Abstract: Verteporfin (VP), commercially known as Visudyne, is a benzoporphyrin derivative originally approved by the FDA as a photosensitizer for the photodynamic therapy (PDT) of age-related macular degeneration. Recently, Verteporfin has emerged as a highly promising candidate for drug repurposing in oncology. Research demonstrates that Verteporfin exerts potent anti-tumor effects through two distinct modalities: as a photoactivated agent that generates cytotoxic reactive oxygen species (ROS) to destroy tumor neovasculature, and as a non-photoactivated targeted therapeutic. In the absence of light, Verteporfin acts as a first-in-class inhibitor of the Hippo signaling pathway by physically disrupting the YAP-TEAD transcriptional complex. Furthermore, it induces ferroptosis, inhibits autophagy via p62 oligomerization, and reactivates mutant p53 family proteins. By effectively targeting cancer stem cells and overcoming chemoresistance, Verteporfin presents a multifaceted approach to treating various malignancies, including glioblastoma, breast, lung, and pancreatic cancers. This review synthesizes current literature on Verteporfin's pharmacological activity, molecular mechanisms, structure-activity relationships, clinical limitations, and future therapeutic perspectives.
1. Introduction
Photodynamic therapy (PDT) has garnered significant attention as a minimally invasive treatment modality for various solid tumors. It relies on the administration of a photosensitizer, followed by localized light irradiation in the presence of oxygen, to generate cytotoxic reactive oxygen species (ROS) [4]. Verteporfin (VP), marketed under the trade name Visudyne, is a second-generation liposomal photosensitizer approved by the FDA in 2000 for the treatment of ocular vascular abnormalities, such as age-related macular degeneration [1][2]. Activated by a 690 nm laser, Verteporfin preferentially accumulates in abnormal neovasculature, making it an attractive agent for vascular-targeted PDT in oncology [1].
Beyond its established role as a photosensitizer, recent oncological research has uncovered a novel, light-independent therapeutic profile for Verteporfin. It has been identified as a potent inhibitor of Yes-associated protein (YAP), a core downstream effector of the Hippo signaling pathway that is frequently hyperactivated in human cancers [1][3]. The dual functionality of Verteporfin—both as a photoactivated ROS generator and a non-photoactivated molecular inhibitor—has positioned it as a highly versatile compound for cancer therapy, capable of targeting bulk tumor cells, disrupting tumor vasculature, and eradicating chemoresistant cancer stem cells (CSCs) [1][9].
2. Pharmacological Activity
The pharmacological activity of Verteporfin in oncology is bifurcated into its photoactivated and non-photoactivated effects.
Under light activation (PDT), Verteporfin exhibits strong anti-angiogenic and cytotoxic properties. It selectively accumulates in the endothelial cells of tumor neovasculature. Upon irradiation with a 690 nm laser, it induces oxidative damage to these endothelial cells, leading to platelet aggregation, vascular occlusion, blood flow stagnation, and ultimately, tumor necrosis [1]. Clinical and preclinical studies have demonstrated the efficacy of Verteporfin-PDT in treating locally advanced pancreatic cancer, prostate cancer, breast cancer, and early-stage lung cancer [2][4].
In the absence of light activation, Verteporfin demonstrates broad-spectrum anti-proliferative, anti-migratory, and pro-apoptotic activities across a variety of malignancies, including glioblastoma, melanoma, osteosarcoma, and carcinomas of the liver, stomach, colon, and endometrium [1][3][6][10]. Crucially, non-photoactivated Verteporfin effectively targets cancer stem cells (CSCs), which are typically responsible for tumor recurrence and metastasis. For instance, it selectively induces cell death in glioblastoma stem cells (GSCs) and gastric CSCs [3][9]. Furthermore, Verteporfin has been shown to reverse multidrug resistance, sensitizing cancer cells to conventional chemotherapeutics such as paclitaxel, gemcitabine, temozolomide, and targeted agents like lapatinib [1][8].
3. Molecular Mechanism of Action
Verteporfin exerts its anti-tumor effects through a complex, multi-pathway mechanism of action:
Hippo-YAP/TEAD Inhibition: The most prominent non-photoactivated mechanism of Verteporfin is its ability to disrupt the Hippo signaling pathway. Verteporfin physically binds to YAP, preventing its interaction with TEA domain (TEAD) transcription factors in the nucleus. This blockade halts the transcription of downstream oncogenic and pro-angiogenic targets, such as CYR61, CTGF, and FOXM1 [1][3][7]. Additionally, Verteporfin upregulates 14-3-3 proteins, which sequester YAP in the cytoplasm, further inhibiting its transcriptional activity [3].
Autophagy Inhibition via p62 Polymerization: Verteporfin directly targets the autophagy cargo receptor p62. It induces the rapid formation of covalently crosslinked, high-molecular-weight p62 oligomers. This polymerization, mediated by low-level singlet oxygen production, impairs p62's ability to bind polyubiquitinated proteins, thereby disrupting autophagosome formation and leading to the accumulation of dysfunctional proteins [1][8].
Ferroptosis and Mitochondrial Dysfunction: In glioblastoma models, Verteporfin acts independently of YAP to inhibit mitochondrial oxidative phosphorylation, reduce mitochondrial membrane potential, and deplete intracellular ATP [3]. Furthermore, it induces ferroptosis—an iron-dependent form of programmed cell death—by inhibiting glutathione peroxidase 4 (GPX4), leading to a lethal accumulation of lipid peroxides [3].
p53 Family Reactivation: Verteporfin has been identified as a molecule capable of stabilizing the TAp73 tumor suppressor protein (a p53 homolog). By inhibiting thioredoxin reductase (TrxR) and generating ROS, Verteporfin induces TAp73-dependent apoptosis in cancer cells harboring TP53 mutations [5].
Additional Signaling Pathways: Verteporfin also modulates several other oncogenic networks, including the suppression of STAT3 phosphorylation, downregulation of Focal Adhesion Kinase (FAK), and inhibition of Wnt/β-catenin signaling [1][9].
4. Structure-Activity Relationship (SAR)
Verteporfin is a benzoporphyrin derivative (chemical formula C41H42N4O8) [3]. Its core porphyrin ring structure is fundamental to its function as a photosensitizer. Upon absorption of 690 nm light, the molecule transitions from a ground state to an excited singlet state, and subsequently to an excited triplet state. This triplet state transfers energy to molecular oxygen, generating highly reactive singlet oxygen and other ROS that cause localized cellular damage [1][2].
The structural similarity of Verteporfin to endogenous iron-binding porphyrins also contributes to its non-photoactivated cytotoxicity. It is hypothesized that Verteporfin can bind free intracellular iron, triggering ROS production and endoplasmic reticulum stress even in hypoxic environments, such as those found in glioblastoma [3].
Due to its highly hydrophobic nature, free Verteporfin exhibits poor aqueous solubility. To overcome this, the clinical formulation (Visudyne) encapsulates the drug within liposomes. This liposomal delivery system not only improves solubility but also facilitates targeted uptake; the liposomes bind to apolipoproteins in the bloodstream, which are then preferentially taken up by tumor and neovascular endothelial cells that overexpress low-density lipoprotein (LDL) receptors [1].
5. Current Limitations
Despite its therapeutic promise, the clinical translation of Verteporfin in oncology faces several hurdles. Pharmacokinetically, Verteporfin has a very short half-life of approximately 5 to 6 hours, which may necessitate frequent dosing or continuous infusion to maintain effective concentrations for non-photoactivated YAP inhibition [2][7]. Its hydrophobic nature also restricts its ability to cross the blood-brain barrier, limiting its bioavailability in the brain parenchyma for the treatment of central nervous system tumors unless administered via specialized intraventricular pumps or microparticles [3].
When used in PDT, Verteporfin's efficacy is strictly dependent on the presence of molecular oxygen. Hypoxic tumor microenvironments can severely diminish ROS generation, thereby blocking the photodynamic effect [4]. Furthermore, light penetration depth limits the application of PDT to superficial tumors or those accessible via interstitial laser fibers [1][4].
Clinically, patients receiving Verteporfin-PDT frequently report adverse effects, including prolonged photosensitivity, injection site reactions (pain, edema, hemorrhage), and visual impairments such as blurred vision and scotoma [2][9].
6. Future Perspectives
The future of Verteporfin in cancer therapeutics lies in advanced drug delivery systems and rational combination strategies. To overcome its pharmacokinetic limitations and poor water solubility, researchers are actively developing novel nanocarriers, including nanostructured lipid carriers (NLCs), mesoporous silica nanoparticles, and PLGA-based smart nanocarriers. These systems aim to enhance tumor-specific accumulation, improve blood-brain barrier penetration, and reduce systemic toxicity [1][3].
Combination therapy represents another highly promising avenue. Because Verteporfin effectively targets CSCs and downregulates survival pathways, it acts as a potent adjuvant. Co-administering Verteporfin with conventional chemotherapies (e.g., temozolomide, gemcitabine), targeted inhibitors (e.g., COX2 or STAT3 inhibitors), or ferroptosis-inducing agents (e.g., erastin) has demonstrated synergistic effects, leading to enhanced tumor necrosis and the reversal of drug resistance [1][3][8][9]. Additionally, to counteract the limitations of hypoxia in PDT, the co-administration of oxygen carriers (such as Perftoran) alongside Verteporfin is being explored to sustain ROS generation in oxygen-deprived tumor cores [4]. As research progresses, Verteporfin's repositioning from an ophthalmological drug to a multifaceted oncological agent holds significant potential for personalized and targeted cancer treatments.
