Isorhamnetin: Reviewing Recent Developments in Anticancer Mechanisms and Nanoformulation-Driven Delivery

Abstract

Natural compounds, particularly flavonoids, have emerged as promising anticancer agents due to their various biological activities and no or negligible toxicity towards healthy tissues. Among these, isorhamnetin, a methylated flavonoid, has gained significant attention for its potential to target multiple cancer hallmarks. This review comprehensively explores the mechanisms by which isorhamnetin exerts its anticancer effects, including cell cycle regulation, apoptosis, suppression of metastasis and angiogenesis, and modulation of oxidative stress and inflammation. Notably, isorhamnetin arrests cancer cell proliferation by regulating cyclins, and CDKs induce apoptosis via caspase activation and mitochondrial dysfunction. It inhibits metastatic progression by downregulating MMPs, VEGF, and epithelial-mesenchymal transition (EMT) markers. Furthermore, its antioxidant and anti-inflammatory properties mitigate reactive oxygen species (ROS) and pro-inflammatory cytokines, restricting cancer progression and modulating tumor microenvironments. Combining isorhamnetin with other treatments was also discussed to overcome multidrug resistance. Importantly, this review integrates the recent literature (2022-2024) and highlights isorhamnetin's roles in modulating cancer-specific signaling pathways, immune evasion, tumor microenvironment dynamics, and combination therapies. We also discuss nanoformulation-based strategies that significantly enhance isorhamnetin's delivery and bioavailability. This positions isorhamnetin as a promising adjunct in modern oncology, capable of improving therapeutic outcomes when used alone or in synergy with conventional treatments. The future perspectives and potential research directions were also summarized. By consolidating current knowledge and identifying critical research gaps, this review positions Isorhamnetin as a potent and versatile candidate in modern oncology, offering a pathway toward safer and more effective cancer treatment strategies.

Keywords: anticancer; apoptosis; isorhamnetin flavonoids; metastasis; nanoformulation.

Figure 3

The isorhamnetin compound induces apoptosis in numerous tumor cells by triggering intrinsic and extrinsic-mediated pathways. In the extrinsic pathway, the isorhamnetin compound triggers the FAS receptor, activates FADD, and cleavages of pro-caspase-8/10. Stimulated caspase-8 then processes BID into tBID, which links the extrinsic pathway to the intrinsic pathway by increasing the permeabilization of the outer membrane of mitochondria. In the intrinsic pathway, isorhamnetin induced mitochondrial dysfunction by increasing endogenous ROS levels and disrupting the balance (upregulating) between pro-apoptotic (BAX, BAK) and (downregulating) anti-apoptotic (BCL-XL, BCL-2, MCL1) proteins. This scenario leads to cytochrome c and SMAC release from mitochondria. Cytochrome c forms the apoptosome with the APAF1 marker, leading to the activation of caspase-9. Both pathways meet to activate effector caspases (caspase-3 and caspase-7) and induce apoptosis by isorhamnetin [20,83,85,86]. The figure was prepared using Biorender.

Figure 4

The effects of isorhamnetin on VEGF signaling and angiogenesis in cancer cells. (A) Upregulated VEGF signaling activates SRC, Sck, and VRAP in cancer cells, leading to increased cell survival, vascular cell permeability, cytoskeleton rearrangement, cell migration, cell proliferation, nitric oxide production, and angiogenesis. (B) Isorhamnetin inhibits VEGF signaling, resulting in the downregulation of SRC, Sck, and VRAP activities. This suppression reduces cell survival, vascular permeability, cytoskeletal changes, migration, proliferation, and nitric oxide production, ultimately blocking angiogenesis [95,99,100,101]. The figure was prepared using Biorender.

Figure 5

Anti-metastatic mechanism of isorhamnetin across three stages of cancer metastasis. (1) Primary Tumor Site: Isorhamnetin suppresses cancer cell migration, invasion, and angiogenesis by downregulating MMP-2/9, VEGF, EMT, STAT3, PI3K/AKT, and uPA. It also upregulates E-cadherin while reducing N-cadherin, preventing epithelial–mesenchymal transition (EMT) and cancer cell detachment. (2) Circulation Phase: Isorhamnetin enhances immunomodulation, promoting immune clearance of circulating tumor cells (CTCs). It also strengthens endothelial tight junctions, inhibiting cancer cell extravasation into distant tissues. (3) Secondary Tumor Site: Isorhamnetin disrupts the tumor microenvironment, inhibiting cancer cell survival, proliferation, and colonization at the secondary site [116,117,118]. The figure was prepared using Biorender.

Figure 9

Overview of the anticancer applications of isorhamnetin and its associated molecular pathways in different cancer types. Isorhamnetin exerts its effects through key action pathways such as PI3K/AKT/mTOR in colon and prostate cancer, P53 and AKT/ERK1/2 in lung cancer, AMPK in bladder cancer, AKT/MAPK in breast cancer, NF-κB in gastric cancer, and Ras/MAPK in pancreatic cancer. These pathways highlight its potential as a versatile therapeutic agent targeting multiple mechanisms involved in cancer progression [62,96,144,166,229,269,275,276,277]. The figure was prepared using Biorender.

Figure 1

(A) The chemical structure of isorhamnetin, a naturally occurring flavonol, is depicted with standard IUPAC carbon numbering and labeled rings (A, B, and C) and key functional groups relevant to its bioactivity. (B) The major pharmacological effects of isorhamnetin are illustrated, highlighting its anticancer, anti-inflammatory, and anti-osteoporotic activities. Isorhamnetin also exerts protective roles in liver, kidney, and lung function, mitigates hypoxic stress, and demonstrates antimicrobial, anti-obesity, and immunomodulatory properties. Together, these features underscore its potential as a multifunctional therapeutic agent. The figure was prepared using BioRender.

Figure 2

Isorhamnetin influences cell cycle regulation by interacting with various CDKs and cyclins in the cell. The cell cycle phases, including G₀, which is also known as resting, G₁, S, G₂, and M phases, indicate important checkpoints that confirm proper cell development. Isorhamnetin can be useful in modulating CDKs and cyclins at different cycle phases. Isorhamnetin can inhibit CDK4/6-Cyclin D action by upregulating the p21 marker at the G₁ phase. At the G₁/S checkpoint, isorhamnetin suppresses CDK2-Cyclin E by upregulating the expression of p21. Similarly, in the S phase, CDK2-Cyclin A activity is inhibited via p27. Through the G₂/M checkpoint, isorhamnetin reduces CDK1-Cyclin A activity by p27 expression, and at the M phase, the activity of CDK1-Cyclin B is inhibited by p21. This determines the potential of isorhamnetin, a bioactive compound, to influence cell cycle progression, possibly induce cell cycle arrest, and contribute to treating various cancers [26,56,62,63]. The figure was prepared using Biorender.

Figure 6

The molecular docking profile of compounds (i.e., isorhamnetin) in the docked cavity of (A) nitric oxide synthase and (B) COX2. Reprinted with permission from [183].

Figure 7

Isorhamnetin activates the ATM/ATR and p53 pathways by influencing or damaging DNA, likely through oxidative stress or cellular homeostasis disruption, generating signals for DNA damage recognition [62,193,194,195]. The figure was prepared using Biorender.

Figure 8

The immunomodulatory effects of isorhamnetin on the innate and adaptive immune responses. Isorhamnetin enhances the innate immune response by activating various immune cells, including NK cells, macrophages, neutrophils, eosinophils, basophils, and mast cells. This activation leads to immune cell infiltration, increased phagocytosis, and NK cell-mediated cytotoxicity, resulting in cancer cell apoptosis and death. Simultaneously, isorhamnetin stimulates adaptive immunity by modulating APCs, B cells, and T cells. Enhanced T cell activity promotes cancer cell death through effector mechanisms involving perforin (PFN), granzyme B (GzmB), interferon-gamma (IFNγ), and tumor necrosis factor-alpha (TNFα). Additionally, isorhamnetin boosts the humoral immune response, amplifying antibody production for further immune defense [19,260]. The figure was prepared using Biorender.

Figure 10

The overview of the major effects of isorhamnetin in combination with commercial drugs, radiation, and other natural compounds shows its probable role in tumor suppression and its protective effects in healthy tissues.

Figure 11

Strategies for optimizing isorhamnetin delivery. This graphical representation highlights innovative approaches to enhance the therapeutic efficacy of isorhamnetin through drug and environmental modifications. Drug modifications, such as functional-group adjustments, PEGylation, ligand targeting, and metal complexation, aim to improve solubility, permeability, and specificity while reducing off-target toxicity. Environmental modifications focus on pH adjustments, endosomal escape, permeation enhancement, and the normalization of cellular environments to optimize drug bioavailability. Together, these advancements integrate into advanced drug delivery systems, including NPs, antibody-drug conjugates, microparticles, transdermal patches, microneedles, and controlled-release implants, providing tailored and efficient therapeutic applications for isorhamnetin.

Figure 12

Benefits of utilizing nanocarriers for isorhamnetin drug delivery in cancer therapy. (A) Isorhamnetin has low systemic availability due to poor water solubility, inadequate absorption, low stability, rapid metabolism, and quick excretion, which diminishes the active drug concentration at tumor sites. The uptake of free isorhamnetin by the tumor cells is also limited, leading to low therapeutic outcomes. (B) Isorhamnetin-loaded, nonfunctionalized nanocarriers improve systemic availability and facilitate higher drug delivery to the tumor microenvironment through the enhanced permeability and retention (EPR) effect, as well as improved cellular penetration, resulting in better therapeutic effects compared to free isorhamnetin. (C) In contrast, ligand-functionalized or surface-engineered nanocarriers achieve greater therapeutic benefits than nonfunctionalized versions owing to their effective entry in more significant quantities into the tumor microenvironment via the EPR effect and targeted delivery to tumor cells, thereby enhancing their therapeutic effectiveness while reducing non-specific interactions toxicity [307,309,352,409,410,411].

Figure 13

Mechanisms of flavonoid-loaded nanocarriers targeting cancer signaling pathways. Nanocarriers enhance the targeting delivery of flavonoids to specific sites via passive and active mechanisms. Passive targeting utilizes the EPR effect, while active targeting engages receptor-mediated endocytosis. The uptake of isorhamnetin by cancer cells interferes with crucial signaling pathways related to cell proliferation, angiogenesis, metastasis, and apoptosis, thus producing anticancer effects [62,96,144,166,229,269,275,276,277]. The arrows ‘↑’ and ‘↓’ represent activation and suppression, respectively.