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Introduction: This study was conducted to assess the systemic pharmacokinetic profiles of half-dose verteporfin photodynamic therapy (PDT) using concentration data from a previous clinical trial and to subsequently suggest safety precaution guidelines. Methods: Coefficients for the bi-exponential model were obtained from published data on post-infusion plasma verteporfin concentrations within a period of 0.17–4 h. Using the extrapolative forecasting method, we plotted the 48-h post-verteporfin plasma concentration model. The time required to achieve a comparable level of verteporfin 48 h after a conventional dose (6 mg/m2 body surface area, BSA) infusion was calculated for a half-dose infusion (3 mg/m2 BSA). Results: At 24 and 48 h post-verteporfin infusion, the plasma concentration following the conventional dose was 1.28 × 10−4 µg/mL and 5.06 × 10−8 µg/mL, compared to 3.57 × 10−5 µg/mL and 7.54 × 10−9 µg/mL for the half-dose PDT, representing concentrations that were 3.6 times and 6.7 times higher, respectively. The estimated time required to attain the same level of verteporfin 48 h after a conventional dose was calculated as 42-h post-half-dose PDT. Conclusions: The results of this study indicate that precautionary measures should be taken to avoid sunlight following both half and conventional doses of PDT during the similar post-treatment periods of two days. Nevertheless, given the substantially higher plasma concentration levels associated with conventional-dose PDT compared with the half-dose, systemic safety should be carefully considered when administering conventional-dose PDT. [ABSTRACT FROM AUTHOR]

Esophageal squamous cell carcinoma (ESCC) is one of the most common malignant tumors. Ferroptosis is a new form of regulated cell death and targeting ferroptosis provides a novel therapeutic approach for human cancers. Verteporfin (VP) has been identified as a Yes-associated protein (YAP) inhibitor for treatment of several human cancers. However, it remains unclear whether VP exerts anticancer activity by inducing ferroptosis in ESCC cells. In the current study, we found that VP reduced cell viability and led to cell death in ESCC cell lines (KYSE150 and KYSE30) by inhibiting YAP expression. Subsequently, the findings revealed that VP treatment triggered significant ferroptosis events, including accumulation of Fe2+, reactive oxygen species (ROS) and malondialdehyde (MDA), reduction of mitochondrial membrane potential (MMP), glutathione (GSH) and glutathione peroxidase 4 (GPX4) expression. Further study showed that the effects of ESCC cell proliferation and death caused by VP could be reversed by ferroptosis inhibitor ferrostatin-1 (Fer-1). Moreover, VP enhanced the chemosensitivity of ESCC resistant cells to paclitaxel (PTX). And VP combined with PTX can synergistically inhibit cell proliferation and induce cell death by triggering ferroptosis of PTX-resistant cells. All these data suggested that VP suppressed ESCC cell survival and reversed resistance to PTX through inducing ferroptosis, which may provide a promising therapeutic strategy for ESCC. [ABSTRACT FROM AUTHOR]

Hypertrophic scarring (HS) is a common skin injury complication with unmet needs. Verteporfin (VP) should be an ideal HS‐targeted therapeutic drug due to its efficient fibrosis and angiogenesis inhibitory abilities. However, its application is restricted by its side effects such as dose‐dependent cytotoxicity on normal cells. Herein, the bioadhesive nanoparticles encapsulated VP (VP/BNPs) are successfully developed to attenuate the side effects of VP and enhance its HS inhibition effects by limiting VP releasing slowly and stably in the lesion site but not diffusing easily to normal tissues. VP/BNPs displayed significant inhibition on the proliferation, migration, collagen deposition, and vessel formation of human hypertrophic scar fibroblasts (HSFBs) and dermal vascular endothelial cells (HDVECs). In a rat tail HS model, VP/BNPs treated HS exhibits dramatic scar repression with almost no side effects compared with free VP or VP‐loaded non‐bioadhesive nanoparticles (VP/NNPs) administration. Further immunofluorescence analysis on scar tissue serial sections validated VP/BNPs effectively inhibited the collagen deposition and angiogenesis by firmly confined in the scar tissue and persistently releasing VP targeted to nucleus Yes‐associated protein (nYAP) of HSFBs and HDVECs. These findings collectively suggest that VP/BNPs can be a promising and technically advantageous agent for HS therapies. [ABSTRACT FROM AUTHOR]

Background and Objectives: Our study compared the visual and anatomical outcomes of polypoidal choroidal vasculopathy (PCV) patients receiving intravitreal aflibercept (IVA) with or without photodynamic therapy (PDT) over 12 months. Materials and Methods: This retrospective study was performed for 60 eyes from 60 patients with treatment-naïve PCV. Thirty eyes were treated using IVA monotherapy (IVA group), and thirty eyes were treated using a combination of IVA with PDT (IVA/PDT group). The baseline characteristics, treatment outcomes, and retreatment rates were compared between the two groups over a one-year follow-up period. Results: The best-corrected visual acuity (BCVA) was found to have improved significantly in the IVA/PDT group at every 3-month visit. However, no significant BCVA improvement was observed in the IVA group. A significantly lower retreatment rate and higher dry macula rate were found in the IVA/PDT group than that in the IVA group. In the entire population of the study, a better baseline vision and younger age were associated with better final visual outcomes. Retreatment was associated with poor baseline BCVA and IVA monotherapy. Conclusions: The combination of IVA and PDT may offer superior visual improvement and a higher dry macula rate compared to IVA monotherapy in the treatment of PCV patients while requiring fewer retreatments over 12 months. [ABSTRACT FROM AUTHOR]

Cancer vaccines offer a promising avenue in cancer immunotherapy by inducing systemic, tumor‐specific immune responses. Tumor extracellular vesicles (TEVs) are nanoparticles naturally laden with tumor antigens, making them appealing for vaccine development. However, their inherent malignant properties from the original tumor cells limit their direct therapeutic use. This study introduces a novel approach to repurpose TEVs as potent personalized cancer vaccines. The study shows that inhibition of both YAP and autophagy not only diminishes the malignancy‐associated traits of TEVs but also enhances their immunogenic attributes by enriching their load of tumor antigens and adjuvants. These revamped TEVs, termed attenuated yet immunogenically potentiated TEVs (AI‐TEVs), showcase potential in inhibiting tumor growth, both as a preventive measure and a possible treatment for recurrent cancers. They prompt a tumor‐specific and enduring immune memory. In addition, by showing that AI‐TEVs can counteract cancer growth in a personalized vaccine approach, a potential strategy is presented for developing postoperative cancer immunotherapy that's enduring and tailored to individual patients. [ABSTRACT FROM AUTHOR]

Objective: Although benign, ameloblastoma is a locally aggressive lesion in some patients and the development of additional treatments is needed. Verteporfin (VP) is a photosensitizer exhibiting considerable photocytotoxicity in various tumor cells. We aimed to investigate the effects of verteporfin photodynamic therapy (VP PDT) on ameloblastoma. Methods: Eighteen patients who underwent surgery for ameloblastoma were randomly selected. We performed an immunohistochemical assessment to investigate the expression of low‐density lipoprotein receptor (LDLR) and Yes‐associated protein (YAP), targets of VP, in human ameloblastoma tissues and cultured human ameloblastoma cell line (HAM1). The effect of VP PDT on cell proliferation and apoptosis in HAM1 was analyzed. Results: The expression of LDLR and YAP were detected in human ameloblastoma tissues and HAM1. LDLR expression was significantly higher in patients who had previously undergone surgery than in patients who were receiving it for the first time. The cytotoxic effect of the combination of low‐concentration VP administration and laser irradiation was comparable to high‐concentration VP administration with and without laser irradiation. The addition of laser irradiation to VP administration significantly accelerated apoptotic bleb formation compared with VP administration alone. Conclusion: VP PDT has the potential to become an additional treatment for large‐sized ameloblastoma. [ABSTRACT FROM AUTHOR]

An ongoing global shortage of verteporfin (Visudyne®) limits the treatment possibilities for several chorioretinal diseases, including central serous chorioretinopathy, choroidal hemangioma, and polypoidal choroidal vasculopathy. Verteporfin is required to perform photodynamic therapy in these ocular diseases. Therefore, the current situation has a substantial impact on eye care worldwide. The worldwide supply of verteporfin appears to be manufactured by a single factory, which is situated in the United States. The distribution of verteporfin is done by different companies for different regions of the world. Official communication on the shortage by the responsible companies has been scarce and over the past years several promises with regards to resolution of the shortage have not been fulfilled. The delivery of new batches of verteporfin is at irregular intervals, unpredictable, and may not be fairly balanced between different regions or countries in the world. To ensure a fair distribution of available verteporfin within a country, several measures can be taken. In the Netherlands, a national committee, consisting of ophthalmologists, is in place to arrange this. On the European level, the European Union and European Medicine Agency have plans to monitor medicine shortages more closely and to intervene if necessary. With a more intensified monitoring and regulation of medicine supplies, future impending shortages may be prevented. Remarkably, the amount of medicine shortages is increasing, having a significant and sometimes irreversible impact on patient care. Thus, efforts should be undertaken to minimize the consequences and, whenever possible, to prevent future medicine shortages. [ABSTRACT FROM AUTHOR]

An ongoing global shortage of verteporfin (Visudyne®) limits the treatment possibilities for several chorioretinal diseases, including central serous chorioretinopathy, choroidal hemangioma, and polypoidal choroidal vasculopathy. Verteporfin is required to perform photodynamic therapy in these ocular diseases. Therefore, the current situation has a substantial impact on eye care worldwide. The worldwide supply of verteporfin appears to be manufactured by a single factory, which is situated in the United States. The distribution of verteporfin is done by different companies for different regions of the world. Official communication on the shortage by the responsible companies has been scarce and over the past years several promises with regards to resolution of the shortage have not been fulfilled. The delivery of new batches of verteporfin is at irregular intervals, unpredictable, and may not be fairly balanced between different regions or countries in the world. To ensure a fair distribution of available verteporfin within a country, several measures can be taken. In the Netherlands, a national committee, consisting of ophthalmologists, is in place to arrange this. On the European level, the European Union and European Medicine Agency have plans to monitor medicine shortages more closely and to intervene if necessary. With a more intensified monitoring and regulation of medicine supplies, future impending shortages may be prevented. Remarkably, the amount of medicine shortages is increasing, having a significant and sometimes irreversible impact on patient care. Thus, efforts should be undertaken to minimize the consequences and, whenever possible, to prevent future medicine shortages. [ABSTRACT FROM AUTHOR]

Copyright of Chinese Journal of Cancer Biotherapy is the property of Editorial Office of Chinese Journal of Cancer Biotherapy and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Secondary lymphedema is a chronic disease associated with deformity of limbs and dysfunction; however, conventional therapies are not curative. Adipose-derived stem cells (ADSCs) based therapy is a promising way, but a single transplantation of ADSCs has limited efficacy. In this study, ADSCs were engineered in vitro and then transplanted into the site of lymphedema. Yes-associated protein (YAP), a crucial regulator of Hippo pathway, plays an important role in regulating stem cell functions. We examined the YAP expression in a mouse tail lymphedema model, and found that transplanted ADSCs exhibited high expression level of YAP and a large number of YAP positive cells existed in lymphedema environment. In vitro, the downregulation of YAP in ADSCs resulted in higher expression levels of genes related to lymphangiogenesis such as Lyve-1, VEGFR-3 and Prox-1. In vivo, YAP-engineered ADSCs generated abundant VEGFR-3-positive lymphatic vessels and significantly improved subcutaneous fibrosis. These results indicated that the transplantation of pre-engineered ADSCs by manipulating YAP is a promising strategy for lymphatic reconstruction.

Background: To evaluate the anatomical and functional outcomes of high-density subthreshold micropulse laser (HSML) treatment in a cohort of patients diagnosed with chronic central serous chorioretinopathy (CSCR) whose treatment with photodynamic therapy (PDT) was delayed due to the worldwide shortage of verteporfin. Methods: Prospective interventional study which included 42 eyes of 40 patients diagnosed with chronic CSCR and on the waiting list for PDT who received rescue therapy with HSML using the Navilas® System device (OD-OS GmBH, Teltwo, Germany). Best corrected visual acuity (BCVA), subretinal fluid (SRF), and subfoveal choroidal thickness (SFCT) were measured at inclusion and during the follow-up visits at 2, 4, and 6 months. Results: The mean waiting time from the indication of PDT until treatment with HSML was 14.6 ± 9.7 months (range 5–21). There were no differences in the pre-treatment BCVA compared with the 6-month follow-up visit (67 ± 16.7 letters and 67.5 ± 8.2 letters respectively, p = 0.136). However, there was a significant decrease in the mean SFCT of -39.6 ± 37.1 μm (p = 0.030). Additionally, there was a decrease in SRF height between the pre-treatment measure (123.0 ± 49.8 μm) and the 2, 4, and 6-month follow-up visits after HSML of -58.5 ± 68.2 μm, -53.2 ± 76.3 μm, and -65.4 ± 53.6 μm respectively (p < 0.001). A complete resolution of the SRF was observed in 16/42 eyes (38.1 %) and a reduction of the SRF height in 85.7 % of the overall cohort was observed after HSML treatment. Conclusion: A significant anatomical improvement in SRF and a decrease in SFCT were observed in patients with CSCR who were previously waiting for PDT and were rescued by HSML. However, the rate of complete SRF resolution was low.

Abstract An ongoing global shortage of verteporfin (Visudyne®) limits the treatment possibilities for several chorioretinal diseases, including central serous chorioretinopathy, choroidal hemangioma, and polypoidal choroidal vasculopathy. Verteporfin is required to perform photodynamic therapy in these ocular diseases. Therefore, the current situation has a substantial impact on eye care worldwide. The worldwide supply of verteporfin appears to be manufactured by a single factory, which is situated in the United States. The distribution of verteporfin is done by different companies for different regions of the world. Official communication on the shortage by the responsible companies has been scarce and over the past years several promises with regards to resolution of the shortage have not been fulfilled. The delivery of new batches of verteporfin is at irregular intervals, unpredictable, and may not be fairly balanced between different regions or countries in the world. To ensure a fair distribution of available verteporfin within a country, several measures can be taken. In the Netherlands, a national committee, consisting of ophthalmologists, is in place to arrange this. On the European level, the European Union and European Medicine Agency have plans to monitor medicine shortages more closely and to intervene if necessary. With a more intensified monitoring and regulation of medicine supplies, future impending shortages may be prevented. Remarkably, the amount of medicine shortages is increasing, having a significant and sometimes irreversible impact on patient care. Thus, efforts should be undertaken to minimize the consequences and, whenever possible, to prevent future medicine shortages.

Lina Yu,1,&ast; Zidan Xu,1,&ast; Guanxiong Zhu,1,&ast; Liting Zeng,1 Zeyu Zhang,1 Yang Yu,2 Siran Wang,1 Xin Zhang,3 Na Zhou,3 Lu Liang1,4 1Department of Preventive Dentistry, School and Hospital of Stomatology, Guangdong Engineering Research Center of Oral Restoration and Reconstruction & Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou Medical University, Guangzhou, People’s Republic of China; 2Department of Sports and Health, Guangzhou Sport University, Guangzhou, People’s Republic of China; 3State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Avenida Wailong, Taipa, Macau, People’s Republic of China; 4Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the State & NMPA Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Lina Yu; Lu Liang, Email yulina@gzhmu.edu.cn; lliangaa@gzhmu.edu.cnBackground: The photodynamic therapy (PDT) showed promising potential in treating tongue squamous cell carcinoma (TSCC). The Food and Drug Administration approved Verteporfin (Ver) is a powerful alternative in this field for its penetrating power and high production of reactive oxygen species (ROS). However, its applications in the treatment of TSCC are still rare.Methods: Ver was loaded onto Poly (lactic-co-glycolic acid) (PLGA) nanoparticles, followed by the modification with RGD peptide as the ligand. The nanostructured was named as RPV. In vitro assessments were conducted to evaluate the cytotoxicity of RPV through the Live/Dead assay analysis and Cell Counting Kit-8 (CCK-8) assay. Using the reactive oxygen species assay kit, the potential for inducing targeted tumor cell death upon laser irradiation by promoting ROS production was investigated. In vivo experiments involved with the biological distribution of RPV, the administration with RPV followed by laser irradiation, and the measurement of the tumor volumes. Immunohistochemical analysis was used to detect the Ki-67 expression, and apoptosis induced by RPV-treated group. Systemic toxicity was evaluated through hematoxylin-eosin staining and blood routine analysis. Real-time monitoring was employed to track RPV accumulation at tumor sites.Results: The in vitro assessments demonstrated the low cytotoxicity of RPV and indicated its potential for targeted killing TSCC cells under laser irradiation. In vivo experiments revealed significant tumor growth inhibition with RPV treatment and laser irradiation. Immunohistochemical analysis showed a notable decrease in Ki-67 expression, suggesting the effective suppression of cell proliferation, and TUNEL assay indicated the increased apoptosis in the RPV-treated group. Pathological examination and blood routine analysis revealed no significant systemic toxicity. Real-time monitoring exhibited selective accumulation of RPV at tumor sites.Conclusion: The findings collectively suggest that RPV holds promise as a safe and effective therapeutic strategy for TSCC, offering a combination of targeted drug delivery with photodynamic therapy.Keywords: photodynamic therapy, verteporfin, RGD sequence, tumor-specific drug delivery

Uveal melanoma (UM) is the predominant form of eye cancer. The genes GNAQ and GNA11, encoding Gq and G11 respectively, are most frequently mutated in UM and are considered the major drivers of UM carcinogenesis by activating YAP. However, the mechanisms by which metastatic UM evades the immune system remain poorly understood. In this study, we found that oncogenic mutations of Gq/G11 promoted YAP and PD-L1 expression, modifying the tumor microenvironment and promoting immune evasion of UM. Consistently, the levels of GNAQ/GNA11 and YAP positively correlated to PD-L1 expression in UM patients. Furthermore, silencing YAP or treating with its inhibitor, Verteporfin, attenuated PD-L1 expression induced by Gq/G11 mutations, thereby enhancing T cell activation and T cell-mediated cytotoxicity. Collectively, this study reveals a potential role of Gq/G11 mutations on immune evasion of UM, a new mechanism of Gq/11 mutations-induced tumorigenesis, highlighting Gq/G11 and YAP as potential immunotherapeutic targets and suggesting Verteporfin as an adjuvant for immunotherapy of UM patients with GNAQ or GNA11 mutations.

Human cytomegalovirus (HCMV), a double-stranded DNA virus from the Betaherpesvirinae subfamily, constitutes significant risks to newborns and immunocompromised individuals, potentially leading to severe neurodevelopmental disorders. The purpose of this study was to identify FDA-approved drugs that can inhibit HCMV replication through a drug repositioning approach. Using an HCMV progeny assay, verteporfin, a medication used as a photosensitizer in photodynamic therapy, was found to inhibit HCMV production in a dose-dependent manner, significantly reducing replication at concentrations as low as 0.5 µM, approximately 1/20th of the concentration used in anti-cancer research. Further analysis revealed that verteporfin did not interfere with HCMV host cell entry or nuclear transport but reduced viral mRNA and protein levels throughout the HCMV life cycle from the immediate-early stages. These results suggest that verteporfin has the potential to be rapidly and safely developed as a repurposed drug to inhibit HCMV infection.

Extensive skin damage requires specialized therapy that stimulates regeneration processes without scarring. The possibility of using combination of a collagen gel application as a wound dressing and fibroblast attractant with verteporfin as an antifibrotic agent was examined in vivo and in vitro. In vitro effects of verteporfin on viability and myofibroblast markers expression were evaluated using fibroblasts isolated from human scar tissue. In vivo the collagen gel and verteporfin (individually and in combination) were applied into the wound to investigate scarring during skin regeneration: deviations in skin layer thickness, collagen synthesis, and extracellular matrix fibers were characterized. The results indicate that verteporfin reduces fibrotic phenotype by suppressing expression of the contractile protein Sm22α without inducing cell death. However, administration of verteporfin in combination with the collagen gel disrupts its ability to direct wound healing in a scarless manner, which may be related to incompatibility of the mechanisms by which collagen and verteporfin control regeneration. [ABSTRACT FROM AUTHOR]

Simple Summary: Rumen development is important to the health and performance of ruminants. The proteins YAP1 and TAZ are key regulators of the mammalian epithelium. However, it is unclear whether YAP1/TAZ mediates the development of rumen epithelium. Therefore, we assessed the effects of YAP1/TAZ on rumen epithelial cell proliferation. Sodium butyrate is a nutrient that can be used to promote rumen development. We also assessed whether sodium butyrate mediated rumen epithelial development through the activation of YAP1/TAZ. The results indicated that YAP1/TAZ activation could promote rumen epithelial cell proliferation but not short-chain fatty acid metabolism, and sodium butyrate did not function in a YAP1/TAZ-dependent manner. Promoting rumen development is closely related to the health and efficient growth of ruminants. The transcriptional co-activators Yes1-associated protein (YAP1) and WW domain-containing transcription regulator protein 1 (TAZ) are key regulators of the mammalian epithelium. In the present study, we assessed the impact of YAP1/TAZ on rumen epithelial (RE) cell proliferation using their activator GA-017 (GA) and inhibitor verteporfin (VP). We also investigated whether YAP1/TAZ-dependent alteration was involved in the RE developmental process induced by sodium butyrate (SB). The results indicated that GA promoted RE cell proliferation, while VP disrupted RE cell proliferation. The Hippo, Wnt, and calcium signaling pathways were altered following the regulation of YAP1/TAZ. Upon YAP1/TAZ activation, the expression of CCN1/2 increased. However, when YAP1/TAZ was inhibited, the expression of BIRC3 decreased. In the SB-treated cells, YAP1/TAZ-induced changes were not observed. SB increased the expressions of differentiated cell marker genes and genes involved in short-chain fatty acid (SCFA) metabolism, while YAP1/TAZ did not. Thus, YAP1/TAZ could be potential targets for regulating RE cell proliferation but not for SCFA metabolism. SB could not affect YAP1/TAZ. These findings broaden our understanding of the role of YAP1/TAZ and their regulators in RE development. [ABSTRACT FROM AUTHOR]

Abstract Cancer vaccines offer a promising avenue in cancer immunotherapy by inducing systemic, tumor‐specific immune responses. Tumor extracellular vesicles (TEVs) are nanoparticles naturally laden with tumor antigens, making them appealing for vaccine development. However, their inherent malignant properties from the original tumor cells limit their direct therapeutic use. This study introduces a novel approach to repurpose TEVs as potent personalized cancer vaccines. The study shows that inhibition of both YAP and autophagy not only diminishes the malignancy‐associated traits of TEVs but also enhances their immunogenic attributes by enriching their load of tumor antigens and adjuvants. These revamped TEVs, termed attenuated yet immunogenically potentiated TEVs (AI‐TEVs), showcase potential in inhibiting tumor growth, both as a preventive measure and a possible treatment for recurrent cancers. They prompt a tumor‐specific and enduring immune memory. In addition, by showing that AI‐TEVs can counteract cancer growth in a personalized vaccine approach, a potential strategy is presented for developing postoperative cancer immunotherapy that's enduring and tailored to individual patients.

Pancreatic ductal adenocarcinoma (PDAC) has extremely poor prognosis, with a 5-year survival rate of approximately 11 %. Yes-associated protein (YAP) is a major downstream effector of the Hippo-YAP pathway and plays a pivotal role in regulation of cell proliferation and organ regeneration and tumorigenesis. Activation of YAP signaling has been associated with PDAC progression and drug resistance. Verteporfin (VP) is a photosensitizer used for photodynamic therapy and previous work showed that it can function as a YAP inhibitor. The efficacy of VP on human cancer are being tested in several trials. In this study, we examined the effect of VP on reactive oxygen species (ROS) and lipid peroxidation in pancreatic cancer cells, by using fluorescent molecular probes and by measuring the levels of malondialdehyde, a metabolic byproduct and marker of lipid peroxidation. We found that VP causes rapid increase of both overall ROS and lipid peroxide levels, independent of light activation. These effects were not dependent on YAP, as knockdown of YAP did not cause ROS or lipid peroxidation or enhance VP-induced ROS production. Temoporfin, another photodynamic drug, did not show similar activities. In addition, VP treatment led to loss of cell membrane integrity and reduction of viability. Notably, the activity of VP to induce lipid peroxidation was neutralized by ferroptosis inhibitors ferrostatin-1 or liproxstatin-1. VP treatment also reduced the levels of glutathione peroxidase 4 (GPX4), an enzyme that protects against lipid peroxidation. These results indicate that VP can induce lipid peroxidation and ferroptosis in the absence of light activation. Our findings reveal a novel mechanism by which VP inhibits tumor growth and provide insights into development of new therapeutic strategies for the treatment of pancreatic cancer. [Display omitted] • Verteporfin induces lipid peroxidation and ferroptosis-like cell death independent of light activation. • Verteporfin disrupts mitochondrial functions. • Verteporfin-induced ROS and mitochondrial changes are rapid and independent of YAP. • Verteporfin treatment decreases GPX4 and increase ATF3 expression levels. [ABSTRACT FROM AUTHOR]

Pathological alterations in the biomechanical properties of the Schlemm’s canal (SC) inner wall endothelium and its immediate vicinity are strongly associated with ocular hypertension in glaucoma due to decreased outflow facility. Specifically, the underlying trabecular meshwork is substantially stiffer in glaucomatous eyes compared with that from normal eyes. This raises the possibility of a critical involvement of mechanotransduction processes in driving SC cell dysfunction. Yes-associated protein (YAP) has emerged as a key contributor to glaucoma pathogenesis. However, the molecular underpinnings of SC cell mechanosignaling via YAP and transcriptional coactivator with PDZ-binding motif (TAZ) in response to glaucomatous extracellular matrix (ECM) stiffening are not well understood. Using a novel biopolymer hydrogel that facilitates dynamic and reversible stiffness tuning, we investigated how ECM stiffening modulates YAP/TAZ activity in primary human SC cells, and whether disruption of YAP/TAZ mechanosignaling attenuates SC cell pathobiology and increases ex vivo outflow facility. We demonstrated that ECM stiffening drives pathologic YAP/TAZ activation and cytoskeletal reorganization in SC cells, which was fully reversible by matrix softening in a distinct time-dependent manner. Furthermore, we showed that pharmacologic or genetic disruption of YAP/TAZ mechanosignaling abrogates stiffness-induced SC cell dysfunction involving altered cytoskeletal and ECM remodeling. Finally, we found that perfusion of the clinically used, small molecule YAP/TAZ inhibitor verteporfin (without light activation) increases ex vivo outflow facility in normal mouse eyes. Collectively, our data provide new evidence for a pathologic role of aberrant YAP/TAZ mechanosignaling in SC cell dysfunction and suggest that YAP/TAZ inhibition has therapeutic value for treating ocular hypertension in glaucoma. NEW & NOTEWORTHY Pathologically altered biomechanical properties of the Schlemm’s canal (SC) inner wall microenvironment were recently validated as the cause for increased outflow resistance in ocular hypertensive glaucoma. However, the involvement of specific mechanotransduction pathways in these disease processes is largely unclear. Here, we demonstrate that Yesassociated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) are central regulators of glaucoma-like SC cell dysfunction in response to extracellular matrix stiffening and that targeted disruption of YAP/TAZ mechanosignaling attenuates SC cell pathobiology and enhances outflow function. [ABSTRACT FROM AUTHOR]

Copyright of Journal of Shenyang Pharmaceutical University is the property of Shenyang Pharmaceutical University and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Purpose: Verteporfin is a benzoporphyrin derivative which is Food and Drug Administration-approved for treatment of choroidal neovascularization in conjunction with photodynamic therapy. It has been shown to prevent fibrosis and scar formation in several organs and represents a promising novel antifibrotic agent for glaucoma surgery. The goal of this study is to determine the effect of verteporfin on wound healing after glaucoma filtration surgery. Design: Preclinical study using a rabbit model of glaucoma filtration surgery. Subjects: Eight New Zealand white rabbits underwent glaucoma filtration surgery in both eyes. Methods: Eyes were randomized into 4 study groups to receive a postoperative subconjunctival injection of 1 mg/mL verteporfin (n = 4), 0.4 mg/mL mitomycin C (MMC; n = 4), 0.4 mg/mL MMC + 1 mg/mL verteporfin (n = 4), or balanced salt solution (BSS) control (n = 4). Bleb survival, vascularity, and morphology were graded using a standard scale over a 30-day period, and intraocular pressure (IOP) was monitored. At 30 days postoperative or surgical failure, histology was performed to evaluate for inflammation, local toxicity, and scarring. Main Outcome Measures: The primary outcome measure was bleb survival. Secondary outcome measures were IOP, bleb morphology, and bleb histology. Results: Compared to BSS control blebs, verteporfin-treated blebs demonstrated a trend toward increased surgical survival (mean 9.8 vs. 7.3 days, log rank P = 0.08). Mitomycin C-treated blebs survived significantly longer than verteporfin-treated blebs (log rank P = 0.009), with all but 1 MMC-treated bleb still surviving at postoperative day 30. There were no significant differences in survival between blebs treated with combination verteporfin + MMC and MMC alone. Mitomycin C-treated blebs were less vascular than verteporfin-treated blebs (mean vascularity score 0.3 ± 0.5 for MMC vs. 1.0 ± 0.0 for verteporfin, P

Lina Yu,1,&ast; Guanxiong Zhu,1,&ast; Zeyu Zhang,1,&ast; Zidan Xu,1 Weijie Peng,1,2 Liting Zeng,1 Yang Yu,3 Siran Wang,1 Zhongxiao Lin,1,2,4 Xin Zhang,4 Na Zhou,4 Lingmin Zhang,1,2 Lu Liang1,2 1Department of Preventive Dentistry, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou, 510182, People’s Republic of China; 2Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the State & NMPA Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, People’s Republic of China; 3Department of Sports and Health, Guangzhou Sport University, Guangzhou, People’s Republic of China; 4State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Avenida Wailong, Taipa, Macau, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Lingmin Zhang; Lu Liang, Email zhanglm@gzhmu.edu.cn; lliangaa@gzhmu.edu.cnBackground: Photodynamic therapy (PDT) has emerged as a promising strategy for oral cancer treatment. Verteporfin is a powerful photosensitizer and widely used in the treatment of macular degeneration. However, rare work has reported its potential in the treatment of oral cancer.Methods: In this study, we introduce an innovative approach of nano-photosensitizer based on Verteporfin, which was prepared by utilizing macrophage membrane to coat Verteporfin-loaded zeolitic imidazolate framework 8 (ZIF-8) for effective photodynamic therapy against oral cancer. Nanoparticle characteristics were assessed including size, zeta potential, and PDI. Cellular uptake studies were conducted using CAL-27 cells. Furthermore, inhibitory effects in both in vitro and in vivo settings were observed, ensuring biosafety. Assessment of anticancer efficacy involved tumor volume measurement, histological analyses, and immunohistochemical staining.Results: In vitro experiments indicated that the nano-photosensitizer showed efficient cellular uptake in the oral cancer cells. Upon the laser irradiation, the nano-photosensitizer induced the generation of reactive oxygen species (ROS), leading to cancer cell apoptosis. The in vivo experiments indicated that the coating with cell membranes enhanced the circulation time of nano-photosensitizer. Moreover, the specificity of the nano-photosensitizer to the cancer cells was also improved by the cell membrane-camouflaged structure in the tumor-bearing mouse model, which inhibited the tumor growth significantly by the photodynamic effect in the presence of laser irradiation.Conclusion: Overall, our findings demonstrate the potential of macrophage membrane-coated ZIF-8-based nanoparticles loaded with Verteporfin for effective photodynamic therapy in oral cancer treatment. This nano-system holds promise for synergistic cancer therapy by combining the cytotoxic effects of PDT with the activation of the immune system, providing a novel therapeutic strategy for combating cancer.Keywords: photodynamic therapy, verteporfin, oral cancer, macrophages, zeolitic imidazolate framework 8

Diabetic retinopathy has a serious impact on the quality of life of diabetes patients. In clinic, anti-vascular endothelial growth factor, laser or surgical treatment are mainly used, which has limited therapeutic effect, so it is urgent to update more effective prevention and treatment methods. The Hippo signaling pathway is a complex kinase chain that includes a series of kinases and transcription factors involved in regulating processes such as cell proliferation, differentiation, and apoptosis. It has been proved that there is a typical Hippo signaling pathway in the human retina, and its main influencing factor YAP/TEA regulates the process of retinal endothelium and angiogenesis. This article reviews the composition and regulatory mechanism of Hippo signaling pathway, the relationship between Hippo signaling pathway and other signaling pathways and risk factors in diabetic retinopathy, and related drug treatment, in order to provide a broader idea for the prevention and treatment of diabetic retinopathy.

Sphingosine kinase 1 (SPHK1) and the sphingosine-1-phosphate (S1P) signaling pathway have been shown to play a role in pulmonary arterial hypertension (PAH). S1P is an important stimulus for pulmonary artery smooth muscle cell (PASMC) proliferation and pulmonary vascular remodeling. We aimed to examine the specific roles of SPHK1 in PASMCs during pulmonary hypertension (PH) progression. We generated smooth muscle cell-specific, Sphk1-deficient (Sphk1f/f TaglnCre+) mice and isolated Sphk1-deficient PASMCs from SPHK1 knockout mice. We demonstrated that Sphk1f/f TaglnCre+ mice are protected from hypoxia or hypoxia/Sugen-mediated PH, and pulmonary vascular remodeling and that Sphk1-deficient PASMCs are less proliferative compared with ones isolated from wild-type (WT) siblings. S1P or hypoxia activated yes-associated protein 1 (YAP1) signaling by enhancing its translocation to the nucleus, which was dependent on SPHK1 enzymatic activity. Further, verteporfin, a pharmacologic YAP1 inhibitor, attenuated the S1P-mediated proliferation of hPASMCs, hypoxia-mediated PH, and pulmonary vascular remodeling in mice and hypoxia/Sugen-mediated severe PH in rats. Smooth muscle cell-specific SPHK1 plays an essential role in PH via YAP1 signaling, and YAP1 inhibition may have therapeutic potential in treating PH.

Background and Objectives: Our study compared the visual and anatomical outcomes of polypoidal choroidal vasculopathy (PCV) patients receiving intravitreal aflibercept (IVA) with or without photodynamic therapy (PDT) over 12 months. Materials and Methods: This retrospective study was performed for 60 eyes from 60 patients with treatment-naïve PCV. Thirty eyes were treated using IVA monotherapy (IVA group), and thirty eyes were treated using a combination of IVA with PDT (IVA/PDT group). The baseline characteristics, treatment outcomes, and retreatment rates were compared between the two groups over a one-year follow-up period. Results: The best-corrected visual acuity (BCVA) was found to have improved significantly in the IVA/PDT group at every 3-month visit. However, no significant BCVA improvement was observed in the IVA group. A significantly lower retreatment rate and higher dry macula rate were found in the IVA/PDT group than that in the IVA group. In the entire population of the study, a better baseline vision and younger age were associated with better final visual outcomes. Retreatment was associated with poor baseline BCVA and IVA monotherapy. Conclusions: The combination of IVA and PDT may offer superior visual improvement and a higher dry macula rate compared to IVA monotherapy in the treatment of PCV patients while requiring fewer retreatments over 12 months.

Abstract Wound healing is a common occurrence. However, delayed healing and aberrant scarring result in pathological wound healing. Accordingly, a scarless wound healing remains a significant clinical challenge. In this study, we constructed hyaluronic acid (HA)-modified and verteporfin (VP)-loaded polylactic acid (PLA) nanogels (HA/VP-PLA) to promote scarless wound healing by accelerating wound re-epithelialization and controlling scar formation. Owing to the unique structure of HA incorporating and coating in VP-loaded PLA nanoparticles, HA/VP-PLA could be topically applied on wound to achieve targeted delivery to fibroblasts. Then, HA/VP-PLA released HA and lactic acid (LA) to stimulate the proliferation and migration of fibroblasts, as well as VP to inhibit Yes-associated protein (YAP) expression and nuclear localization to suppress fibrosis. In vitro (skin fibroblasts) and in vivo (rat and rabbit models) experiments strongly suggested that HA/VP-PLA promoted scarless wound healing by accelerating wound re-epithelialization and controlling scar formation. Therefore, our work provides a feasible strategy for scarless wound healing, and the sophisticated HA/VP-PLA exhibit a great potential for clinical applications.

Abstract Introduction This study aimed to describe the effects of no-dose full-fluence photodynamic therapy without verteporfin (no-dose PDT) and to compare no-dose PDT with half-dose verteporfin full-fluence photodynamic therapy (HDFF PDT) for managing chronic central serous chorioretinopathy (cCSC). Methods This retrospective study evaluated 11 patients with chronic recurrent CSC treated with no-dose PDT between January 2019 and March 2022. Most of these patients were also treated with HDFF PDT a minimum of 3 months before and were considered as the control group. We described the changes of best corrected visual acuity (BCVA), maximum subretinal fluid (mSRF), foveal subretinal fluid (fSRF), and choroidal thickness (CT) 8 ± 2 weeks after no-dose PDT, and we compared BVCA, mSRF, fSRF, and CT of no-dose PDT with those of the of same patients previously treated with HDFF PDT. Results Fifteen eyes of 11 patients (10 male, mean age 54 ± 12 years) received no-dose PDT; among these, 10 eyes of 8 patients (7 male, mean age 53 ± 12 years) also received HDFF PDT. Three eyes showed complete resolution of fSRF after no-dose PDT. No significant differences were disclosed between treatment with and without verteporfin comparing BCVA, mSRF, fSRF, and CT at baseline and 8 ± 2 weeks from the treatment (p > 0.05 in all analyses). Conclusion BVCA and CT significantly improved after no-dose PDT. Short-term functional and anatomical treatment outcomes for cCSC were similar for HDFF PDT and no-dose PDT. We hypothesize that the potential benefits of no-dose PDT may arise from thermal elevation that triggers and enhances photochemical activities by endogenous fluorophores, activating a biochemical cascade response that rescues/replaces sick, dysfunctional retinal pigment epithelial (RPE) cells. Results of this study suggest the potential value of a prospective clinical trial to evaluate no-dose PDT for managing cCSC, especially when verteporfin is contraindicated or unavailable.

The electronic and geometrical structure of the well-known photosensitizer verteporfin VD (1), as well as its guanidine and dicarboxylic acid derivatives VD(Gua)1 (2), VD(COOH)2 (3), and VD(Gua)3 (4) are analyzed using density functional theory (DFT) calculations. The investigation of compound’s thermal and kinetic stability supports their potential use as photodynamic therapeutics. Though there are reports about the biological applications of verteporfin and its derivatives, the basic structural futures at molecular level which play a crucial role in their potential applications, are not well-explored. The results of electronic and spectral analyses by DFT calculation in this work reveal important points underlying the applications of these compounds.

Objective The inhibition of the Hippo pathway through targeting the Yes-associated protein (YAP) presents a novel and promising approach for treating tumors. However, the efficacy of YAP inhibitors in the context of breast cancer (BC) remains incompletely understood. Here, we aimed to investigate the involvement of YAP in BC's metabolic reprogramming and reveal the potential underlying mechanisms. To this end, we assessed the function of verteporfin (VP), a YAP-TEAD complex inhibitor, on the glycolytic activity of BC cells. Methods We evaluated the expression of YAP by utilizing immunohistochemistry (IHC) in BC patients who have undergone 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) prior to biopsy/surgery. We employed RNA immunoprecipitation (RIP) and fluorescent in situ hybridization (FISH) assays to assess the interaction between YAP mRNA and human antigen R (HuR) in BC cells. The biological importance of YAP in the metabolism and malignancy of BC was evaluated in vitro. Finally, the effect of VP on glycolysis was determined by using 18F-FDG uptake, glucose consumption, and lactate production assays. Results Our studies revealed that high expression of YAP was positively correlated with the maximum uptake value (SUVmax) determined by 18F-FDG PET/CT imaging in BC samples. Inhibition of YAP activity suppressed glycolysis in BC. The mechanism underlying this phenomenon could be the binding of YAP to HuR, which promotes glycolysis in BC cells. Treatment with VP effectively suppressed glycolysis induced by YAP overexpression in BC cells. Conclusion VP exhibited anti-glycolytic effect on BC cells, indicating its therapeutic value as an FDA-approved drug.

Introduction: Triple negative breast cancer (TNBC) is a subtype of breast cancer characterised by its high tumourigenic, invasive, and immunosuppressive nature. Photodynamic therapy (PDT) is a focal therapy that uses light to activate a photosensitizing agent and induce a cytotoxic effect. 5-aza-2'-deoxycytidine (5-ADC) is a clinically approved immunomodulatory chemotherapy agent. The mechanism of the combination therapy using PDT and 5-ADC in evoking an anti-tumour response is not fully understood. Methods: The present study examined whether a single dose of 5-ADC enhances the cytotoxic and anti-tumour immune effect of low dose PDT with verteporfin as the photosensitiser in a TNBC orthotopic syngeneic murine model, using the triple negative murine mammary tumour cell line 4T1. Histopathology analysis, digital pathology and immunohistochemistry of treated tumours and distant sites were assessed. Flow cytometry of splenic and breast tissue was used to identify T cell populations. Bioinformatics were used to identify tumour immune microenvironments related to TNBC patients. Results: Functional experiments showed that PDT was most effective when used in combination with 5-ADC to optimize its efficacy. 5-ADC/PDT combination therapy elicited a synergistic effect in vitro and was significantly more cytotoxic than monotherapies on 4T1 tumour cells. For tumour therapy, all types of treatments demonstrated histopathologically defined margins of necrosis, increased T cell expression in the spleen with absence of metastases or distant tissue destruction. Flow cytometry and digital pathology results showed significant increases in CD8 expressing cells with all treatments, whereas only the 5-ADC/PDT combination therapy showed increase in CD4 expression. Bioinformatics analysis of in silico publicly available TNBC data identified BCL3 and BCL2 as well as the following anti-tumour immune response biomarkers as significantly altered in TNBC compared to other breast cancer subtypes: GZMA, PRF1, CXCL1, CCL2, CCL4, and CCL5. Interestingly, molecular biomarker assays showed increase in anti-tumour response genes after treatment. The results showed concomitant increase in BCL3, with decrease in BCL2 expression in TNBC treatment. In addition, the treatments showed decrease in PRF1, CCL2, CCL4, and CCL5 genes with 5-ADC and 5-ADC/PDT treatment in both spleen and breast tissue, with the latter showing the most decrease. Discussion: To our knowledge, this is the first study that shows which of the innate and adaptive immune biomarkers are activated during PDT related treatment of the TNBC 4T1 mouse models. The results also indicate that some of the immune response biomarkers can be used to monitor the effectiveness of PDT treatment in TNBC murine model warranting further investigation in human subjects. [ABSTRACT FROM AUTHOR]

Purpose: Central serous chorioretinopathy (CSCR) patients are sometimes referred to Photodynamic Therapy (PDT) with very long-term disease. The purpose of this study was to analyze the results of PDT in CSCR eyes with long-standing disease. Methods: The medical records of the patients that underwent PDT for CSCR between 2009 and 2019 were reviewed. Cases were divided into two groups based on the duration of disease before PDT treatment: early treatment (3 to 6 months) and delayed treatment (longer than 6 months). The treatment was defined as successful when the subfoveal fluid was absorbed during follow-up. Results: The PDT treatment was successful in 76% and 77% of eyes in the early and delayed treatment groups, respectively. Both groups showed significant improvement in central retina measurements at the 3-months follow-up which persisted to the last follow-up visit. The visual acuity (VA) at baseline was significantly worse in the delayed treatment group (0.5 ± 0.26 vs. 0.3 ± 0.24, P = 0.042) and improved in both groups but remained low in the delayed treatment group during the study. Conclusion: We suggest that if CSCR is not spontaneously improving over 3 months the patient should be offered PDT, to prevent VA loss from the long-term presence of subretinal fluid in the macula. PDT is not associated with loss of vision in eyes with chronic CSCR, and can be safely used in eyes with relatively good VA. [ABSTRACT FROM AUTHOR]

Glioblastoma multiforme (GBM) is a highly aggressive malignancy and represents the most common brain tumor in adults. To better understand its biology for new and effective therapies, we examined the role of GDP-mannose pyrophosphorylase B (GMPPB), a key unit of the GDP-mannose pyrophosphorylase (GDP-MP) that catalyzes the formation of GDP-mannose. Impaired GMPPB function will reduce the amount of GDP-mannose available for O-mannosylation. Abnormal O-mannosylation of alpha dystroglycan (α-DG) has been reported to be involved in cancer metastasis and arenavirus entry. Here, we found that GMPPB is highly expressed in a panel of GBM cell lines and clinical samples and that expression of GMPPB is positively correlated with the WHO grade of gliomas. Additionally, expression of GMPPB was negatively correlated with the prognosis of GBM patients. We demonstrate that silencing GMPPB inhibits the proliferation, migration, and invasion of GBM cells both in vitro and in vivo and that overexpression of GMPPB exhibits the opposite effects. Consequently, targeting GMPPB in GBM cells results in impaired GBM tumor growth and invasion. Finally, we identify that the Hippo/MMP3 axis is essential for GMPPB-promoted GBM aggressiveness. These findings indicate that GMPPB represents a potential novel target for GBM treatment. [ABSTRACT FROM AUTHOR]

Hidradenitis suppurativa (HS) is a chronic inflammatory disease characterized by abscesses, nodules, dissecting/ draining tunnels, and extensive fibrosis. Here, we integrate single-cell RNA sequencing, spatial transcriptomics, and immunostaining to provide an unprecedented view of the pathogenesis of chronic HS, characterizing the main cellular players and defining their interactions. We found a striking layering of the chronic HS infiltrate and identified the contribution of 2 fibroblast subtypes ([SFRP4.sup.+] and [CXCL13.sup.+]) in orchestrating this compartmentalized immune response. We further demonstrated the central role of the Hippo pathway in promoting extensive fibrosis in HS and provided preclinical evidence that the profibrotic fibroblast response in HS can be modulated through inhibition of this pathway. These data provide insights into key aspects of HS pathogenesis with broad therapeutic implications., Introduction Hidradenitis suppurativa (HS) is a chronic inflammatory disease of the skin that affects 1% of the general population (1). The disease is characterized by acute, recurrent inflammatory nodules and [...]

Promoting rumen development is closely related to the health and efficient growth of ruminants. The transcriptional co-activators Yes1-associated protein (YAP1) and WW domain-containing transcription regulator protein 1 (TAZ) are key regulators of the mammalian epithelium. In the present study, we assessed the impact of YAP1/TAZ on rumen epithelial (RE) cell proliferation using their activator GA-017 (GA) and inhibitor verteporfin (VP). We also investigated whether YAP1/TAZ-dependent alteration was involved in the RE developmental process induced by sodium butyrate (SB). The results indicated that GA promoted RE cell proliferation, while VP disrupted RE cell proliferation. The Hippo, Wnt, and calcium signaling pathways were altered following the regulation of YAP1/TAZ. Upon YAP1/TAZ activation, the expression of CCN1/2 increased. However, when YAP1/TAZ was inhibited, the expression of BIRC3 decreased. In the SB-treated cells, YAP1/TAZ-induced changes were not observed. SB increased the expressions of differentiated cell marker genes and genes involved in short-chain fatty acid (SCFA) metabolism, while YAP1/TAZ did not. Thus, YAP1/TAZ could be potential targets for regulating RE cell proliferation but not for SCFA metabolism. SB could not affect YAP1/TAZ. These findings broaden our understanding of the role of YAP1/TAZ and their regulators in RE development.

IntroductionTriple negative breast cancer (TNBC) is a subtype of breast cancer characterised by its high tumourigenic, invasive, and immunosuppressive nature. Photodynamic therapy (PDT) is a focal therapy that uses light to activate a photosensitizing agent and induce a cytotoxic effect. 5-aza-2’-deoxycytidine (5-ADC) is a clinically approved immunomodulatory chemotherapy agent. The mechanism of the combination therapy using PDT and 5-ADC in evoking an anti-tumour response is not fully understood.MethodsThe present study examined whether a single dose of 5-ADC enhances the cytotoxic and anti-tumour immune effect of low dose PDT with verteporfin as the photosensitiser in a TNBC orthotopic syngeneic murine model, using the triple negative murine mammary tumour cell line 4T1. Histopathology analysis, digital pathology and immunohistochemistry of treated tumours and distant sites were assessed. Flow cytometry of splenic and breast tissue was used to identify T cell populations. Bioinformatics were used to identify tumour immune microenvironments related to TNBC patients.ResultsFunctional experiments showed that PDT was most effective when used in combination with 5-ADC to optimize its efficacy. 5-ADC/PDT combination therapy elicited a synergistic effect in vitro and was significantly more cytotoxic than monotherapies on 4T1 tumour cells. For tumour therapy, all types of treatments demonstrated histopathologically defined margins of necrosis, increased T cell expression in the spleen with absence of metastases or distant tissue destruction. Flow cytometry and digital pathology results showed significant increases in CD8 expressing cells with all treatments, whereas only the 5-ADC/PDT combination therapy showed increase in CD4 expression. Bioinformatics analysis of in silico publicly available TNBC data identified BCL3 and BCL2 as well as the following anti-tumour immune response biomarkers as significantly altered in TNBC compared to other breast cancer subtypes: GZMA, PRF1, CXCL1, CCL2, CCL4, and CCL5. Interestingly, molecular biomarker assays showed increase in anti-tumour response genes after treatment. The results showed concomitant increase in BCL3, with decrease in BCL2 expression in TNBC treatment. In addition, the treatments showed decrease in PRF1, CCL2, CCL4, and CCL5 genes with 5-ADC and 5-ADC/PDT treatment in both spleen and breast tissue, with the latter showing the most decrease. DiscussionTo our knowledge, this is the first study that shows which of the innate and adaptive immune biomarkers are activated during PDT related treatment of the TNBC 4T1 mouse models. The results also indicate that some of the immune response biomarkers can be used to monitor the effectiveness of PDT treatment in TNBC murine model warranting further investigation in human subjects.

Verteporfin and 5-ALA are used for visualizing malignant tissue components in different body tumors and as photodynamic therapy in treating isocitrate dehydrogenase (IDH) wild-type glioblastoma (GBM). Additionally, verteporfin interferes with Yes-associated protein 1 (YAP)/Transcriptional coactivator with PDZ-binding motif - TEA domain (TAZ-TEAD) pathway, thus inhibiting the downstream effect of these oncogenes and reducing the malignant properties of GBM. Animal studies have shown verteporfin to be successful in increasing survival rates, which have led to the conduction of phase 1 and 2 clinical trials to further investigate its efficacy in treating GBM. In this article, we aimed to review the novel mechanism of verteporfin's action, the impact of its interaction with YAP/TAZ-TEAD, its effect on glioblastoma stem cells, and its role in inducing ferroptosis. [ABSTRACT FROM AUTHOR]