Uncaria-derived alkaloids: A review on the mechanism in inducing apoptosis in oral squamous cell carcinoma

  • Authors

  • Alkaloids, the major secondary metabolite compounds identified in the genus Uncaria, exhibit the ability to induce apoptosis in oral squa-mous cell carcinoma (OSCC). Various potential alkaloids in herbal medicine have been explored and provided promising results, one of which is the potential to induce apoptosis. This study aims to provide a more comprehensive review of the mechanism of alkaloids derived from Uncaria in inducing apoptosis in OSCC. In the systematic search conducted, the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines were adhered to conduct this review through the databases, including PubMed, ScienceDirect, Wiley and a manual search using Google Scholar. According to the findings, this review states that several types of alkaloids derived from Uncaria that have been reviewed, such as hirsutine, rhynchophylline, isorhynchophylline, and hirsuteine, have different mechanisms in in-ducing apoptosis in OSCC, both through intrinsic and extrinsic pathways. The evidence presented in the present study provides an oppor-tunity for future research to determine the appropriate therapeutic dose based on the specific alkaloid, duration of therapeutic administration, and in vivo and/or in human testing.

  • References

    1. G. G. Dark, Oncology at a Glance. Oxford: John Wiley & Sons, 2013.
    2. C. Scully and J. Bagan, “Oral squamous cell carcinoma overview,” Oral Oncol, vol. 45, no. 4–5, pp. 301–308, Apr. 2009, https://doi.org/10.1016/j.oraloncology.2009.01.004.
    3. M. Miloro, G. E. Ghali, P. E. Larsen, and P. D. Waite, Peterson’s Principles of Oral and Maxillofacial Surgery, 3rd ed. Connecti-cut: People’s Medical Publishing House, 2011.
    4. R. D. Coletta, W. A. Yeudall, and T. Salo, “Grand Challenges in Oral Cancers,” Frontiers in Oral Health, vol. 1, no. 3, Jun. 2020, https://doi.org/10.3389/froh.2020.00003.
    5. F. Bray, J. Ferlay, I. Soerjomataram, R. L. Siegel, L. A. Torre, and A. Jemal, “Global cancer statistics 2018: GLOBOCAN esti-mates of incidence and mortality worldwide for 36 cancers in 185 countries,” CA Cancer J Clin, vol. 68, no. 6, pp. 394–424, Nov. 2018, https://doi.org/10.3322/caac.21492.
    6. C. Scully and J. Bagan, “Oral squamous cell carcinoma: overview of current understanding of aetiopathogenesis and clinical impli-cations,” Oral Dis, vol. 15, no. 6, pp. 388–399, Sep. 2009, https://doi.org/10.1111/j.1601-0825.2009.01563.x.
    7. L. Feller and J. Lemmer, “Oral Squamous Cell Carcinoma: Epidemiology, Clinical Presentation and Treatment,” J Cancer Ther, vol. 03, no. 04, pp. 263–268, 2012, https://doi.org/10.4236/jct.2012.34037.
    8. S. Petti, “Lifestyle risk factors for oral cancer,” Oral Oncol, vol. 45, no. 4–5, pp. 340–350, Apr. 2009, https://doi.org/10.1016/j.oraloncology.2008.05.018.
    9. S. H. Hassanpour and M. Dehghani, “Review of cancer from perspective of molecular,” Journal of Cancer Research and Practice, vol. 4, no. 4, pp. 127–129, Dec. 2017, https://doi.org/10.1016/j.jcrpr.2017.07.001.
    10. G. H. Lyman, J. Cassidy, D. Bisset, and R. A. J. Spence, Oxford American Handbook of Oncology, 2nd ed. Oxford: Oxford Uni-versity Press, 2015. https://doi.org/10.1093/med/9780199689842.001.0001.
    11. S. Choi and J. N. Myers, “Molecular Pathogenesis of Oral Squamous Cell Carcinoma: Implications for Therapy,” J Dent Res, vol. 87, no. 1, pp. 14–32, Jan. 2008, https://doi.org/10.1177/154405910808700104.
    12. R. Sjamsuhidajat and W. De Jong, Buku Ajar Ilmu Bedah, 3rd ed. Jakarta: EGC, 2017.
    13. L. M. Sari, “Apoptosis: mekanisme molekuler kematian sel,” Cakradonya Dent J, vol. 10, no. 2, pp. 65–70, 2018. https://doi.org/10.24815/cdj.v10i2.11701.
    14. K. Matsuura, K. Canfield, W. Feng, and M. Kurokawa, “Metabolic regulation of apoptosis in cancer,” Int Rev Cell Mol Biol, vol. 327, pp. 43–87, 2016, https://doi.org/10.1016/bs.ircmb.2016.06.006.
    15. S. A. Gharat, M. M. Momin, and C. Bhavsar, “Oral squamous cell carcinoma: current treatment strategies and nanotechnology-based approaches for prevention and therapy,” Crit Rev Ther Drug Carrier Syst, vol. 33, no. 4, 2016. https://doi.org/10.1615/CritRevTherDrugCarrierSyst.2016016272.
    16. K. Omura, “Current status of oral cancer treatment strategies: surgical treatments for oral squamous cell carcinoma,” Int J Clin Oncol, vol. 19, no. 3, pp. 423–430, Jun. 2014, https://doi.org/10.1007/s10147-014-0689-z.
    17. U. J. Moore, Principles of Oral and Maxillofacial Surgery, 6th ed. West Sussex: Wiley-Blackwell, 2011.
    18. Q.-Y. Zhang, F.-X. Wang, K.-K. Jia, and L.-D. Kong, “Natural Product Interventions for Chemotherapy and Radiotherapy-Induced Side Effects,” Front Pharmacol, vol. 9, Nov. 2018, https://doi.org/10.3389/fphar.2018.01253.
    19. J. Fernando and R. Jones, “The principles of cancer treatment by chemotherapy,” Surgery (Oxford), vol. 33, no. 3, pp. 131–135, Mar. 2015, https://doi.org/10.1016/j.mpsur.2015.01.005.
    20. R. Abdul, M.-R. Wang, C.-J. Zhong, Y.-Y. Liu, W. Hou, and H.-R. Xiong, “An updated review on the antimicrobial and pharma-cological properties of Uncaria (Rubiaceae),” J Herb Med, vol. 34, p. 100573, Jul. 2022, https://doi.org/10.1016/j.hermed.2022.100573.
    21. F. Ciani et al., “Anti-proliferative and pro-apoptotic effects of Uncaria tomentosa aqueous extract in squamous carcinoma cells,” J Eth-nopharmacol, vol. 211, pp. 285–294, Jan. 2018, https://doi.org/10.1016/j.jep.2017.09.031.
    22. Erwin, “Review kandungan metabolit sekunder beberapa tumbuhan Uncaria yang terdapat di Kalimantan Timur,” Jurnal Atomik, vol. 05, no. 1, pp. 18–24, 2020.
    23. M. Almeida et al., “The Potency of the Genus Uncaria from East Borneo for Herbal Medicine Purposes: A Mini-review,” Journal of Tropical Pharmacy and Chemistry, vol. 6, no. 2, pp. 167–176, Oct. 2022, https://doi.org/10.25026/jtpc.v6i2.457.
    24. A. S. Ravipati, N. Reddy, and S. R. Koyyalamudi, “Biologically active compounds from the genus Uncaria (Rubiaceae),” Studies in Natural Products Chemistry, vol. 43, pp. 381–408, 2014, https://doi.org/10.1016/B978-0-444-63430-6.00013-8.
    25. Q. Zhang, J. J. Zhao, J. Xu, F. Feng, and W. Qu, “Medicinal uses, phytochemistry and pharmacology of the genus Uncaria,” J Eth-nopharmacol, vol. 173, pp. 48–80, Sep. 2015, https://doi.org/10.1016/j.jep.2015.06.011.
    26. W. Yang, S.-P. Ip, L. Liu, Y.-F. Xian, and Z.-X. Lin, “Uncaria rhynchophylla and its Major Constituents on Central Nervous System: A Review on Their Pharmacological Actions,” Curr Vasc Pharmacol, vol. 18, no. 4, pp. 346–357, Jun. 2020, https://doi.org/10.2174/1570161117666190704092841.
    27. F. M. Ridho, “Mechanism of Alkaloids and Flavonoids in Bajakah (Uncaria nervosa Elmer) as Antidiabetic Agents,” Jurnal Ilmu Medis Indonesia, vol. 3, no. 1, pp. 9–16, 2023.
    28. J.-H. Liang et al., “The genus Uncaria: A review on phytochemical metabolites and biological aspects,” Fitoterapia, vol. 147, p. 104772, Nov. 2020, https://doi.org/10.1016/j.fitote.2020.104772.
    29. K. J. Aprely, S. Misfadhila, and R. A. Asra, “Review: The Phytochemistry, Pharmacology and Traditional Use of Gambir (Un-caria gambir (Hunter) Roxb.),” EAS J. Pharm. Pharmacol, vol. 3, pp. 21–25, 2021.
    30. K. M. M. Koriem, “Cortex Uncariae: A Review on Pharmacology, Toxicology, Precautions, and Dosage,” Biointerface Res Appl Chem, vol. 13, no. 4, p. 334, Sep. 2022, https://doi.org/10.33263/BRIAC134.334.
    31. F. M. Ridho, “Kandungan Metabolit Sekunder dari Ekstrak Kayu Bajakah (Uncaria nervosa Elmer) dan Bioaktivitasnya Sebagai Anti-kanker,” Universitas Airlangga, Surabaya, 2020. Accessed: Jul. 24, 2023. [Online]. Available: http://lib.unair.ac.id
    32. S. Sultan, K. A. Mohd Ali, N. D. Mohamed Akram, K. Ashraf, M. Ashraf, and G. K. Surindar Singh, “Antimicrobial Activity of Sec-ondary Metabolites Isolated from Endophytic Fungi Associated with Rubiaceae Species,” International Journal of Pharmaceu-ticals, Nutraceuticals and Cosmetic Science, vol. 5, no. 1, pp. 33–47, Jun. 2022.
    33. M. Yang, B. Yao, and R. Lin, “Profiles of Metabolic Genes in Uncaria rhynchophylla and Characterization of the Critical Enzyme In-volved in the Biosynthesis of Bioactive Compounds-(iso)Rhynchophylline,” Biomolecules, vol. 12, no. 12, p. 1790, Nov. 2022.
    34. D. Martins and C. Nunez, “Secondary Metabolites from Rubiaceae Species,” Molecules, vol. 20, no. 7, pp. 13422–13495, Jul. 2015.
    35. J. Song, B. Zhang, M. Li, and J. Zhang, “The current scenario of naturally occurring indole alkaloids with anticancer potential,” Fitot-erapia, vol. 165, p. 105430, Mar. 2023.
    36. A. Dhiman, R. Sharma, and R. K. Singh, “Target-based anticancer indole derivatives and insight into structure‒activity relationship: A mechanistic review update (2018–2021),” Acta Pharm Sin B, vol. 12, no. 7, pp. 3006–3027, Jul. 2022.
    37. M.-L. Luo, W. Huang, H.-P. Zhu, C. Peng, Q. Zhao, and B. Han, “Advances in indole-containing alkaloids as potential anticancer agents by regulating autophagy,” Biomedicine & Pharmacotherapy, vol. 149, p. 112827, May 2022.
    38. N. Qin et al., “Recent research progress of Uncaria spp. based on alkaloids: phytochemistry, pharmacology and structural chemis-try,” Eur J Med Chem, Oct. 2020.
    39. H. Lee et al., “Isorhynchophylline, a Potent Plant Alkaloid, Induces Apoptotic and Anti-Metastatic Effects in Human Hepatocellu-lar Carcinoma Cells through the Modulation of Diverse Cell Signaling Cascades,” Int J Mol Sci, vol. 18, no. 5, p. 1095, May 2017.
    40. F. Song et al., “Indole Alkaloids, Synthetic Dimers and Hybrids with Potential In Vivo Anticancer Activity,” Curr Top Med Chem, vol. 21, no. 5, pp. 377–403, Mar. 2021.
    41. Y. Jia, X. Wen, Y. Gong, and X. Wang, “Current scenario of indole derivatives with potential anti-drug-resistant cancer activity,” Eur J Med Chem, vol. 200, p. 112359, Aug. 2020.
    42. P. Dey et al., “Analysis of alkaloids (indole alkaloids, isoquinoline alkaloids, tropane alkaloids),” in Recent Advances in Natural Prod-ucts Analysis, Elsevier, 2020, pp. 505–567.
    43. A. S. Saroya, Herbalism, Phytochemistry and Ethnopharmacology. New Hampshire: Science Publisher, 2011.
    44. N. Bribi, “Pharmacological activity of Alkaloids: A Review,” Asian Journal of Botany, vol. 1, no. 1, pp. 1–6, 2018.
    45. N. Qin et al., “Recent research progress of Uncaria spp. based on alkaloids: phytochemistry, pharmacology and structural chemis-try,” Eur J Med Chem, vol. 210, p. 112960, Jan. 2021.
    46. S. He, R. Chakraborty, and S. Ranganathan, “Proliferation and Apoptosis Pathways and Factors in Oral Squamous Cell Carcino-ma,” Int J Mol Sci, vol. 23, no. 3, p. 1562, Jan. 2022.
    47. C. Pfeffer and A. Singh, “Apoptosis: A Target for Anticancer Therapy,” Int J Mol Sci, vol. 19, no. 2, p. 448, Feb. 2018.
    48. L. Villanova, S. Careccia, R. De Maria, and M. Fiori, “Micro-Economics of Apoptosis in Cancer: ncRNAs Modulation of BCL-2 Family Members,” Int J Mol Sci, vol. 19, no. 4, p. 958, Mar. 2018.
    49. D. Hanahan and R. A. Weinberg, “Hallmarks of cancer: the next generation,” Cell, vol. 144, no. 5, pp. 646–674, Mar. 2011.
    50. C. M. Coutinho-Camillo et al., “Profile of apoptotic proteins in oral squamous cell carcinoma: A cluster analysis of 171 cases,” Ap-plied Cancer Research, vol. 37, no. 1, p. 2, Dec. 2017.
    51. S. Lin, J. Pan, X. Huang, Z. Wang, X. Zhao, and S.-K. Sun, “Near-infrared-inducible Bcl-2-associated X protein system for apop-tosis regulation in vivo,” Chemical Engineering Journal, vol. 461, p. 141771, Apr. 2023.
    52. R. Singh, A. Letai, and K. Sarosiek, “Regulation of apoptosis in health and disease: the balancing act of BCL-2 family proteins,” Nat Rev Mol Cell Biol, vol. 20, no. 3, pp. 175–193, Mar. 2019.
    53. S. Elmore, “Apoptosis: A Review of Programmed Cell Death,” Toxicol Pathol, vol. 35, no. 4, pp. 495–516, Jun. 2007.
    54. V. T. DeVita, T. S. Lawrence, and S. A. Rosenberg, Cancer: principles & practice of oncology: primer of the molecular biology of can-cer. Lippincott Williams & Wilkins, 2012.
    55. E. Dirican, H. Özcan, S. Karabulut Uzunçakmak, and U. Takım, “Evaluation Expression of the Caspase-3 and Caspase-9 Apoptot-ic Genes in Schizophrenia Patients,” Clinical Psychopharmacology and Neuroscience, vol. 21, no. 1, pp. 171–178, Feb. 2023.
    56. B. Alberts, Molecular biology of the cell. Garland science, 2017.
    57. D. B. Kiselevsky, “Granzymes and Mitochondria,” Biochemistry (Moscow), vol. 85, no. 2, pp. 131–139, Feb. 2020.
    58. F. Velotti, I. Barchetta, F. A. Cimini, and M. G. Cavallo, “Granzyme B in Inflammatory Diseases: Apoptosis, Inflammation, Ex-tracellular Matrix Remodeling, Epithelial-to-Mesenchymal Transition and Fibrosis,” Front Immunol, vol. 11, Nov. 2020.
    59. R. Pilarski et al., “Enhanced proapoptotic response of the promyelocytic leukemia HL-60 cells treated with an Uncaria tomentosa alka-loid preparation,” J Herb Med, vol. 3, no. 4, pp. 149–156, Dec. 2013.
    60. L. Z. de Oliveira et al., “Effect of Uncaria tomentosa Extract on Apoptosis Triggered by Oxaliplatin Exposure on HT29 Cells,” Evi-dence-Based Complementary and Alternative Medicine, vol. 2014, pp. 1–10, 2014.
    61. S. Kaiser et al., “Catʼs Claw Oxindole Alkaloid Isomerization Induced by Cell Incubation and Cytotoxic Activity against T24 and RT4 Human Bladder Cancer Cell Lines,” Planta Med, vol. 79, no. 15, pp. 1413–1420, Aug. 2013.
    62. P. Katyal and S. Sharma, “Emerging Alkaloids Against Cancer: A Peep into Factors, Regulation, and Molecular Mechanisms,” in Bioac-tive Natural Products for the Management of Cancer: from Bench to Bedside, Singapore: Springer Singapore, 2019, pp. 37–60.
    63. C. Lou, S. Yokoyama, I. Saiki, and Y. Hayakawa, “Selective anticancer activity of hirsutine against HER2-positive breast cancer cells by inducing DNA damage,” Oncol Rep, vol. 33, no. 4, pp. 2072–2076, Apr. 2015.
    64. R. Zhang et al., “Hirsutine induces mPTP-dependent apoptosis through ROCK1/PTEN/PI3K/GSK3β pathway in human lung cancer cells,” Cell Death Dis, vol. 9, no. 6, p. 598, May 2018.
    65. Md. S. Bhuia et al., “Hirsutine, an Emerging Natural Product with Promising Therapeutic Benefits: A Systematic Review,” Mole-cules, vol. 28, no. 16, p. 6141, Aug. 2023.
    66. Q.-W. Huang, N.-N. Zhai, T. Huang, and D.-M. Li, “Hirsutine induces apoptosis of human breast cancer MDA-MB-231 cells through mitochondrial pathway,” Acta Physiologica Sinica, vol. 70, no. 1, pp. 40–46, Feb. 2018.
    67. J. Meng, R. Su, L. Wang, B. Yuan, and L. Li, “Inhibitory effect and mechanism of action (MOA) of hirsutine on the proliferation of T-cell leukemia Jurkat clone E6-1 cells,” PeerJ, vol. 9, p. e10692, Feb. 2021.
    68. M. Zheng et al., “Protection by rhynchophylline against MPTP/MPP+-induced neurotoxicity via regulating PI3K/Akt pathway,” J Eth-nopharmacol, vol. 268, p. 113568, Mar. 2021.
    69. Z. Zhang, Y. Li, G. Wu, Y.-M. Li, D. Zhang, and R. Wang, “A comprehensive review of phytochemistry, pharmacology and clin-ical applications of Uncariae Ramulus Cum Uncis,” Arabian Journal of Chemistry, vol. 16, no. 5, p. 104638, May 2023.
    70. R. Qin et al., “Naturally derived indole alkaloids targeting regulated cell death (RCD) for cancer therapy: from molecular mecha-nisms to potential therapeutic targets,” J Hematol Oncol, vol. 15, no. 1, p. 133, Sep. 2022.
    71. C. Liu et al., “Alkaloids from Traditional Chinese Medicine against hepatocellular carcinoma,” Biomedicine & Pharmacotherapy, vol. 120, p. 109543, Dec. 2019.
    72. J. Meng, Y. Yuan, Y. Li, and B. Yuan, “Effects of hirsuteine on MDA MB 453 breast cancer cell proliferation,” Oncol Lett, vol. 25, no. 1, p. 4, Nov. 2022.
    73. X. Yun et al., “Inhibitory effect and mechanism of hirsuteine on NCI H1299 lung cancer cell lines,” Oncol Lett, vol. 25, no. 5, p. 202, Apr. 2023.
    74. S. Gao et al., “Growth Inhibitory and Pro-Apoptotic Effects of Hirsuteine in Chronic Myeloid Leukemia Cells through Targeting Sphin-gosine Kinase 1,” Biomol Ther (Seoul), vol. 30, no. 6, pp. 553–561, Nov. 2022.
    75. S. Wang et al., “Combined Expression of c-jun, c-fos, and p53 Improves Estimation of Prognosis in Oral Squamous Cell Carci-noma,” Cancer Invest, vol. 34, no. 8, pp. 393–400, Sep. 2016.
    76. Z. Gao, Y. Zhang, H. Zhou, and J. Lv, “Baicalein inhibits the growth of oral squamous cell carcinoma cells by downregulating the ex-pression of transcription factor Sp1,” Int J Oncol, vol. 56, no. 1, pp. 273–282, Oct. 2019.
    77. R. P. Krishnan, D. Pandiar, P. Ramani, and S. Jayaraman, “Necroptosis in human cancers with special emphasis on oral squamous cell carcinoma,” J Stomatol Oral Maxillofac Surg, p. 101565, Jul. 2023.
    78. B. Tummers and D. R. Green, “Caspase‐8: regulating life and death,” Immunol Rev, vol. 277, no. 1, pp. 76–89, May 2017.
    79. C. Harsha et al., “Targeting AKT/mTOR in Oral Cancer: Mechanisms and Advances in Clinical Trials.,” Int J Mol Sci, vol. 21, no. 9, May 2020.
    80. H.-M. Yun, Y.-J. Kwon, E. Kim, H.-J. Chung, and K.-R. Park, “Machilin D Promotes Apoptosis and Autophagy, and Inhibits Necrop-tosis in Human Oral Squamous Cell Carcinoma Cells,” Int J Mol Sci, vol. 24, no. 5, p. 4576, Feb. 2023.
    81. L. L. Loro, A. C. Johannessen, and O. K. Vintermyr, “Loss of BCL-2 in the progression of oral cancer is not attributable to muta-tions.,” J Clin Pathol, vol. 58, no. 11, pp. 1157–62, Nov. 2005.
    82. L. L. Loro, O. K. Vintermyr, P. G. Liavaag, R. Jonsson, and A. C. Johannessen, “Oral squamous cell carcinoma is associated with de-creased bcl-2/bax expression ratio and increased apoptosis.,” Hum Pathol, vol. 30, no. 9, pp. 1097–105, Sep. 1999.
    83. M. Brentnall, L. Rodriguez-Menocal, R. L. De Guevara, E. Cepero, and L. H. Boise, “Caspase-9, caspase-3 and caspase-7 have distinct roles during intrinsic apoptosis,” BMC Cell Biol, vol. 14, no. 1, p. 32, Dec. 2013.
    84. R. Aikin, D. Maysinger, and L. Rosenberg, “Cross-Talk between Phosphatidylinositol 3-Kinase/AKT and c-Jun NH2-Terminal Kinase Mediates Survival of Isolated Human Islets,” Endocrinology, vol. 145, no. 10, pp. 4522–4531, Oct. 2004.
    85. R. Fragoso and J. T. Barata, “Kinases, tails and more: Regulation of PTEN function by phosphorylation,” Methods, vol. 77–78, pp. 75–81, May 2015.
    86. G. Li et al., “Mitochondrial translocation and interaction of cofilin and Drp1 are required for erucin-induced mitochondrial fission and apoptosis,” Oncotarget, vol. 6, no. 3, pp. 1834–1849, Jan. 2015.
    87. Q. Zhang et al., “ROCK1 induces dopaminergic nerve cell apoptosis via the activation of Drp1-mediated aberrant mitochondrial fission in Parkinson’s disease,” Exp Mol Med, vol. 51, no. 10, pp. 1–13, Oct. 2019.
    88. J. Hu et al., “ROCK1 activation-mediated mitochondrial translocation of Drp1 and cofilin are required for arnidiol-induced mito-chondrial fission and apoptosis,” Journal of Experimental & Clinical Cancer Research, vol. 39, no. 1, p. 37, Dec. 2020.
    89. Y. Cheng, J. Chen, Y. Shi, X. Fang, and Z. Tang, “MAPK Signaling Pathway in Oral Squamous Cell Carcinoma: Biological Function and Targeted Therapy,” Cancers (Basel), vol. 14, no. 19, p. 4625, Sep. 2022.
    90. J.-H. Seo, G. Yoon, S. Park, J.-H. Shim, J.-I. Chae, and Y.-J. Jeon, “Deoxypodophyllotoxin Induces ROS-Mediated Apoptosis by Modulating the PI3K/AKT and p38 MAPK-Dependent Signaling in Oral Squamous Cell Carcinoma,” J Microbiol Biotechnol, vol. 32, no. 9, pp. 1103–1109, Sep. 2022.
    91. J. Yue and J. M. López, “Understanding MAPK Signaling Pathways in Apoptosis,” Int J Mol Sci, vol. 21, no. 7, p. 2346, Mar. 2020.
    92. I. Gkouveris, N. Nikitakis, D. Avgoustidis, M. Karanikou, G. Rassidakis, and A. Sklavounou, “ERK1/2, JNK and STAT3 activa-tion and correlation with tumor differentiation in oral SCC.,” Histol Histopathol, vol. 32, no. 10, pp. 1065–1076, Oct. 2017.
    93. X. Huang et al., “IL-6/STAT3 Axis Activates Glut5 to Regulate Fructose Metabolism and Tumorigenesis.,” Int J Biol Sci, vol. 18, no. 9, pp. 3668–3675, 2022.
    94. M. Jiang and B. Li, “STAT3 and Its Targeting Inhibitors in Oral Squamous Cell Carcinoma,” Cells, vol. 11, no. 19, p. 3131, Oct. 2022.
    95. A. Steven et al., “What turns CREB on? And off? And why does it matter?,” Cellular and Molecular Life Sciences, vol. 77, no. 20, pp. 4049–4067, Oct. 2020.
    96. R.-W. Lin et al., “P53 enhances apoptosis induced by doxorubicin only under conditions of severe DNA damage,” Cell Cycle, vol. 17, no. 17, pp. 2175–2186, Sep. 2018.
    97. B. J. Aubrey, G. L. Kelly, A. Janic, M. J. Herold, and A. Strasser, “How does p53 induce apoptosis and how does this relate to p53-mediated tumour suppression?,” Cell Death Differ, vol. 25, no. 1, pp. 104–113, Jan. 2018.
    98. Y. Duan et al., “Targeted silencing of CXCR4 inhibits epithelial-mesenchymal transition in oral squamous cell carcinoma,” Oncol Lett, vol. 12, no. 3, pp. 2055–2061, Sep. 2016.
    99. C. Jiang et al., “Effect of CXCR4 on Apoptosis in Osteosarcoma Cells via the PI3K/Akt/NF-κβ Signaling Pathway,” Cellular Physiology and Biochemistry, vol. 46, no. 6, pp. 2250–2260, 2018.
    100. C.-D. Kim, J.-D. Cha, S. Li, and I.-H. Cha, “The mechanism of acacetin-induced apoptosis on oral squamous cell carcinoma,” Arch Oral Biol, vol. 60, no. 9, pp. 1283–1298, Sep. 2015.
    101. L. Zhao et al., “Hydrogen peroxide induces programmed necrosis in rat nucleus pulposus cells through the RIP1/RIP3‐PARP‐AIF pathway,” Journal of Orthopaedic Research, vol. 36, no. 4, pp. 1269–1282, Apr. 2018.
    102. N. B. Madungwe et al., “Mitochondrial inner membrane protein (mitofilin) knockdown induces cell death by apoptosis via an AIF-PARP-dependent mechanism and cell cycle arrest,” American Journal of Physiology-Cell Physiology, vol. 315, no. 1, pp. C28–C43, Jul. 2018.
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    Ridho, F. M., Ulfah, K., Aruan, I. A., Pramaztri, N. N., Laksono, E. P., & Putri, A. N. A. (2024). Uncaria-derived alkaloids: A review on the mechanism in inducing apoptosis in oral squamous cell carcinoma. International Journal of Pharmacology and Toxicology, 12(1), 1-7. https://doi.org/10.14419/mp67x884