OTDOncology Treatment Discovery3083-49962981-8079Bio-Byword Scientific Publishing Pty. Ltd.10.26689/otd.v3i3.12259ArticleMolecular Targets and Developmental Potential of Alkaloid Monomers from Traditional Chinese Medicine as Anticancer Agentshttps://artdesignp.com/journal/OTD/3/3/10.26689/otd.v3i3.12259YangBeiqi,HeTongtong,ZhiTingting,TangJing2025332025-10-16Plant-derived alkaloids exhibit significant anticancer potential, yet their multi-target mechanisms, spanning signaling pathways, programmed cell death, immunity, and metabolism, remain fragmented. This narrative review synthesizes recent preclinical evidence on five representative alkaloids: dendrobine (DDB), aloperine (ALO), levo-tetrahydropalmatine (L-THP), solamargine (SM), and cyclovirobuxine D (CVB-D). Using a dual-framework of compound-specific analysis and key regulatory modules (NF-κB, MAPK, PI3K/AKT/mTOR, JAK/STAT; apoptosis, autophagy, ferroptosis; immune checkpoints; metabolism/microbiota), the study identified convergent anticancer mechanisms with translational relevance. These alkaloids consistently suppress NF-κB, PI3K/AKT/mTOR, and MAPK pathways, and modulate JAK/STAT signaling. They induce apoptosis and ferroptosis, and block autophagic flux. Notably, EVO and SM downregulate PD-L1 via the MUC1-C/NF-κB/c-MYC axis, enhancing CD8⁺ T cell function. L-THP activates AMPK and remodels tumor metabolism. These mechanistic insights support rational co-therapies such as L-THP plus metabolic inhibitors, or ALO combined with bispecific immune checkpoint inhibitors. Overall, these alkaloids demonstrate systemic, multi-pathway anticancer efficacy, and represent promising partners in precision combination therapy. Clinical translation should prioritize formulation and pharmacokinetic optimization, biomarker-guided stratification, and preclinical validation of synergistic regimens.

Liu Y, Yang S, Wang K, et al., 2020, Cellular Senescence and Cancer: Focusing on Traditional Chinese Medicine and Natural Products. Cell Prolif, 53(10): e12894.

Miller K, Nogueira L, Devasia T, et al., 2022, Cancer Treatment and Survivorship Statistics, 2022. CA Cancer J Clin, 72(5): 409–436.

Wang S, Fu J L, Hao H F, et al., 2021, Metabolic Reprogramming by Traditional Chinese Medicine and Its Role in Effective Cancer Therapy. Pharmacol Res, 170: 105728.

Liu J, Wang S, Zhang Y, et al., 2015, Traditional Chinese Medicine and Cancer: History, Present Situation, and Development. Thorac Cancer, 6(5): 561–569.

Bhambhani S, Kondhare K, Giri A, 2021, Diversity in Chemical Structures and Biological Properties of Plant Alkaloids. Molecules, 26(11): 3374.

Shin H, Kim T, Kim Y, et al., 2017, Protective Effects of Dendrobium nobile Against Cisplatin Nephrotoxicity Both In-vitro and In-vivo. Iran J Pharm Res, 16(Suppl): 197–206.

Olofinsan K, Abrahamse H, George B, 2023, Therapeutic Role of Alkaloids and Alkaloid Derivatives in Cancer Management. Molecules, 28(14): 5578.

Jia X, Chen Z, Chen X, et al., 2025, Elucidating the Anticancer Potential of Dendrobine in Renal Cell Carcinoma Treatment. Naunyn Schmiedebergs Arch Pharmacol, 398(6): 7517–7528.

Wu Y, Jia Q, Tang Q, et al., 2024, A Specific Super-Enhancer Actuated by Berberine Regulates EGFR-Mediated RAS-RAF1-MEK1/2-ERK1/2 Pathway to Induce Nasopharyngeal Carcinoma Autophagy. Cell Mol Biol Lett, 29(1): 92.

Liu Q, Tang J, Chen S, et al., 2022, Berberine for Gastric Cancer Prevention and Treatment: Multi-Step Actions on the Correa’s Cascade Underlie Its Therapeutic Effects. Pharmacol Res, 184: 106440.

Xu M, Ren L, Fan J, et al., 2022, Berberine Inhibits Gastric Cancer Development and Progression by Regulating the JAK2/STAT3 Pathway and Downregulating IL-6. Life Sci, 290: 120266.

Zhang Q, Wang X, Cao S, et al., 2020, Berberine Represses Human Gastric Cancer Cell Growth In Vitro and In Vivo by Inducing Cytostatic Autophagy via Inhibition of MAPK/mTOR/p70S6K and Akt Signaling Pathways. Biomed Pharmacother, 128: 110245.

Li J, Jiang L, Ma Q, et al., 2025, Evodiamine Inhibits Programmed Cell Death Ligand 1 Expression via the PI3K/AKT Signaling Pathway to Regulate Antitumor Immunity in Melanoma. Sci Rep, 15(1): 6649.

Liu J, He L, Zhang W, et al., 2024, Evodiamine Inhibits Proliferation and Induces Apoptosis of Nasopharyngeal Carcinoma Cells via the SRC/ERBB2-Mediated MAPK/ERK Signaling Pathway. J Transl Med, 22(1): 859.

Jung Y, Baek S, Narula A, et al., 2021, Potential Function of Oxymatrine as a Novel Suppressor of Epithelial-to-Mesenchymal Transition in Lung Tumor Cells. Life Sci, 284: 119893.

Chen M, Gu Y, Zhang A, et al., 2021, Biological Effects and Mechanisms of Matrine and Other Constituents of Sophora flavescens in Colorectal Cancer. Pharmacol Res, 171: 105778.

Xu B, Qiu T, Yang R, et al., 2024, Oxymatrine Inhibits Migration and Invasion of Esophageal Squamous Cell Carcinoma Cell Lines via the MEK1/ERK/β-Catenin Pathway. Chem Biol Interact, 404: 111270.

Guo W, Zhou H, Wang J, et al., 2024, Aloperine Suppresses Cancer Progression by Interacting with VPS4A to Inhibit Autophagosome-Lysosome Fusion in NSCLC. Adv Sci (Weinh), 11(31): e2308307.

Zhang L, Li L, Chen X, et al., 2023, Evodiamine Inhibits ESCC by Inducing M-Phase Cell-Cycle Arrest via CUL4A/p53/p21 Axis and Activating Noxa-Dependent Intrinsic and DR4-Dependent Extrinsic Apoptosis. Phytomedicine, 108: 154493.

Li L, Lu J, Fu S, et al., 2025, Evodiamine Induces Ferroptosis in Prostate Cancer Cells by Inhibiting TRIM26-Mediated Stabilization of GPX4. Chin Med, 20(1): 71.

Hu C, Wu H, Shan Y, et al., 2023, Evodiamine Exhibits Anti-Bladder Cancer Activity by Suppression of Glutathione Peroxidase 4 and Induction of Ferroptosis. Int J Mol Sci, 24(7): 6021.

Wang H, Wei L, Mao D, et al., 2023, Combination of Oxymatrine (Om) and Astragaloside IV (As) Enhances the Infiltration and Function of TILs in Triple-Negative Breast Cancer (TNBC). Int Immunopharmacol, 125(Pt A): 111026.

Yin S, Jin W, Qiu Y, et al., 2022, Solamargine Induces Hepatocellular Carcinoma Cell Apoptosis and Autophagy via Inhibiting LIF/miR-192-5p/CYR61/Akt Signaling Pathways and Eliciting Immunostimulatory Tumor Microenvironment. J Hematol Oncol, 15(1): 32.

Hu J, Shi Q, Xue C, Wang Q, 2024, Berberine Protects Against Hepatocellular Carcinoma Progression by Regulating Intrahepatic T Cell Heterogeneity. Adv Sci (Weinh), 11(39): e2405182.

Jiang Z, Huang J, Xie Y, et al., 2020, Evodiamine Suppresses Non-Small Cell Lung Cancer by Elevating CD8(+) T Cells and Downregulating the MUC1-C/PD-L1 Axis. J Exp Clin Cancer Res, 39(1): 249.

Yu Y, Huang X, Liang C, et al., 2023, Evodiamine Impairs HIF1A Histone Lactylation to Inhibit Sema3A-Mediated Angiogenesis and PD-L1 by Inducing Ferroptosis in Prostate Cancer. Eur J Pharmacol, 957: 176007.

Sun Y, Zhou Q, Chen F, et al., 2023, Berberine Inhibits Breast Carcinoma Proliferation and Metastasis Under Hypoxic Microenvironment Involving Gut Microbiota and Endogenous Metabolites. Pharmacol Res, 193: 106817.

Chen H, Ye C, Wu C, et al., 2023, Berberine Inhibits High Fat Diet-Associated Colorectal Cancer Through Modulation of the Gut Microbiota-Mediated Lysophosphatidylcholine. Int J Biol Sci, 19(7): 2097–2113.

Yin X, Zhang J, Zhao W, et al., 2022, Combined Levo-Tetrahydropalmatine and Diphenyleneiodonium Chloride Enhances Antitumor Activity in Hepatocellular Carcinoma. Pharmacol Res, 179: 106219.

Bhardwaj K, Bhargav R, Patocka J, et al., 2024, Dendrobine: A Neuroprotective Sesquiterpenic Alkaloid for the Prevention and Treatment of Diseases: A Review. Mini Rev Med Chem, 24(15): 1395–1408.

Tahir M, Ali S, Zhang W, et al., 2022, Aloperine: A Potent Modulator of Crucial Biological Mechanisms in Multiple Diseases. Biomedicines, 10(4): 905.

Chen H, Wang S, Chen Q, et al., 2024, Aloperine Ameliorates Acetaminophen-Induced Acute Liver Injury through HMGB1/TLR4/NF-κB and NLRP3/Inflammasome Pathway. Mediators Inflamm, 2024: 3938136.

Liu L, Liu M, Zhao W, et al., 2021, Levo-tetrahydropalmatine: A New Potential Medication for Methamphetamine Addiction and Neurotoxicity. Exp Neurol, 344: 113809.

Li J, Tang W, Yang Y, et al., 2021, A Programmed Cell-Mimicking Nanoparticle Driven by Potato Alkaloid for Targeted Cancer Chemoimmunotherapy. Adv Healthc Mater, 10(13): e2100311.

Li S, Yan M, Wang Z, et al., 2024, Phytochemistry of Genus Buxus and Pharmacology of Cyclovirobuxine D. Chem Biodivers, 21(8): e202400494.

Zeng C, Zou T, Qu J, et al., 2021, Cyclovirobuxine D Induced-Mitophagy through the p65/BNIP3/LC3 Axis Potentiates Its Apoptosis-Inducing Effects in Lung Cancer Cells. Int J Mol Sci, 22(11): 5820.

Xue T, Chen Y, Xu J, et al., 2023, Cyclovirobuxine D Inhibits Growth and Progression of Non-Small Cell Lung Cancer Cells by Suppressing the KIF11-CDC25C-CDK1-CyclinB1 G(2)/M Phase Transition Regulatory Network and the NFκB/JNK Signaling Pathway. Int J Oncol, 62(5): 57.

Chen Y, Tang Q, Wu J, et al., 2015, Inactivation of PI3-K/Akt and Reduction of SP1 and p65 Expression Increase the Effect of Solamargine on Suppressing EP4 Expression in Human Lung Cancer Cells. J Exp Clin Cancer Res, 34: 154.

Halim C, Xinjing S, Fan L, et al., 2019, Anti-Cancer Effects of Oxymatrine Are Mediated through Multiple Molecular Mechanism(s) in Tumor Models. Pharmacol Res, 147: 104327.

Li P, Ren K, Liang Y, et al., 2020, Aloin Promotes Cell Apoptosis by Targeting HMGB1-TLR4-ERK Axis in Human Melanoma Cells. Excli J, 19: 641–651.

Chen Y, Tang Q, Xiao Q, et al., 2017, Targeting EP4 Downstream c-Jun through ERK1/2-Mediated Reduction of DNMT1 Reveals Novel Mechanism of Solamargine-Inhibited Growth of Lung Cancer Cells. J Cell Mol Med, 21(2): 222–233.

Kim Y, Han A, Kim J, et al., 2021, Dendrobine Inhibits γ-Irradiation-Induced Cancer Cell Migration, Invasion and Metastasis in Non-Small Cell Lung Cancer Cells. Biomedicines, 9(8): 954.

Shao Y, Lu D, Jin W, et al., 2025, Targeting LIF With Cyclovirobuxine D to Suppress Tumor Progression via LIF/p38MAPK/p62-Modulated Mitophagy in Hepatocellular Carcinoma. MedComm (2020), 6(6): e70227.

Fu R, Wang X, Hu Y, et al., 2019, Solamargine Inhibits Gastric Cancer Progression by Regulating the Expression of lncNEAT1_2 via the MAPK Signaling Pathway. Int J Oncol, 54(5): 1545–1554.

Jiang F, Chen Y, Ren S, et al., 2020, Cyclovirobuxine D Inhibits Colorectal Cancer Tumorigenesis via the CTHRC1-AKT/ERK-Snail Signaling Pathway. Int J Oncol, 57(1): 183–196.

Li Y, Tang D, Yan H, et al., 2023, Network Pharmacology and Molecular Docking-Based Analyses to Predict the Potential Mechanism of Huangqin Decoction in Treating Colorectal Cancer. World J Clin Cases, 11(19): 4553–4566.

Tang Q, Zheng F, Liu Z, et al., 2019, Novel Reciprocal Interaction of lncRNA HOTAIR and miR-214-3p Contribute to the Solamargine-Inhibited PDPK1 Gene Expression in Human Lung Cancer. J Cell Mol Med, 23(11): 7749–7761.

Liu F, Liu T, Li H, 2021, Aloperine Inhibits the Progression of Non-Small-Cell Lung Cancer through the PI3K/Akt Signaling Pathway. Cancer Cell Int, 21(1): 662.

Tao H, Tang T, Wang S, et al., 2019, The Molecular Mechanisms of Aloin Induce Gastric Cancer Cells Apoptosis by Targeting High Mobility Group Box 1. Drug Des Devel Ther, 13: 1221–1231.

Liu J, Huo C, Cao H, et al., 2021, Corrigendum to Aloperine Induces Apoptosis and G2/M Cell Cycle Arrest in Hepatocellular Carcinoma Cells through the PI3K/Akt Signaling Pathway Phytomedicine 61(2019) 152843. Phytomedicine, 92: 153731.

Liu J, Huo C, Cao H, et al., 2019, Aloperine Induces Apoptosis and G2/M Cell Cycle Arrest in Hepatocellular Carcinoma Cells through the PI3K/Akt Signaling Pathway. Phytomedicine, 61: 152843.

Liu A, Liu C, 2024, In Vitro and In Vivo Antineoplastic Activities of Solamargine in Colorectal Cancer through the Suppression of PI3K/AKT Pathway. Histol Histopathol, 39(10): 1317–1328.

Ling Z, Guan H, You Z, et al., 2018, Aloperine Executes Antitumor Effects through the Induction of Apoptosis and Cell Cycle Arrest in Prostate Cancer In Vitro and In Vivo. Onco Targets Ther, 11: 2735–2743.

Ge J, Wang P, Ma H, et al., 2022, Solamargine Inhibits Prostate Cancer Cell Growth and Enhances the Therapeutic Efficacy of Docetaxel via Akt Signaling. J Oncol, 2022: 9055954.

Lu J, Sun D, Gao S, et al., 2014, Cyclovirobuxine D Induces Autophagy-Associated Cell Death via the Akt/mTOR Pathway in MCF-7 Human Breast Cancer Cells. J Pharmacol Sci, 125(1): 74–82.

Li L, Nong J, Li J, et al., 2024, Dendrobine Suppresses Tumor Growth by Regulating the PD-1/PD-L1 Checkpoint Pathway in Lung Cancer. Curr Cancer Drug Targets, 25(9): 1108–1117.

Luo Y, Liu G, Hou P, 2023, Synergism Effect of Dendrobine on Cisplatin in Treatment of H1299 by Modulating the Balance of Treg/Th17. Anticancer Agents Med Chem, 23(1): 105–112.

Tang Q, Zhou Q, Li J, et al., 2023, Solamargine Enhanced Gefitinib Antitumor Effect via Regulating MALAT1/miR-141-3p/Sp1/IGFBP1 Signaling Pathway in Non-Small Cell Lung Cancer. Carcinogenesis, 44(6): 497–510.

Liu Q, Xu M, Qiu M, et al., 2024, Solamargine Improves the Therapeutic Efficacy of Anti-PD-L1 in Lung Adenocarcinoma by Inhibiting STAT1 Activation. Phytomedicine, 128: 155538.

Han Y, Shi J, Xu Z, et al., 2022, Identification of Solamargine as a Cisplatin Sensitizer through Phenotypical Screening in Cisplatin-Resistant NSCLC Organoids. Front Pharmacol, 13: 802168.

Yin X, Li W, Zhang J, et al., 2021, AMPK-Mediated Metabolic Switching Is High Effective for Phytochemical Levo-Tetrahydropalmatine (l-THP) to Reduce Hepatocellular Carcinoma Tumor Growth. Metabolites, 11(12): 811.

Jiang X, Li H, Liu Y, 2024, Cyclovirobuxine D Inhibits Hepatocellular Carcinoma Growth by Inducing Ferroptosis of Hepatocellular Carcinoma Cells. Discov Oncol, 15(1): 96.

Tang Q, Li X, Chen Y, et al., 2022, Solamargine Inhibits the Growth of Hepatocellular Carcinoma and Enhances the Anticancer Effect of Sorafenib by Regulating HOTTIP-TUG1/miR-4726-5p/MUC1 Pathway. Mol Carcinog, 61(4): 417–432.

Liu X, Song L, Liu W, et al., 2025, Solamargine Inhibits Gastric Cancer Progression via Inactivation of STAT3/PD-L1 Signaling. Mol Med Rep, 31(2): 35.

Wang Z, Wu Z, Chen J, et al., 2025, Cyclovirobuxine D Inhibits Triple-Negative Breast Cancer via YAP/TAZ Suppression and Activation of the FOXO3a/PINK1-Parkin Pathway-Induced Mitophagy. Phytomedicine, 136: 156287.

Chen Y, Cai F, Mao Y, et al., 2021, The Anti-Neoplastic Activities of Aloperine in HeLa Cervical Cancer Cells Are Associated with Inhibition of the IL-6-JAK1-STAT3 Feedback Loop. Chin J Nat Med, 19(11): 815–824.

Qu X, Xie J, Zhang Y, et al., 2022, Solamargine Alleviates Proliferation and Metastasis of Cervical Cancer Cells by Blocking the CXCL3-Mediated Erk Signaling Pathway. Evid Based Complement Alternat Med, 2022: 7634754.

Qiu M, Yu L, Liang J, et al., 2023, Aloperine Prevents Migration, Invasion, and Adhesion by Upregulating TIMP-4 in Human Bladder Cancer Cells. Protein Pept Lett, 30(3): 250–259.

Pereira I, Silva L, Luis R, et al., 2024, Evaluation of in Vivo and in Vitro Efficacy of Solasonine/Solamargine-Loaded Lipid-Polymer Hybrid Nanoparticles Against Bladder Cancer. Int J Pharm, 661: 124411.