Hypericin phototoxicity induces different modes of cell death in melanoma and human skin cells

Davids, Lester M.; Kleemann, Britta; Kacerovská, Denisa; Pizinger, Karel; Kidson, Susan H.

doi:10.1016/j.jphotobiol.2008.01.011

Cited by 107 publications

(93 citation statements)

References 52 publications

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“…The selective cytotoxicity observed here is in agreement with a previous study, which demonstrated that hypericin is preferably internalized by tumor cells, where it accumulates into the membranes of mitochondria, the Golgi apparatus, and the endoplasmic reticulum and then induces apoptosis (39). This accumulation is apparently due to alterations in the expression of protein complexes like E cadherin (40).…”

Section: Discussionsupporting

confidence: 92%

Development of a Novel Formulation with Hypericin To Treat Cutaneous Leishmaniasis Based on Photodynamic Therapy inIn VitroandIn VivoStudies

Montoya

Daza

Muñoz

et al. 2015

Antimicrob Agents Chemother

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An evaluation of the leishmanicidal activity in vitro and in vivo of hypericin, an expanded-spectrum photosensitizer found in Hypericum perforatum, is presented. Hypericin was evaluated against intracellular amastigotes in vitro of Leishmania (Viannia) panamensis. A topical formulation containing 0.5% hypericin was developed and assayed in vivo in a hamster model of cutaneous leishmaniasis. Results demonstrate that hypericin induces a significant antiamastigote effect in vitro against L. panamensis by decreasing the number of parasites inside infected cells. The topical formulation of 0.5% hypericin allows healing of L. panamensis-induced lesions upon a topical application of 40 mg/day plus visible-light irradiation (5 J/cm 2 , 15 min), twice a week for 3 weeks. Cutaneous leishmaniasis (CL) is a parasitic disease caused by protozoa of the genus Leishmania, which manifests as a chronic infection affecting mainly mononuclear phagocytes of the skin (1). The disease affects the poorest populations in 99 countries in tropical and subtropical regions of the world (2, 3). It is estimated that 14 million people are infected, 350 million are at risk, and there are about 1.5 million new cases per year (3, 4). The parasite is transmitted by the bite of an insect vector belonging to the genus Lutzomyia (in America) or Phlebotomus (in Europe, Asia, and Africa) in the subfamily Phlebotominae (5).Only three types of drugs are available to treat CL. They are the pentavalent antimonials (meglumine antimoniate and sodium stibogluconate), pentamidine isethionate, and miltefosine. Miltefosine is the only one available for oral administration (4). These medications are delivered at high doses and for long periods, thus leading to high toxicity. Therefore, their use is contraindicated in pregnant women, in patients with cardiovascular, renal, or hepatic disease, and in children with low body weight (6). Overall, the efficacy of these drugs varies between 55 and 98% depending on the compound and on the Leishmania species causing the clinical manifestation (7,8). However, their elevated toxicity encourages abandonment of treatment and consequently a decrease in the efficacy (9).More recently, photodynamic therapy (PDT) has emerged as an alternative to treat CL (10). This therapy is based on the application of a photosensitizing agent (PA) that, when excited by light of a certain wavelength, induces the production of reactive oxygen species (ROS) that can destroy the microorganism or the target cell (11). In spite of its potential, only a few PAs have been tested against CL in animal models, and only one in humans. Topical application of 5-aminolevulinic acid (ALA) and light in a murine model of CL caused by L. major showed a significant reduction of the parasitic load and the size of lesions (12). Intralesional administration of ALA (one to three PDT sessions) in a patient with CL by L. major produced a 10 to 20% cure, although it is probable that clinical outcome resulted from nonspecific destruction of infected macrophages instead of...

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Section: Discussionsupporting

confidence: 92%

Development of a Novel Formulation with Hypericin To Treat Cutaneous Leishmaniasis Based on Photodynamic Therapy inIn VitroandIn VivoStudies

Montoya

Daza

Muñoz

et al. 2015

Antimicrob Agents Chemother

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“…Ma et al (7) showed that violet light PDT was able to bleach melanin in melanotic tumors and therefore increase their sensitivity to red light PDT. The hypericin photocytoxicity toward pigmented UCT MEL-1 melanoma cells was found to be lower than that in unpigmented A375 melanoma, due to the protective properties of melanin on ROS (8). Recently, Mroz et al (9) reported the effectiveness of Photofrin and bacteriochlorin 3 in relation to the melanin content of B16 melanoma cells.…”

Section: Discussionmentioning

confidence: 98%

Photodynamic treatment induces cell death by apoptosis or autophagy depending on the melanin content in two B16 melanoma cell lines

Sparsa¹,

Bellaton²,

Naves³

et al. 2012

Oncology Reports

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Abstract. Photodynamic therapy (PDT) is now a well-established treatment modality for cutaneous carcinomas and is based on the administration of a light-activated drug followed by illumination of the pathological area. The treatment of metastatic melanoma remains a therapeutic challenge. To define the possible role of melanin in relative phototoxicity of 5-aminolevulinic acid (5-ALA), a photosensitizer used in PDT in vivo, we studied cell death in two variants (with or without melanin, B16F10 and B16G4F cells, respectively) of a melanoma cell line. Concentrations of 5-Ala up to 10 mM induced similar cytostatic effects in the B16G4F and B16F10 cells. PDT and high 5-ALA concentrations induced photocytotoxicity in both melanoma cell lines (at 10 mM for B16F10 cells and at 5 mM for B16G4F cells). Cell death corresponded to p53-dependent apoptotic signaling in pigmented B16F10 cells, whereas an autophagic response leading to a caspase-independent death was detected in nonpigmented B16G4F cells. Therefore, the PDT-induced cell death pathway appeared to correlate with melanin synthesis capacity in melanoma cells. To reduce the cytotoxicity of 5-ALA without irradiation, a low drug concentration could be used. Consequently, in combination with current therapeutics, a moderate concentration of 5-ALA and PDT may constitute a supplementary promising approach to eliminate metastatic melanoma. IntroductionPhotodynamic therapy (PDT) has been used in clinical application for many years, either systemically, or locally or topically applied to a patient bearing a lesion (cancerous or not). PDT with systemic photosensitizers has been used to treat a range of internal malignancies (lung and brain cancers) and for skin cancers (1). This cancer treatment is approved by many countries for the treatment of non-melanotic skin cancers such as basal cell carcinomas and Bowen's disease. PDT does not seem to be an appropriate treatment of melanotic melanoma in vivo, and several reasons can justify this low use. Almost all melanomas overexpress the classical ATP-binding cassette transporters (ABC protein family), leading to drug release into the extracellular medium and to the resistance by tumor cells. The antioxidant activity of melanoma is much higher than observed in other skin cancers (basal and squamous carcinomas) reducing the cytotoxic effect of ROS generated by PDT (2). Nearly all photosensitizers (PS) show a significant absorbance in ultraviolet (UV) wavelengths, while melanin absorbs a large portion of the light intended to activate PS. The light absorption by pigment strongly reduces its penetration into the tumor. Studies have been carried out with pigmented or amelanotic melanoma cells suggesting that amelanotic cells may be more susceptible to PDT (2). Among the molecules used in PDT, 5-aminolevulinic acid (5-ALA) is not itself a photosensitizer and instead it is used as a prodrug leading to the accumulation of protoporphyrin IX in the mitochondria inducing damage and subsequently cell death after light irradiation (3).It is w...

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“…It has been assumed that presences of melanosomes serve as targets for PDT and different modes of cell death in pigmented and unpigmented melanomas are thought to be associated with melanosomes themselves. In a study conducted by Davids et al (Davids, Kleemann et al 2008) when cells were treated with HYP-PDT, it was observed that pigmented cells died by necrosis, whereas unpigmented cells died by apoptosis. However, initially both melanoma cell types showed a similar cytoprotective response through the induction of autophagy, which is a cell survival program of cells undergoing environmental stress (Davids, Kleemann et al 2009).…”

Section: Melanoma Resistance To Pdtmentioning

confidence: 99%

Melanoma resistance to photodynamic therapy: new insights

Huang¹,

Vecchio²,

Avci

et al. 2013

Biological Chemistry

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Melanoma is the most dangerous form of skin cancer, with a steeply rising incidence and a poor prognosis in its advanced stages. Melanoma is highly resistant to traditional chemotherapy and radiotherapy, although modern targeted therapies such as BRAF inhibitors are showing some promise. Photodynamic therapy (PDT, the combination of photosensitizing dyes and visible light) has been tested for melanoma with some promising results, but melanoma is generally considered to also be resistant to PDT. Optical interference by the highly-pigmented melanin, the anti-oxidant effect of melanin, the sequestration of photosensitizers inside melanosomes, defects in apoptotic pathways, and the efflux of photosensitizers by ATP-binding cassette (ABC) transporters have all been implicated in melanoma resistance to PDT. Approaches to overcoming melanoma resistance to PDT include: the discovery of highly active photosensitizers absorbing in the 700-800-nm near infrared spectral region; interventions that can temporarily reduce the amount or the pigmentation of the melanin; compounds that can reverse apoptotic defects or inhibit drug-efflux of photosensitizers; and immunotherapy approaches that can take advantage of the ability of PDT to activate the host immune system to the treated tumor.

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Hypericin phototoxicity induces different modes of cell death in melanoma and human skin cells

Cited by 107 publications

References 52 publications

Development of a Novel Formulation with Hypericin To Treat Cutaneous Leishmaniasis Based on Photodynamic Therapy inIn VitroandIn VivoStudies

Development of a Novel Formulation with Hypericin To Treat Cutaneous Leishmaniasis Based on Photodynamic Therapy inIn VitroandIn VivoStudies

Photodynamic treatment induces cell death by apoptosis or autophagy depending on the melanin content in two B16 melanoma cell lines

Melanoma resistance to photodynamic therapy: new insights

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