10.1093/nar/gkab1061 PMID: 34791371
  46. Kim S, Chen J, Cheng T, et al. PubChem in 2021: New data content and improved web interfaces. Nucleic Acids Res 2021; 49(D1): D1388-95. doi: 10.1093/nar/gkaa971 PMID: 33151290
  47. Morris GM, Huey R, Lindstrom W, et al. AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. J Comput Chem 2009; 30(16): 2785-91. doi: 10.1002/jcc.21256 PMID: 19399780
  48. Schrödinger L. The PyMOL molecular graphics system, version 1.8. 2015.
  49. Benson AB III, Schrag D, Somerfield MR, et al. American Society of Clinical Oncology recommendations on adjuvant chemotherapy for stage II colon cancer. J Clin Oncol 2004; 22(16): 3408-19. doi: 10.1200/JCO.2004.05.063 PMID: 15199089
  50. Yothers G, O’Connell MJ, Allegra CJ, et al. Oxaliplatin as adjuvant therapy for colon cancer: Updated results of NSABP C-07 trial, including surviv-al and subset analyses. J Clin Oncol 2011; 29(28): 3768-74. doi: 10.1200/JCO.2011.36.4539 PMID: 21859995
  51. Liu SS, Shi Q, Li HJ, et al. Right- and left-sided colorectal cancers respond differently to traditional Chinese medicine. World J Gastroenterol 2017; 23(42): 7618-25. doi: 10.3748/wjg.v23.i42.7618 PMID: 29204061
  52. Li YB. Exploration the similarities and differences of correlation analysis and frequency statistics methods of TCM prescription. China J Chin Med 2013; 28(187)
  53. Lu YT, Li J, Qi X, Pei YX, Shi WG, Lin HS. Effects of Shugan Jianpi Formula on myeloid-derived suppression cells-mediated depression breast can-cer mice. Chin J Integr Med 2017; 23(6): 453-60. doi: 10.1007/s11655-016-2734-4 PMID: 27796822
  54. Goh JXH, Tan LT, Goh JK, et al. Nobiletin and derivatives: Functional compounds from citrus fruit peel for colon cancer chemoprevention. Cancers (Basel) 2019; 11(6): 867. doi: 10.3390/cancers11060867 PMID: 31234411
  55. Tian H, Liu Z, Pu Y, Bao Y. Immunomodulatory effects exerted by Poria Cocos polysaccharides via TLR4/TRAF6/NF-κB signaling in vitro and in vivo. Biomed Pharmacother 2019; 112: 108709. doi: 10.1016/j.biopha.2019.108709 PMID: 30970514
  56. Mo Z, Cao Z, Yu L, et al. An integrative analysis reveals the potential mechanism between herbal medicine yinchen and immunoregulation in hepa-tocellular carcinoma. BioMed Res Int 2020; 2020: 1-10. doi: 10.1155/2020/8886914 PMID: 33457419
  57. Bailly C. Atractylenolides, essential components of Atractylodes-based traditional herbal medicines: Antioxidant, anti-inflammatory and anticancer properties. Eur J Pharmacol 2021; 891: 173735. doi: 10.1016/j.ejphar.2020.173735 PMID: 33220271
  58. Wang K, Chen Q, Shao Y, et al. Anticancer activities of TCM and their active components against tumor metastasis. Biomed Pharmacother 2021; 133: 111044. doi: 10.1016/j.biopha.2020.111044 PMID: 33378952
  59. Malik A, Sharma D, Malireddi RKS, et al. SYK-CARD9 signaling axis promotes gut fungi-mediated inflammasome activation to restrict colitis and colon cancer. Immunity 2018; 49(3): 515-530.e5. doi: 10.1016/j.immuni.2018.08.024 PMID: 30231985
  60. Sanchez-Lopez E, Zhong Z, Stubelius A, et al. Choline uptake and metabolism Modulate Macrophage IL-1β and IL-18 production. Cell Metab 2019; 29(6): 1350-1362.e7. doi: 10.1016/j.cmet.2019.03.011 PMID: 30982734
  61. Ni J, Wang X, Stojanovic A, et al. Single-cell RNA sequencing of tumor-infiltrating NK cells reveals that inhibition of transcription factor HIF-1α unleashes NK cell activity. Immunity 2020; 52(6): 1075-1087.e8. doi: 10.1016/j.immuni.2020.05.001 PMID: 32445619
  62. Li W, Zong S, Shi Q, Li H, Xu J, Hou F. Hypoxia-induced vasculogenic mimicry formation in human colorectal cancer cells: Involvement of HIF-1a, Claudin-4, and E-cadherin and Vimentin. Sci Rep 2016; 6(1): 37534. doi: 10.1038/srep37534 PMID: 27869227
  63. Zong S, Li W, Li H, et al. Identification of hypoxia-regulated angiogenic genes in colorectal cancer. Biochem Biophys Res Commun 2017; 493(1): 461-7. doi: 10.1016/j.bbrc.2017.08.169 PMID: 28928094
  64. Zong S, Tang Y, Li W, et al. A Chinese herbal formula suppresses colorectal cancer migration and vasculogenic mimicry through ROS/HIF-1α/MMP2 pathway in hypoxic microenvironment. Front Pharmacol 2020; 11: 705. doi: 10.3389/fphar.2020.00705 PMID: 32499699
  65. Hossini AM, Eberle J. Apoptosis induction by Bcl-2 proteins independent of the BH3 domain. Biochem Pharmacol 2008; 76(11): 1612-9. doi: 10.1016/j.bcp.2008.08.013 PMID: 18778689
  66. Choi S, Chen Z, Tang LH, et al. Bcl-xL promotes metastasis independent of its anti-apoptotic activity. Nat Commun 2016; 7(1): 10384. doi: 10.1038/ncomms10384 PMID: 26785948
  67. Kim EM, Jung CH, Song JY, Park JK, Um HD. Pro-apoptotic Bax promotes mesenchymal-epithelial transition by binding to respiratory complex-I and antagonizing the malignant actions of pro-survival Bcl-2 proteins. Cancer Lett 2018; 424: 127-35. doi: 10.1016/j.canlet.2018.03.033 PMID: 29596889
  68. Um HD. Bcl-2 family proteins as regulators of cancer cell invasion and metastasis: A review focusing on mitochondrial respiration and reactive oxygen species. Oncotarget 2016; 7(5): 5193-203. doi: 10.18632/oncotarget.6405 PMID: 26621844
  69. Jin Y, Lu X, Wang M, Zhao X, Xue L. X-linked inhibitor of apoptosis protein accelerates migration by inducing epithelial–mesenchymal transition through TGF-β signaling pathway in esophageal cancer cells. Cell Biosci 2019; 9(1): 76. doi: 10.1186/s13578-019-0338-3 PMID: 31548877
  70. Li S, Pan B, Li L, Shi B, Xie F, He C. Prognostic significance of X-linked inhibitor of apoptosis protein in solid tumors: A systematic review and meta-analysis. J Cell Physiol 2019; 234(10): 18111-22. doi: 10.1002/jcp.28443 PMID: 30847951
  71. Geng Y, Zhang L, Wang GY, et al. Xanthatin mediates G2/M cell cycle arrest, autophagy and apoptosis via ROS/XIAP signaling in human colon cancer cells. Nat Prod Res 2020; 34(18): 2616-20. doi: 10.1080/14786419.2018.1544976 PMID: 30587055
  72. Pommier Y. Topoisomerase I inhibitors: Camptothecins and beyond. Nat Rev Cancer 2006; 6(10): 789-802. doi: 10.1038/nrc1977 PMID: 16990856
  73. Tang Q, Ji F, Wang J, Guo L, Li Y, Bao Y. Quercetin exerts synergetic anti-cancer activity with 10-hydroxy camptothecin. Eur J Pharm Sci 2017; 109: 223-32. doi: 10.1016/j.ejps.2017.08.013 PMID: 28822757
  74. Li X, Guo S, Xiong XK, et al. Combination of quercetin and cisplatin enhances apoptosis in OSCC cells by downregulating xIAP through the NF-κB pathway. J Cancer 2019; 10(19): 4509-21. doi: 10.7150/jca.31045 PMID: 31528215
  75. Chiang SCC, Owsley E, Panchal N, et al. Quercetin ameliorates XIAP deficiency-associated hyperinflammation. Blood 2022; 140(7): 706-15. doi: 10.1182/blood.2021014335 PMID: 35687753
  76. Abaza MSI, Orabi KY, Al-Quattan E, Al-Attiyah RJ. Growth inhibitory and chemo-sensitization effects of naringenin, a natural flavanone purified from Thymus vulgaris, on human breast and colorectal cancer. Cancer Cell Int 2015; 15(1): 46. doi: 10.1186/s12935-015-0194-0 PMID: 26074733
  77. Xu J, Guo Z, Yuan S, Li H. BCL2L1 is identified as a target of naringenin in regulating ovarian cancer progression. Mol Cell Biochem 2022; 477(5): 1541-53. doi: 10.1007/s11010-022-04389-1 PMID: 35184257
  78. Ashrafizadeh M, Zarrabi A, Saberifar S, et al. Nobiletin in cancer therapy: How this plant derived-natural compound targets various oncogene and onco-suppressor pathways. Biomedicines 2020; 8(5): 110. doi: 10.3390/biomedicines8050110 PMID: 32380783
  79. Zhang Z, Zhang Z, Jiang G, Sun H, Yu D. Nobiletin sensitizes colorectal cancer cells to oxaliplatin by PI3K Akt MTOR pathway. Front Biosci 2019; 24(2): 303-12. doi: 10.2741/4719 PMID: 30468657
  80. Wu X, Song M, Wang M, et al. Chemopreventive effects of nobiletin and its colonic metabolites on colon carcinogenesis. Mol Nutr Food Res 2015; 59(12): 2383-94. doi: 10.1002/mnfr.201500378 PMID: 26445322
  81. Glunde K, Jacobs MA, Bhujwalla ZM. Choline metabolism in cancer: Implications for diagnosis and therapy. Expert Rev Mol Diagn 2006; 6(6): 821-9. doi: 10.1586/14737159.6.6.821 PMID: 17140369
  82. García-Molina P, Sola-Leyva A, Luque-Navarro PM, et al. Anticancer activity of the choline kinase inhibitor PL48 is due to selective disruption of choline metabolism and transport systems in cancer cell lines. Pharmaceutics 2022; 14(2): 426. doi: 10.3390/pharmaceutics14020426 PMID: 35214160
  83. Naumann U, Wischhusen J, Weit S, et al. Alkylphosphocholine-induced glioma cell death is BCL-XL-sensitive, caspase-independent and character-ized by massive cytoplasmic vacuole formation. Cell Death Differ 2004; 11(12): 1326-41. doi: 10.1038/sj.cdd.4401503 PMID: 15389288
  84. Nitter M, Norgård B, de Vogel S, et al. Plasma methionine, choline, betaine, and dimethylglycine in relation to colorectal cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC). Ann Oncol 2014; 25(8): 1609-15. doi: 10.1093/annonc/mdu185 PMID: 24827130
  85. Li YR, Li S, Ho CT, et al. Tangeretin derivative, 5-acetyloxy-6,7,8,4′-tetramethoxyflavone induces G2/M arrest, apoptosis and autophagy in human non-small cell lung cancer cells in vitro and in vivo. Cancer Biol Ther 2016; 17(1): 48-64. doi: 10.1080/15384047.2015.1108491 PMID: 26569090
  86. Cheng YP, Li S, Chuang WL, et al. Blockade of STAT3 signaling contributes to anticancer effect of 5-acetyloxy-6,7,8,4′-tetra-methoxyflavone, a tangeretin derivative, on human glioblastoma multiforme cells. Int J Mol Sci 2019; 20(13): 3366. doi: 10.3390/ijms20133366 PMID: 31323961
  87. Dey DK, Chang SN, Vadlamudi Y, Park JG, Kang SC. Synergistic therapy with tangeretin and 5-fluorouracil accelerates the ROS/ JNK mediated apoptotic pathway in human colorectal cancer cell. Food Chem Toxicol 2020; 143: 111529. doi: 10.1016/j.fct.2020.111529 PMID: 32619557
  88. Chouchani ET, Pell VR, Gaude E, et al. Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS. Nature 2014; 515(7527): 431-5. doi: 10.1038/nature13909 PMID: 25383517
  89. Mills EL, Kelly B, Logan A, et al. Succinate dehydrogenase supports metabolic repurposing of mitochondria to drive inflammatory macrophages. Cell 2016; 167(2): 457-470.e13. doi: 10.1016/j.cell.2016.08.064 PMID: 27667687
  90. Kasarci G, Ertugrul B, Iplik ES, Cakmakoglu B. The apoptotic efficacy of succinic acid on renal cancer cell lines. Med Oncol 2021; 38(12): 144. doi: 10.1007/s12032-021-01577-9 PMID: 34687367

Supplementary files

Supplementary Files
Action
1. JATS XML
Download

Copyright (c) 2024 Bentham Science Publishers