Hypericin as a potential phototherapeutic agent in superficial transitional cell carcinoma of the bladder

Kamuhabwa, Appolinary; Agostinis, Patrizia; Ahmed, Bisan; Landuyt, Willy; Cleynenbreugel, Ben Van; Poppel, Hendrik Van; Witte, Peter de

doi:10.1039/b315586b

Cited by 62 publications

(46 citation statements)

References 75 publications

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“…Generally, the paternal drug-sensitive cell lines were more resistant to hypericin than their MDR counterparts. A concentration-and light duration-dependent cell killing of the MGHU1 cell lines was observed, with longer exposure and higher concentrations resulting in higher toxicity, in line with previous work in the field (Adreoni et al, 1994;Yu et al, 1996;Kamuhabwa et al, 2004;Theodossiou et al, 2004). Hypericin at 0.2 mM was the lowest concentration at our chosen duration of illumination (2 min), which resulted in significant cytotoxicity in MGHU1/R cells, but this dose did not affect MGHU1/S growth.…”

Section: Hypericin-induced Photodynamic Therapysupporting

confidence: 88%

Photochemical internalisation of chemotherapy potentiates killing of multidrug-resistant breast and bladder cancer cells

et al. 2007

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Multidrug resistance (MDR) is the major confounding factor in adjuvant solid tumour chemotherapy. Increasing intracellular amounts of chemotherapeutics to circumvent MDR may be achieved by a novel delivery method, photochemical internalisation (PCI). PCI consists of the co-administration of drug and photosensitiser; upon light activation the latter induces intracellular release of organellebound drug. We investigated whether co-administration of hypericin (photosensitiser) with mitoxantrone (MTZ, chemotherapeutic) plus illumination potentiates cytotoxicity in MDR cancer cells. We mapped the extent of intracellular co-localisation of drug/ photosensitiser. We determined whether PCI altered drug-excreting efflux pump P-glycoprotein (Pgp) expression or function in MDR cells. Bladder and breast cancer cells and their Pgp-overexpressing MDR subclones (MGHU1, MGHU1/R, MCF-7, MCF-7/R) were given hypericin/MTZ combinations, with/without blue-light illumination. Pilot experiments determined appropriate sublethal doses for each. Viability was determined by the 3-[4,5-dimethylthiazolyl]-2,5-diphenyltetrazolium bromide assay. Intracellular localisation was mapped by confocal microscopy. Pgp expression was detected by immunofluorescence and Pgp function investigated by Rhodamine123 efflux on confocal microscopy. MTZ alone (0.1 -0.2 mg ml À1 ) killed up to 89% of drug-sensitive cells; MDR cells exhibited less cytotoxicity (6 -28%). Hypericin (0.1 -0.2 mM) effects were similar for all cells; light illumination caused none or minimal toxicity. In combination, MTZ /hypericin plus illumination, potentiated MDR cell killing, vs hypericin or MTZ alone. (MGHU1/R: 38.65 and 36.63% increase, Po0.05; MCF-7/R: 80.2 and 46.1% increase, Po0.001). Illumination of combined MTZ/hypericin increased killing by 28.15% (Po0.05 MGHU1/R) compared to dark controls. Intracytoplasmic vesicular co-localisation of MTZ/hypericin was evident before illumination and at serial times post-illumination. MTZ was always found in sensitive cell nuclei, but not in dark resistant cell nuclei. In illuminated resistant cells there was some mobilisation of MTZ into the nucleus. Pgp expression remained unchanged, regardless of drug exposure. Pgp efflux was blocked by the Pgp inhibitor verapamil (positive control) but not impeded by hypericin. The increased killing of MDR cancer cells demonstrated is consistent with PCI. PCI is a promising technique for enhancing treatment efficacy.

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Section: Hypericin-induced Photodynamic Therapysupporting

confidence: 88%

Photochemical internalisation of chemotherapy potentiates killing of multidrug-resistant breast and bladder cancer cells

et al. 2007

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“…Hypericin is a powerful photocytotoxic sensitizer with pronounced tumor-localizing properties (Kamuhabwa et al, 2004;Van De Putte et al, 2005). We recently found that hypericin localizes in the neoplastic urothelium with higher specificity and selectivity to that displayed by aminolaevulinic acid, a precursor of the endogenous sensitizer protoporphyrin IX (D'Hallewin et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Molecular effectors and modulators of hypericin-mediated cell death in bladder cancer cells

et al. 2007

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Photodynamic therapy (PDT) is an anticancer approach utilizing a light-absorbing molecule and visible light irradiation to generate, in the presence of O 2 , cytotoxic reactive oxygen species, which cause tumor ablation. Given that the photosensitizer hypericin is under consideration for PDT treatment of bladder cancer we used oligonucleotide microarrays in the T24 bladder cancer cell line to identify differentially expressed genes with therapeutic potential. This study reveals that the expression of several genes involved in various metabolic processes, stress-induced cell death, autophagy, proliferation, inflammation and carcinogenesis is strongly affected by PDT and pinpoints the coordinated induction of a cluster of genes involved in the unfolded protein response pathway after endoplasmic reticulum stress and in antioxidant response. Analysis of PDT-treated cells after p38 MAPK inhibition or silencing unraveled that the induction of an important subset of differentially expressed genes regulating growth and invasion, as well as adaptive mechanisms against oxidative stress, is governed by this stress-activated kinase. Moreover, p38 MAPK inhibition blocked autonomous regrowth and migration of cancer cells escaping PDT-induced cell death. This analysis identifies new molecular effectors of the cancer cell response to PDT opening attractive avenues to improve the therapeutic efficacy of hypericin-based PDT of bladder cancer.

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“…Exposure to light and the presence of oxygen result in tissue damage through development of oxygen radicals (5). Hypericin is a hydroxylated phenanthroperylenequinone derivate and is found in plants of the species Hypericum (5,6).…”

Section: Introductionmentioning

confidence: 99%

In vitro photodynamic therapy of childhood rhabdomyosarcoma

Seitz

Warmann²,

Armeanu³

et al. 2007

Int J Oncol

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Abstract. Treatment of childhood rhabdomyosarcoma is limited by recurrent disease and the development of multidrug resistance. Therefore, novel treatment options are desirable. Photodynamic therapy (PDT) using the photodynamic agent hypericin is proposed as an alternative approach for intraoperative visualization and treatment of this disease. The aim of this study was to investigate in vitro effects of hypericin on childhood rhabdomyosarcoma and to evaluate photodynamic therapy as a possible basis for treatment. Rhabdomyosarcoma cells and fibroblasts (control) were incubated with increasing concentrations of hypericin. In vitro uptake and visualization of hypericin was evaluated by fluorescence microscopy and FACS. For photodynamic therapy, cells were exposed to white light for different time periods. Cytopathologic effects were assessed using standard histology. Cancer cells were investigated for cell viability (MTT assay), proliferative activity (Ki-67 assay), and apoptosis (TUNEL test). A 100% uptake of hypericin was found within the population of rhabdomyosarcoma cells. Uptake of hypericin in the fibroblasts was much less than in rhabdomyosarcoma cells. Hypericin without exposure to white light had no effect on tumor cell viability. After irradiation, PDT resulted in a nearly complete inhibition of cell proliferation of rhabdomyosarcoma cells with a corresponding increase in the frequency of apoptosis. In fibroblasts, PDT was less effective compared to tumor cells. Our data suggest hypericin as a novel tool for visualization and photodynamic therapy of childhood rhabdomyosarcoma. IntroductionRhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. About two thirds of all sarcomas and 7-8% of all solid malignant tumors in childhood are rhabdomyosarcomas (1). The two main histopathological subtypes of this malignancy in children are embryonal and alveolar RMS (2). Specific genetic alterations (3) such as the translocation t(2;13)(q35;q14) which occurs in 55% of all cases and t(1;13)(p36;q14) in 22% contribute to the diagnosis of alveolar RMS (1). No specific genetic alterations are found in embryonal rhabdomyosarcomas (1).The prognosis of these tumors is still poor and therapy is limited due to recurrent disease, development of metastases and multidrug resistance. Radical surgery plays a key role for the prognosis of these tumors. Mutilating surgery is often necessary for survival. Surgical procedures are complicated due to a lack of possible visualization of these tumors in vivo.In vivo visualization of childhood rhabdomyosarcoma can be performed using fluorescent proteins. Tumors and their behaviour can be studied in vivo using this imaging tool (4). Up to now, fluorescent proteins are mainly a basic research tool and have not been used in humans. Therefore, the investigation of other treatment modalities is of increasing interest.Photodynamic therapy (PDT) can be performed after local or systemic administration of a photodynamic drug. Exposure to light and the presence of oxygen result in...

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Hypericin as a potential phototherapeutic agent in superficial transitional cell carcinoma of the bladder

Cited by 62 publications

References 75 publications

Photochemical internalisation of chemotherapy potentiates killing of multidrug-resistant breast and bladder cancer cells

Photochemical internalisation of chemotherapy potentiates killing of multidrug-resistant breast and bladder cancer cells

Molecular effectors and modulators of hypericin-mediated cell death in bladder cancer cells

In vitro photodynamic therapy of childhood rhabdomyosarcoma

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