<?xml version="1.1" encoding="utf-8"?>
<article xsi:noNamespaceSchemaLocation="http://jats.nlm.nih.gov/publishing/1.1/xsd/JATS-journalpublishing1-mathml3.xsd" dtd-version="1.1" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"><front><journal-meta><journal-id journal-id-type="publisher-id">PAR</journal-id><journal-title-group><journal-title>Proceedings of Anticancer Research</journal-title></journal-title-group><issn>2208-3545</issn><eissn>2208-3553</eissn><publisher><publisher-name>Bio-Byword Scientific Publishing Pty. Ltd.</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="doi">10.26689/par.v10i3.14288</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title>Lidocaine Regulates the Proliferation and Apoptosis of Colorectal Cancer Cells by Modulating AKR1B1/miR-21-5p Pathway</title><url>https://artdesignp.com/journal/PAR/10/3/10.26689/par.v10i3.14288</url><author>WangLuyao,ZhouJie,YangHui,ShenLulu,ZhengWenzhuang,WangLei,XieChenglan</author><pub-date pub-type="publication-year"><year>2026</year></pub-date><volume>10</volume><issue>3</issue><history><date date-type="pub"><published-time>2026-05-31</published-time></date></history><abstract>This study was to investigate the effect of lidocaine on the proliferation and apoptosis of the human colorectal carcinoma cell line (HCT116) and explore the underlying mechanism. HCT116 cells’ proliferation and apoptosis rate were determined by CCK8 assay flow cytometry, followed by treating the cells with 0.5 mM and 1 mM lidocaine. HCT116 cells were transfected with NC-mimic, Mimic-miR-21-5p, inhibitor-NC, and Inhibitor-miR-21-5p, followed by treatment with Lidocaine and fidarestat, combined and both alone. The expression of miR-21-5p and of AKR1B1, PTEN, p-AKT, AKT, and PI3K proteins was determined by qRT-PCR and Western blot. This study find lidocaine inhibited cell proliferation and promoted apoptosis in a time-dose dependent manner. Lidocaine and fidarestat, both alone and in combination, reduced the expression of miR-21-5p and AKR1B1. Lidocaine and fidarestat alone and combined treatments and the miR-21-5p-inhibitor group decreased the expression of p-AKT and PI3K and vice versa in the mimic-miR-21-5p group. The expression of PTEN was increased in the lidocaine + fidarestat group, decreased in the mimic-miR-21-5p group. These results suggest that lidocaine inhibited the proliferation of HCT116 cells and promoted cell apoptosis by downregulating the expression of AKR1B1/miR-21-5p and further modulating the PTEN/AKT/PI3K signaling pathway.</abstract><keywords/></article-meta></front><body/><back><ref-list><ref id="B1" content-type="article"><label>1</label><element-citation publication-type="journal"><p>Bray F, Laversanne M, Sung H, et al., 2024, Global Cancer Statistics 2022: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin, 74(3): 229–263.</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B2" content-type="article"><label>2</label><element-citation publication-type="journal"><p>Zhao S, Wang S, Pan P, et al., 2022, FIT-Based Risk-Stratification Model Effectively Screens Colorectal Neoplasia and Early-Onset Colorectal Cancer in Chinese Population: A Nationwide Multicenter Prospective Study. J Hematol Oncol, 15(1): 162.</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B3" content-type="article"><label>3</label><element-citation publication-type="journal"><p>Al-Joufi FA, Setia A, Salem-Bekhit MM, et al., 2022, Molecular Pathogenesis of Colorectal Cancer With an Emphasis on Recent Advances in Biomarkers, as Well as Nanotechnology-Based Diagnostic and Therapeutic Approaches. Nanomaterials (Basel), 12(1): 169.</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B4" content-type="article"><label>4</label><element-citation publication-type="journal"><p>Dothan D, Raisin G, Malchi N, et al., 2022, Intravesical Sustained Release System of Lidocaine and Oxybutynin Results From In Vitro and Animal Study. Inter Urol Nephrol, 54(9): 2167–2174.</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B5" content-type="article"><label>5</label><element-citation publication-type="journal"><p>Wall TP, Buggy DJ, 2021, Perioperative Intravenous Lidocaine and Metastatic Cancer Recurrence - A Narrative Review. Front Oncol, 11: 688896.</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B6" content-type="article"><label>6</label><element-citation publication-type="journal"><p>Liu H, Weng J, Huang CL, et al., 2024, Voltage-Gated Sodium Channels in Cancers. Biomark Res, 12(1): 70.</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B7" content-type="article"><label>7</label><element-citation publication-type="journal"><p>Chida K, Kanazawa H, Kinoshita H, et al., 2024, The Role of Lidocaine in Cancer Progression and Patient Survival. Pharmacol Ther, 259: 108654.</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B8" content-type="article"><label>8</label><element-citation publication-type="journal"><p>Wu J, Yang J, Duan J, 2025, Anesthetic Agents as Therapeutic Tools in Breast Cancer: Insights Into Cancer Progression and Recurrence. Clin Breast Cancer, 25(5): e561–e576.</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B9" content-type="article"><label>9</label><element-citation publication-type="journal"><p>Sempere LF, Azmi AS, Moore A, 2021, MicroRNA-Based Diagnostic and Therapeutic Applications in Cancer Medicine. Wiley Interdiscip Rev RNA, 12(6): e1662.</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B10" content-type="article"><label>10</label><element-citation publication-type="journal"><p>Yang L, Belaguli N, Berger DH, 2009, MicroRNA and Colorectal Cancer. World J Surg, 33(4): 638–646.</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B11" content-type="article"><label>11</label><element-citation publication-type="journal"><p>Qu K, Zhang X, Lin T, et al., 2017, Circulating miRNA-21-5p as a Diagnostic Biomarker for Pancreatic Cancer: Evidence From Comprehensive miRNA Expression Profiling Analysis and Clinical Validation. Sci Rep, 7(1): 1692.</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B12" content-type="article"><label>12</label><element-citation publication-type="journal"><p>Gebrie A, 2022, Disease Progression Role as Well as the Diagnostic and Prognostic Value of MicroRNA-21 in Patients With Cervical Cancer: A Systematic Review and Meta-Analysis. PLoS One, 17(7): e0268480.</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B13" content-type="article"><label>13</label><element-citation publication-type="journal"><p>Qu X, Yang L, Shi Q, et al., 2018, Lidocaine Inhibits Proliferation and Induces Apoptosis in Colorectal Cancer Cells by Upregulating miR-520a-3p and Targeting EGFR. Pathol Res Pract, 214(12): 1974–1979.</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B14" content-type="article"><label>14</label><element-citation publication-type="journal"><p>Yang Q, Zhang Z, Xu H, et al., 2019, Lidocaine Alleviates Cytotoxicity-Resistance in Lung Cancer A549/DDP Cells via Down-Regulation of miR-21. Mol Cell Biochem, 456(1–2): 63–72.</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B15" content-type="article"><label>15</label><element-citation publication-type="journal"><p>Zhao H, Dong X, Huang T, et al., 2022, A Potential Prognostic Biomarker for Glioma: Aldo-Keto Reductase Family 1 Member B1. Comput Intel Neurosc, 2022: 9979200.</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B16" content-type="article"><label>16</label><element-citation publication-type="journal"><p>Schwab A, Siddiqui A, Vazakidou ME, et al., 2018, Polyol Pathway Links Glucose Metabolism to the Aggressiveness of Cancer Cells. Cancer Res, 78(7): 1604–1618.</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B17" content-type="article"><label>17</label><element-citation publication-type="journal"><p>Saxena A, Tammali R, Ramana KV, et al., 2013, Aldose Reductase Inhibition Prevents Colon Cancer Growth by Restoring Phosphatase and Tensin Homolog Through Modulation of miR-21 and FOXO3a. Antioxid Redox Sign, 18(11): 1249–1262.</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B18" content-type="article"><label>18</label><element-citation publication-type="journal"><p>Wang H, Zhang X, Li Y, et al., 2022, Lidocaine Hampers Colorectal Cancer Process via circITFG2/miR-1204/SOCS2 Axis. Anti-Cancer Drug, 33(3): 235–244.</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B19" content-type="article"><label>19</label><element-citation publication-type="journal"><p>Sui H, Lou A, Li Z, et al., 2019, Lidocaine Inhibits Growth, Migration and Invasion of Gastric Carcinoma Cells by Up-Regulation of miR-145. BMC Cancer, 19(1): 233.</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B20" content-type="article"><label>20</label><element-citation publication-type="journal"><p>Gao P, Peng F, Liu J, et al., 2025, Lidocaine Enhanced Antitumor Efficacy and Relieved Chemotherapy-Induced Hyperalgesia in Mice With Metastatic Gastric Cancer. Int J Mol Sci, 26(2): 828.</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B21" content-type="article"><label>21</label><element-citation publication-type="journal"><p>Long D, Fang X, Yuan P, et al., 2022, Lidocaine Promotes Apoptosis in Breast Cancer Cells by Affecting VDAC1 Expression. BMC Anesthesiology, 22(1): 273.</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B22" content-type="article"><label>22</label><element-citation publication-type="journal"><p>Ma X, Yan W, He N, 2022, Lidocaine Attenuates Hypoxia/Reoxygenation-Induced Inflammation, Apoptosis and Ferroptosis in Lung Epithelial Cells by Regulating the p38 MAPK Pathway. Mol Med Rep, 25(5): 150.</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B23" content-type="article"><label>23</label><element-citation publication-type="journal"><p>Zeng W, Xing ZT, Tan MY, et al., 2021, Lidocaine Suppresses the Malignant Behavior of Gastric Cancer Cells via the c-Met/c-Src Pathway. Exp Therap Med, 21(5): 424.</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B24" content-type="article"><label>24</label><element-citation publication-type="journal"><p>Sun H, Sun Y, 2019, Lidocaine Inhibits Proliferation and Metastasis of Lung Cancer Cell via Regulation of miR-539/EGFR Axis. Artif Cell Nanomed B, 47(1): 2866–2874.</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B25" content-type="article"><label>25</label><element-citation publication-type="journal"><p>Yang Y, Yang JJ, Tao H, et al., 2015, MicroRNA-21 Controls hTERT via PTEN in Human Colorectal Cancer Cell Proliferation. Journal of Physiology and Biochemistry, 71(1): 59–68.</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B26" content-type="article"><label>26</label><element-citation publication-type="journal"><p>Banerjee S, 2021, Aldo Keto Reductases AKR1B1 and AKR1B10 in Cancer: Molecular Mechanisms and Signaling Networks. Adv Exp Med Biol, 1347: 65–82.</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B27" content-type="article"><label>27</label><element-citation publication-type="journal"><p>Khayami R, Hashemi SR, Kerachian MA, 2020, Role of Aldo-Keto Reductase Family 1 Member B1 (AKR1B1) in the Cancer Process and Its Therapeutic Potential. J Cell Mol Med, 24(16): 8890–8902.</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B28" content-type="article"><label>28</label><element-citation publication-type="journal"><p>Zhao Q, Han B, Wang L, et al., 2024, AKR1B1-Dependent Fructose Metabolism Enhances Malignancy of Cancer Cells. Cell Death Differ, 31(12): 1611–1624.</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B29" content-type="article"><label>29</label><element-citation publication-type="journal"><p>Tammali R, Reddy AB, Saxena A, et al., 2011, Inhibition of Aldose Reductase Prevents Colon Cancer Metastasis. Carcinogenesis, 32(8): 1259–1267.</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B30" content-type="article"><label>30</label><element-citation publication-type="journal"><p>Sonowal H, Pal PB, Wen JJ, et al., 2017, Aldose Reductase Inhibitor Increases Doxorubicin-Sensitivity of Colon Cancer Cells and Decreases Cardiotoxicity. Sci Rep, 7(1): 3182.</p><pub-id pub-id-type="doi"/></element-citation></ref></ref-list></back></article>
