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Parihar A, Gaur K, Sarbadhikary P. Advanced 2D Nanomaterials for Phototheranostics of Breast Cancer: A Paradigm Shift. Adv Biol (Weinh) 2025; 9:e2400441. [PMID: 39543015 DOI: 10.1002/adbi.202400441] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2024] [Revised: 10/29/2024] [Indexed: 11/17/2024]
Abstract
Breast cancer is the leading cause of women's deaths and associated comorbidities. The advanced and targeted strategies against breast cancer have gained considerable attention due to their potential enhanced therapeutic efficacy over conventional therapies. In this context, phototherapies like photodynamic therapy (PDT) and photothermal therapy (PTT) have shown promise as an effective and alternative strategy due to reduced side effects, noninvasiveness, and spatiotemporal specificity. With the advent of nanotechnology, several types of nanomaterials that have shown excellent prospects in increasing the efficacy of photo therapies have been exploited in cancer treatment. In recent years, 2D nanomaterials have stood out promising because of their unique ultrathin planar structure, chemical, physical, tunable characteristics, and corresponding remarkable physiochemical/biological properties. In this review, the potential and the current status of several types of 2D nanomaterials such as graphene-based nanomaterials, Mxenes, Black phosphorous, and Transition Metal Dichalcogenides for photo/thermo and combination-based imaging and therapy of breast cancer have been discussed. The current challenges and prospects in terms of translational potential in future clinical oncology are highlighted.
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Affiliation(s)
- Arpana Parihar
- Department of Translational Medicine, All India Institute of Medical Sciences Bhopal, Saket Nagar, Bhopal, Madhya Pradesh, 462020, India
| | - Kritika Gaur
- Central Sheep and wool research institute, ICAR- Indian Council of Agricultural Research, Avikanagr, Malpura, Rajasthan, 304501, India
| | - Paromita Sarbadhikary
- Laser Research Centre, Faculty of Health Sciences, University of Johannesburg, Doornfontein, P.O. Box 17011, Johannesburg, 2028, South Africa
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Minagawa E, Yamauchi N, Taguchi Y, Umeda M. Photodynamic reactions using high-intensity red LED promotes gingival wound healing by ROS induction. Sci Rep 2023; 13:17081. [PMID: 37816801 PMCID: PMC10564724 DOI: 10.1038/s41598-023-43966-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Accepted: 09/30/2023] [Indexed: 10/12/2023] Open
Abstract
Photodynamic therapy is a treatment that combines a light source with a photosensitizer. LEDs have attracted considerable attention in clinical dentistry because they are inexpensive and safe to use. Although the interaction between photosensitizers and LEDs in dental practice is effective for treating periodontal disease by killing periodontopathic bacteria, little is known about the effects of LEDs on human gingival fibroblasts (HGnFs), which play an important role in gingival wound healing. In this study, we investigated the effects of high-intensity red LED irradiation on HGnFs after the addition of methylene blue (MB), one of the least harmful photosensitizers, on wound healing and reactive oxygen species (ROS) production induced by photodynamic reactions. We found that irradiation of MB with high-intensity red LED at controlled energy levels promoted cell proliferation, migration, and production of wound healing factors. Furthermore, ROS production by a photodynamic reaction enabled the translocation of phosphorylated Grb2-associated binder-1, activating Extracellular signal-regulated kinase 1/2 and c-Jun N-terminal kinase signals. Our findings suggest that proper control of ROS production has a beneficial effect on gingival fibroblasts, which constitute periodontal tissue, from the perspective of gingival wound healing.
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Affiliation(s)
- Emika Minagawa
- Department of Periodontology, Osaka Dental University, 8-1 Kuzuhahanazono-cho, Hirakata, Osaka, Japan
| | - Nobuhiro Yamauchi
- Department of Periodontology, Osaka Dental University, 8-1 Kuzuhahanazono-cho, Hirakata, Osaka, Japan
| | - Yoichiro Taguchi
- Department of Periodontology, Osaka Dental University, 8-1 Kuzuhahanazono-cho, Hirakata, Osaka, Japan.
| | - Makoto Umeda
- Department of Periodontology, Osaka Dental University, 8-1 Kuzuhahanazono-cho, Hirakata, Osaka, Japan
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Akkoç B, Samsunlu T, Işık Ş, Özçeşmeci M, Atmaca GY, Erdoğmuş A, Serhatlı M, Hamuryudan E. Pegylated metal-free and zinc(II) phthalocyanines: synthesis, photophysicochemical properties and in vitro photodynamic activities against head, neck and colon cancer cell lines. Dalton Trans 2022; 51:10136-10147. [PMID: 35734907 DOI: 10.1039/d2dt00704e] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
In this study, a series of peripherally and non-peripherally tetra-substituted metal-free and zinc(II) phthalocyanines were successfully prepared in good yields by cyclotetramerization of the phthalonitrile derivative bearing a tetraethylene glycol methyl ether group at 3- and 4- positions. All newly synthesized compounds were characterized using spectroscopic methods, such as FT-IR, NMR, mass and UV-Vis spectroscopy. To determine the therapeutic potential of the synthesized phthalocyanines, the effects of the substitution pattern (peripheral and non-peripheral) and central metal atom on the photophysicochemical properties were investigated. When comparing their singlet oxygen generation capabilities (ΦΔ), metallo-phthalocyanine derivatives with zinc (0.73 for 1b and 0.70 for 2b) showed higher singlet oxygen yield than metal-free derivatives (0.21 for 1a and 0.12 for 2a) in DMSO. The photodynamic therapy activities of the water-soluble phthalocyanines were tested via in vitro studies using the A253, FaDu (head and neck cancer cell lines), and HT29 (colon cancer) cell lines. The strongest photodynamic activity was found in 1b and 2b molecules with a metal core among the four molecules studied. The results suggested that the non-peripherally tetra-substituted 1b molecule was regarded as a suitable photodynamic therapy agent due to its light cytotoxicity and secondary impact induced by ROS production.
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Affiliation(s)
- Berkay Akkoç
- Department of Chemistry, Istanbul Technical University, 34469, Maslak, Istanbul, Turkey.
| | - Taylan Samsunlu
- Department of Chemistry, Istanbul Technical University, 34469, Maslak, Istanbul, Turkey.
| | - Şeyma Işık
- Genetic Engineering and Biotechnology Institute GEBI, TUBITAK Marmara Research Center MRC, 41470, Gebze, Kocaeli, Turkey.,Department of Medical Biotechnology, Institute of Health Sciences, Acibadem Mehmet Ali Aydınlar University, 34684, Atasehir, Istanbul, Turkey
| | - Mukaddes Özçeşmeci
- Department of Chemistry, Istanbul Technical University, 34469, Maslak, Istanbul, Turkey.
| | - Göknur Yaşa Atmaca
- Department of Chemistry, Yildiz Technical University, 34210, Esenler, Istanbul, Turkey
| | - Ali Erdoğmuş
- Department of Chemistry, Yildiz Technical University, 34210, Esenler, Istanbul, Turkey
| | - Müge Serhatlı
- Genetic Engineering and Biotechnology Institute GEBI, TUBITAK Marmara Research Center MRC, 41470, Gebze, Kocaeli, Turkey
| | - Esin Hamuryudan
- Department of Chemistry, Istanbul Technical University, 34469, Maslak, Istanbul, Turkey.
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Parihar A, Dube A. Structural alterations in cell organelles induced by photodynamic treatment with chlorin p 6 -histamine conjugate in human oral carcinoma cells probed by 3D fluorescence microscopy. LUMINESCENCE 2022. [PMID: 35698308 DOI: 10.1002/bio.4307] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2022] [Revised: 03/27/2022] [Accepted: 04/18/2022] [Indexed: 11/09/2022]
Abstract
We have explored the intracellular cell organelle's structural alterations after photodynamic treatment with chlorin p6 -histamine conjugate (Cp6 -his) in human oral cancer cells. Herein, the cells were treated with Cp6 -his (10 μm) and counterstained with organelle-specific fluorescence probes to find the site of intracellular localization using confocal microscopy. For photodynamic therapy (PDT), the cells were exposed to ~30 kJ/m2 red light (660 ± 20 nm) to induce ~90% cytotoxicity. We used the three-dimensional (3D) image reconstruction approach to analyze the photodynamic damage to cell organelles. The result showed that Cp6 -his localized mainly in the endoplasmic reticulum (ER) and lysosomes but not in mitochondria and Golgi apparatus (GA). The 3D model revealed that in necrotic cells, PDT led to extensive fragmentation of ER and fragmentation and swelling of GA as well. Results suggest that the indirect damage to GA occurred due to loss of connection between ER and GA. Moreover, in damaged cells with no sign of necrosis, the perinuclear ER appeared condensed and surrounded by several small clumps at the peripheral region of the cell, and the GA was observed to form a single condensed structure. Since these structural changes were associated with apoptotic cell death, it is suggested that the necrotic and apoptotic death induced by PDT with Cp6 -his is determined by the severity of damage to ER and indirect damage to GA. The results suggest that the indirect damage to cell organelle apart from the sites of photosensitizer localization and the severity of damage at the organelle level contribute significantly to the mode of cell death in PDT.
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Affiliation(s)
- Arpana Parihar
- Industrial Waste Utilization, Nano and Biomaterials, CSIR - Advanced Materials and Processes Research Institute (AMPRI), Bhopal, India
| | - Alok Dube
- Laser Biomedical Applications Division, Raja Ramanna Center for Advanced Technology Indore, Madhya Pradesh, India
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Monaco H, Yokomizo S, Choi HS, Kashiwagi S. Quickly evolving near‐infrared photoimmunotherapy provides multifaceted approach to modern cancer treatment. VIEW 2022. [DOI: 10.1002/viw.20200110] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Affiliation(s)
- Hailey Monaco
- Gordon Center for Medical Imaging Department of Radiology Massachusetts General Hospital and Harvard Medical School Boston Massachusetts USA
| | - Shinya Yokomizo
- Gordon Center for Medical Imaging Department of Radiology Massachusetts General Hospital and Harvard Medical School Boston Massachusetts USA
- Department of Radiological Sciences Tokyo Metropolitan University Arakawa Tokyo Japan
| | - Hak Soo Choi
- Gordon Center for Medical Imaging Department of Radiology Massachusetts General Hospital and Harvard Medical School Boston Massachusetts USA
| | - Satoshi Kashiwagi
- Gordon Center for Medical Imaging Department of Radiology Massachusetts General Hospital and Harvard Medical School Boston Massachusetts USA
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Linares IA, Martinelli LP, Moritz MN, Selistre-de-Araujo HS, de Oliveira KT, Rodrigues Perussi J. Cytotoxicity of structurally-modified chlorins aimed for photodynamic therapy applications. J Photochem Photobiol A Chem 2022. [DOI: 10.1016/j.jphotochem.2021.113647] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
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Dual targeting smart drug delivery system for multimodal synergistic combination cancer therapy with reduced cardiotoxicity. Acta Biomater 2021; 131:493-507. [PMID: 34139367 DOI: 10.1016/j.actbio.2021.06.016] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 06/05/2021] [Accepted: 06/08/2021] [Indexed: 11/23/2022]
Abstract
This study first reports the development of a smart drug delivery system (DDS) for multimodal synergistic cancer therapy combining chemo-photothermal-starvation approaches. A magnetic photothermal agent was synthesized by preparing iron oxide (IO) nanoparticles (NPs) with covalently attached indocyanine green (ICG) and glucose oxidase (GOx) (ICGOx@IO). Synthesized ICGOx@IO NPs were co-encapsulated with doxorubicin (Dox) and EGCG ((-)-epigallocatechin-3-gallate) inside PLGA (poly(lactic-co-glycolic acid)) NPs using multiple emulsion solvent evaporation method. Such formulation gave the advantage of triggered drug release by near-infrared (NIR) laser irradiation (808 nm at 1 W/cm2). RGD peptide was attached to the surface of PLGA NPs and the final hydrodynamic size was around 210 nm. Dual targeting by peptide and 240 mT external magnet significantly improved cellular uptake. Cellular uptake was observed using FACS, electron and optical microscopy. Dual targeting along with laser irradiation could reduce in vitro cell viability by 90 ± 2% (Dox-equivalent dose: 10 µg/ml) and complete tumor ablation was achieved in vivo due to synergetic therapeutic effect. Another attractive feature of the DDS was the significant reduction of cardiotoxicity of doxorubicin by EGCG. This new platform is thus expected to hold strong promise for future multimodal combination therapy of cancers. STATEMENT OF SIGNIFICANCE: Doxorubicin is one of the most studied and effective chemotherapeutic agents whose application is hindered due to its cardiotoxicity. In this study, we used (-)-Epigallocatechin-3-gallate (EGCG) to overcome that limitation. However, drug delivery to tumor sites with no/minimum accumulation in healthy organs is always challenging. Although peptide-based targeting is very popular, the effectiveness of receptor/ligand binding active targeting is sometimes questioned which motivated us to apply dual targeting approach. Multimodal therapies can exhibit synergistic effects and subsequently reduce the required dose of drug over monotherapy. We aimed to achieve chemo-photothermal-starvation combination therapy in this study and such achievement is yet to be reported. Our developed system also has the advantage of triggered drug release by near-infrared (NIR) laser irradiation.
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Gunaydin G, Gedik ME, Ayan S. Photodynamic Therapy-Current Limitations and Novel Approaches. Front Chem 2021; 9:691697. [PMID: 34178948 PMCID: PMC8223074 DOI: 10.3389/fchem.2021.691697] [Citation(s) in RCA: 285] [Impact Index Per Article: 71.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Accepted: 05/14/2021] [Indexed: 12/17/2022] Open
Abstract
Photodynamic therapy (PDT) mostly relies on the generation of singlet oxygen, via the excitation of a photosensitizer, so that target tumor cells can be destroyed. PDT can be applied in the settings of several malignant diseases. In fact, the earliest preclinical applications date back to 1900’s. Dougherty reported the treatment of skin tumors by PDT in 1978. Several further studies around 1980 demonstrated the effectiveness of PDT. Thus, the technique has attracted the attention of numerous researchers since then. Hematoporphyrin derivative received the FDA approval as a clinical application of PDT in 1995. We have indeed witnessed a considerable progress in the field over the last century. Given the fact that PDT has a favorable adverse event profile and can enhance anti-tumor immune responses as well as demonstrating minimally invasive characteristics, it is disappointing that PDT is not broadly utilized in the clinical setting for the treatment of malignant and/or non-malignant diseases. Several issues still hinder the development of PDT, such as those related with light, tissue oxygenation and inherent properties of the photosensitizers. Various photosensitizers have been designed/synthesized in order to overcome the limitations. In this Review, we provide a general overview of the mechanisms of action in terms of PDT in cancer, including the effects on immune system and vasculature as well as mechanisms related with tumor cell destruction. We will also briefly mention the application of PDT for non-malignant diseases. The current limitations of PDT utilization in cancer will be reviewed, since identifying problems associated with design/synthesis of photosensitizers as well as application of light and tissue oxygenation might pave the way for more effective PDT approaches. Furthermore, novel promising approaches to improve outcome in PDT such as selectivity, bioengineering, subcellular/organelle targeting, etc. will also be discussed in detail, since the potential of pioneering and exceptional approaches that aim to overcome the limitations and reveal the full potential of PDT in terms of clinical translation are undoubtedly exciting. A better understanding of novel concepts in the field (e.g. enhanced, two-stage, fractional PDT) will most likely prove to be very useful for pursuing and improving effective PDT strategies.
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Affiliation(s)
- Gurcan Gunaydin
- Department of Basic Oncology, Hacettepe University Cancer Institute, Sihhiye, Ankara, Turkey
| | - M Emre Gedik
- Department of Basic Oncology, Hacettepe University Cancer Institute, Sihhiye, Ankara, Turkey
| | - Seylan Ayan
- Department of Chemistry, Bilkent University, Ankara, Turkey
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Turna O, Baykal A, Sozen Kucukkara E, Ozten O, Deveci Ozkan A, Guney Eskiler G, Kamanli AF, Bilir C, Yildiz SZ, Kaleli S, Ucmak M, Kasikci G, Lim HS. Efficacy of 5-aminolevulinic acid-based photodynamic therapy in different subtypes of canine mammary gland cancer cells. Lasers Med Sci 2021; 37:867-876. [PMID: 33937952 DOI: 10.1007/s10103-021-03324-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2020] [Accepted: 04/20/2021] [Indexed: 10/21/2022]
Abstract
Canine mammary gland tumors (CMGTs) are heterogeneous disease and subclassified [sarcomas (S), carcinomas (C), and carcinosarcomas (CS)] according to histopathological differentiation. Photodynamic therapy (PDT) is a promising treatment strategy based on the use of a photosensitizer (PS) activated by light. However, the therapeutic potential of PDT in the treatment of CMGTs has not been investigated, yet. Therefore, the aim of this study was to determine the in vitro protocol of 5-ALA-based-PDT for the treatment of three subtypes of CMGTs, for the first time. The intracellular PpIX florescence intensity was measured for 5-ALA (0.5 and 1 mM). After irradiation with different light doses (6, 9, 12, 18, and 24 J/cm2) for two different modes [continuous wave (CW) and pulse radiation (PR)], the cytotoxic effects of 5-ALA (0.5 and 1 mM) on the subtypes (C, S, and CS) of CMGTs were analyzed by WST-1. Finally, the optimal PDT treatment protocol was validated through Annexin V and AO/EtBr staining. Our results showed that 1 mM 5-ALA for 4-h incubation was the best treatment condition in all subtypes of CMGTs due to higher intracellular PpIX level. After irradiation with different light doses, PR mode was more effective in S primary cells at 9 J/cm2. However, a significant decrease in the viability of C and CS cells was detected at 12 /cm2 in CW mode (p < 0.05). Additionally, 1 mM 5-ALA induced apoptotic cell death in each subtype of CMGTs. Our preliminary findings suggest that (i) each subtype of CMGTs differentially responds to PDT and (ii) the light dose and mode could play an important role in the effective PDT treatment. However, further studies are needed to investigate the role of the different light sources and PDT-based apoptotic cell death in CMGTs cells.
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Affiliation(s)
- Ozge Turna
- Department of Obstetrics and Gynecology, Faculty of Veterinary Medicine, Istanbul-Cerrahpasa University, Istanbul, Turkey
| | - Aslihan Baykal
- Department of Obstetrics and Gynecology, Faculty of Veterinary Medicine, Istanbul-Cerrahpasa University, Istanbul, Turkey
| | - Elif Sozen Kucukkara
- Department of Medical Biochemistry, Institute of Health Sciences, Sakarya University, Sakarya, Turkey
| | - Ozge Ozten
- Department of Biomedical Engineering, Institute of Graduate Education, Sakarya University of Applied Science, Sakarya, Turkey
| | - Asuman Deveci Ozkan
- Department of Medical Biology, Faculty of Medicine, Sakarya University, Korucuk Campus, 54290, Sakarya, Turkey
| | - Gamze Guney Eskiler
- Department of Medical Biology, Faculty of Medicine, Sakarya University, Korucuk Campus, 54290, Sakarya, Turkey.
| | - Ali Furkan Kamanli
- Department of Electric and Electronics Engineering, Technology Faculty, Sakarya University of Applied Sciences, Sakarya, Turkey
| | - Cemil Bilir
- Department of Medical Oncology, Faculty of Medicine, Sakarya University, Sakarya, Turkey
| | - Salih Zeki Yildiz
- Department of Chemistry, Faculty of Arts and Sciences, Sakarya University, Sakarya, Turkey
| | - Suleyman Kaleli
- Department of Medical Biology, Faculty of Medicine, Sakarya University, Korucuk Campus, 54290, Sakarya, Turkey
| | - Melih Ucmak
- Department of Obstetrics and Gynecology, Faculty of Veterinary Medicine, Istanbul-Cerrahpasa University, Istanbul, Turkey
| | - Guven Kasikci
- Department of Obstetrics and Gynecology, Faculty of Veterinary Medicine, Istanbul-Cerrahpasa University, Istanbul, Turkey
| | - Hyun Soo Lim
- Department of Electric and Electronics Engineering, Technology Faculty, Sakarya University of Applied Sciences, Sakarya, Turkey
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Analysis of the effects of Photodynamic therapy with Photodithazine on the treatment of 9l/lacZ cells, in vitro study. Photodiagnosis Photodyn Ther 2021; 34:102233. [PMID: 33639321 DOI: 10.1016/j.pdpdt.2021.102233] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2020] [Revised: 01/27/2021] [Accepted: 02/19/2021] [Indexed: 01/21/2023]
Abstract
Gliosarcoma is an aggressive brain tumor. Photodynamic Therapy (PDT) is a treatment that can be used for various cancers of the CNS. The aim of this study was to analyze the effects of PDT with Photodithazine (PDZ) in the treatment of gliosarcoma, using 9 L/lacZ cells and serial concentrations of 200 μg/mL to 3.1 μg/mL of PDZ. The samples were divided into two groups: dark and light (10 J/cm²). The PDZ was internalized along all the cytoplasmic extension. Viability tests demonstrated a reduction in viable cells after PDT. The production of ROS was concentration-dependent and PDZ was found in mitochondria and lysosomes, presenting a discrete connection with α-tubulin. However, this structure is likely damaged, evidenced by changes in the morphological analysis. Thus, according to the parameters of this study, PDZ proved to be an interesting PS in PDT for the treatment of gliosarcoma, with the inherent limitations of an in vitro study.
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Marinho MAG, da Silva Marques M, Lettnin AP, de Souza Votto AP, de Moraes Vaz Batista Filgueira D, Horn AP. Interaction Between Near-Infrared Radiation and Temozolomide in a Glioblastoma Multiform Cell Line: A Treatment Strategy? Cell Mol Neurobiol 2021; 41:91-104. [PMID: 32236902 PMCID: PMC11448574 DOI: 10.1007/s10571-020-00835-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2020] [Accepted: 03/24/2020] [Indexed: 02/08/2023]
Abstract
Photodynamic therapy (PDT) is a potential therapeutic modality against cancer, resulting from the interaction of a photosensitizer (PS) and radiation that generates damage to tumor cells. The use of near-infrared radiation (IR-A) is relevant because presents recognized biological effects, such as antioxidant, neuroprotective and antitumor effects. Glioblastoma is the most aggressive central nervous system (CNS) neoplasm with high proliferation and tissue invasion capacity and is resistant to radio and chemotherapy. Here, we evaluated in vitro the possible interaction of temozolomide (TMZ) with IR-A in a glioblastoma cell line (C6) and in a human keratinocyte cell line (HaCat) how non-tumor cell model, in an attempt to search for a new treatment strategy. The effects of TMZ, IR-A and the interaction between TMZ and IR-A was evaluated by viability exclusion with trypan blue. To perform the interaction experiments, we have chosen 10 μM TMZ and 4.5 J/cm2 of IR-A. From this, we evaluated cytotoxicity, cell proliferation, intracellular reactive oxygen species levels (ROS), as well as the process of cell migration and the P-gp and MRP-1 activity. Cell death mainly due to apoptosis, followed by necrosis, decreased cell proliferation, increased ROS levels, decreased cell migration and decreased P-gp and MRP1 activity were observed only when there was interaction between TMZ and IR-A in the C6 cell line. The interaction between TMZ and IR-A was not able to affect cell proliferation in the HaCat non-tumor cell line. Our results suggest that this interaction could be a promising approach and that in the future may serve as an antitumor strategy for PDT application.
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Affiliation(s)
- Marcelo Augusto Germani Marinho
- Programa de Pós-Graduação Em Ciências Fisiológicas, Instituto de Ciências Biológicas, Universidade Federal Do Rio Grande-FURG, Av. Itália, Km 8, Rio Grande, RS, CEP 96210-900, Brazil.
- Laboratório de Cultura Celular, Instituto de Ciências Biológicas, Universidade Federal Do Rio Grande-FURG, Rio Grande, RS, Brazil.
| | - Magno da Silva Marques
- Programa de Pós-Graduação Em Ciências Fisiológicas, Instituto de Ciências Biológicas, Universidade Federal Do Rio Grande-FURG, Av. Itália, Km 8, Rio Grande, RS, CEP 96210-900, Brazil
- Laboratório de Neurociências, Instituto de Ciências Biológicas, Universidade Federal Do Rio Grande-FURG, Rio Grande, RS, Brazil
| | - Aline Portantiolo Lettnin
- Programa de Pós-Graduação Em Ciências Fisiológicas, Instituto de Ciências Biológicas, Universidade Federal Do Rio Grande-FURG, Av. Itália, Km 8, Rio Grande, RS, CEP 96210-900, Brazil
- Laboratório de Cultura Celular, Instituto de Ciências Biológicas, Universidade Federal Do Rio Grande-FURG, Rio Grande, RS, Brazil
| | - Ana Paula de Souza Votto
- Programa de Pós-Graduação Em Ciências Fisiológicas, Instituto de Ciências Biológicas, Universidade Federal Do Rio Grande-FURG, Av. Itália, Km 8, Rio Grande, RS, CEP 96210-900, Brazil
- Laboratório de Cultura Celular, Instituto de Ciências Biológicas, Universidade Federal Do Rio Grande-FURG, Rio Grande, RS, Brazil
| | - Daza de Moraes Vaz Batista Filgueira
- Programa de Pós-Graduação Em Ciências Fisiológicas, Instituto de Ciências Biológicas, Universidade Federal Do Rio Grande-FURG, Av. Itália, Km 8, Rio Grande, RS, CEP 96210-900, Brazil
- Laboratório de Cultura Celular, Instituto de Ciências Biológicas, Universidade Federal Do Rio Grande-FURG, Rio Grande, RS, Brazil
| | - Ana Paula Horn
- Programa de Pós-Graduação Em Ciências Fisiológicas, Instituto de Ciências Biológicas, Universidade Federal Do Rio Grande-FURG, Av. Itália, Km 8, Rio Grande, RS, CEP 96210-900, Brazil
- Laboratório de Neurociências, Instituto de Ciências Biológicas, Universidade Federal Do Rio Grande-FURG, Rio Grande, RS, Brazil
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De Silva P, Saad MA, Thomsen HC, Bano S, Ashraf S, Hasan T. Photodynamic therapy, priming and optical imaging: Potential co-conspirators in treatment design and optimization - a Thomas Dougherty Award for Excellence in PDT paper. J PORPHYR PHTHALOCYA 2020; 24:1320-1360. [PMID: 37425217 PMCID: PMC10327884 DOI: 10.1142/s1088424620300098] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/25/2023]
Abstract
Photodynamic therapy is a photochemistry-based approach, approved for the treatment of several malignant and non-malignant pathologies. It relies on the use of a non-toxic, light activatable chemical, photosensitizer, which preferentially accumulates in tissues/cells and, upon irradiation with the appropriate wavelength of light, confers cytotoxicity by generation of reactive molecular species. The preferential accumulation however is not universal and, depending on the anatomical site, the ratio of tumor to normal tissue may be reversed in favor of normal tissue. Under such circumstances, control of the volume of light illumination provides a second handle of selectivity. Singlet oxygen is the putative favorite reactive molecular species although other entities such as nitric oxide have been credibly implicated. Typically, most photosensitizers in current clinical use have a finite quantum yield of fluorescence which is exploited for surgery guidance and can also be incorporated for monitoring and treatment design. In addition, the photodynamic process alters the cellular, stromal, and/or vascular microenvironment transiently in a process termed photodynamic priming, making it more receptive to subsequent additional therapies including chemo- and immunotherapy. Thus, photodynamic priming may be considered as an enabling technology for the more commonly used frontline treatments. Recently, there has been an increase in the exploitation of the theranostic potential of photodynamic therapy in different preclinical and clinical settings with the use of new photosensitizer formulations and combinatorial therapeutic options. The emergence of nanomedicine has further added to the repertoire of photodynamic therapy's potential and the convergence and co-evolution of these two exciting tools is expected to push the barriers of smart therapies, where such optical approaches might have a special niche. This review provides a perspective on current status of photodynamic therapy in anti-cancer and anti-microbial therapies and it suggests how evolving technologies combined with photochemically-initiated molecular processes may be exploited to become co-conspirators in optimization of treatment outcomes. We also project, at least for the short term, the direction that this modality may be taking in the near future.
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Affiliation(s)
- Pushpamali De Silva
- Wellman Center for Photomedicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
| | - Mohammad A. Saad
- Wellman Center for Photomedicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
| | - Hanna C. Thomsen
- Wellman Center for Photomedicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
| | - Shazia Bano
- Wellman Center for Photomedicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
| | - Shoaib Ashraf
- Wellman Center for Photomedicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
| | - Tayyaba Hasan
- Wellman Center for Photomedicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
- Division of Health Sciences and Technology, Harvard University and Massachusetts Institute of Technology, Cambridge, MA 02139, USA
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13
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Linares IA, Velásquez AM, Graminha MA, de Oliveira KT, Perussi JR. Antileishmanial activity of amphiphilic chlorin derivatives mediated by photodynamic therapy. Photodiagnosis Photodyn Ther 2020; 31:101769. [DOI: 10.1016/j.pdpdt.2020.101769] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2020] [Revised: 03/31/2020] [Accepted: 04/02/2020] [Indexed: 02/07/2023]
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14
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Valli F, García Vior MC, Roguin LP, Marino J. Oxidative stress generated by irradiation of a zinc(II) phthalocyanine induces a dual apoptotic and necrotic response in melanoma cells. Apoptosis 2019; 24:119-134. [DOI: 10.1007/s10495-018-01512-w] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
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15
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Nishie H, Kataoka H, Yano S, Kikuchi JI, Hayashi N, Narumi A, Nomoto A, Kubota E, Joh T. A next-generation bifunctional photosensitizer with improved water-solubility for photodynamic therapy and diagnosis. Oncotarget 2018; 7:74259-74268. [PMID: 27708235 PMCID: PMC5342051 DOI: 10.18632/oncotarget.12366] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2016] [Accepted: 09/23/2016] [Indexed: 12/29/2022] Open
Abstract
Photodynamic therapy (PDT) exploits light interactions and photosensitizers to induce cytotoxic reactive oxygen species. Photodynamic diagnosis (PDD) uses the phenomenon of photosensitizer emitting fluorescence to distinguish some tumors from normal tissue. The standard photosensitizer used for PDD is 5-aminolevulinic acid (5-ALA), although it is not entirely satisfactory. We previously reported glucose-conjugated chlorin (G-chlorin) as a more effective photosensitizer than another widely used photosensitizer, talaporfin sodium (TS); however, G-chlorin is hydrophobic. We synthesized oligosaccharide-conjugated chlorin (O-chlorin) with improved water-solubility. We report herein on its accumulation and cytotoxicity. O-chlorin was synthesized and examined for solubility. Flow cytometric analysis was performed to evaluate O-chlorin accumulation in cancer cells. To evaluate the intracellular localization of photosensitizer, cells were stained with O-chlorin and organelle-specific fluorescent probes. We then measured the in vitro fluorescence of various photosensitizers and the half-maximal inhibitory concentrations to evaluate effects in PDD and PDT, respectively. Xenograft tumor models were established, and antitumor and visibility effects were analyzed. O-chlorin was first shown to be hydrophilic. Flow cytometry then revealed a 20- to 40-times higher accumulation of O-chlorin in cancer cells than of TS, and a 7- to 23-times greater fluorescence than 5-ALA. In vitro, the cytotoxicity of O-chlorin PDT was stronger than that of TS PDT, and O-chlorin tended to accumulate in lysosomes. In vivo, O-chlorin showed the best effect in PDT and PDD compared to other photosensitizers. O-chlorin was hydrophilic and showed excellent tumor accumulation and fluorescence. O-chlorin is promising as a next-generation bifunctional photosensitizer candidate for both PDT and PDD.
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Affiliation(s)
- Hirotada Nishie
- Departments of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan
| | - Hiromi Kataoka
- Departments of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan
| | - Shigenobu Yano
- Graduate School of Materials Science, Nara Institute of Science and Technology, Ikoma, Nara 630-0192, Japan
| | - Jun-Ichi Kikuchi
- Graduate School of Materials Science, Nara Institute of Science and Technology, Ikoma, Nara 630-0192, Japan
| | - Noriyuki Hayashi
- Departments of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan
| | - Atsushi Narumi
- Department of Organic Materials Science, Graduate School of Organic Materials Science, Yamagata University, Yamagata, Yonezawa 992-8510, Japan
| | - Akihiro Nomoto
- Department of Applied Chemistry, Graduate School of Engineering, Osaka Prefecture University, Nakaku, Sakai, Osaka 599-8531, Japan
| | - Eiji Kubota
- Departments of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan
| | - Takashi Joh
- Departments of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan
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16
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Park CK, Kim YH, Hwangbo S, Cho H. Photodynamic therapy by conjugation of cell-penetrating peptide with fluorochrome. Int J Nanomedicine 2017; 12:8185-8196. [PMID: 29184407 PMCID: PMC5689026 DOI: 10.2147/ijn.s148332] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
Photodynamic therapy (PDT) is a promising alternative therapy that could be used as an adjunct to chemotherapy and surgery for cancer, and works by destroying tissue with visible light in the presence of a photosensitizer (PS) and oxygen. The PS should restrict tissue destruction only to the tumor and be activated by light of a specific wavelength; both of these properties are required. Arginine-rich peptides, such as cell-penetrating peptides, have membrane-translocating and nuclear-localizing activities, which have led to their application in various drug delivery modalities. Protamine (Pro) is an arginine-rich peptide with membrane-translocating and nuclear-localizing properties. The reaction of an N-hydroxysuccinimide (NHS) ester of rhodamine (Rho) and clinical Pro was carried out in this study to yield RhoPro, and a demonstration of its phototoxicity, wherein clinical Pro improved the effect of PDT, was performed. The reaction between Pro and the NHS ester of Rho is a solution-phase reaction that results in the complete modification of the Pro peptides, which feature a single reactive amine at the N-terminal proline and a single carboxyl group at the C-terminal arginine. This study aimed to identify a new type of PS for PDT by in vitro and in vivo experiments and to assess the antitumor effects of PDT, using the Pro-conjugated PS, on a cancer cell line. Photodynamic cell death studies showed that the RhoPro produced has more efficient photodynamic activities than Rho alone, causing rapid light-induced cell death. The attachment of clinical Pro to Rho, yielding RhoPro, confers the membrane-internalizing activity of its arginine-rich content on the fluorochrome Rho and can induce rapid photodynamic cell death, presumably owing to light-induced cell membrane rupture. PDT using RhoPro for HT-29 cells was very effective and these findings suggest that RhoPro is a suitable candidate as a PS for solid tumors.
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Affiliation(s)
- Chul-Kyu Park
- Department of Physiology, College of Medicine, Gachon University, Incheon
| | - Yong Ho Kim
- Department of Physiology, College of Medicine, Gachon University, Incheon
| | - Suhyun Hwangbo
- School of Materials Science & Engineering, Chonnam National University, Gwangju, South Korea
| | - Hoonsung Cho
- School of Materials Science & Engineering, Chonnam National University, Gwangju, South Korea
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17
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Penjweini R, Deville S, Haji Maghsoudi O, Notelaers K, Ethirajan A, Ameloot M. Investigating the effect of poly-l-lactic acid nanoparticles carrying hypericin on the flow-biased diffusive motion of HeLa cell organelles. ACTA ACUST UNITED AC 2017; 71:104-116. [PMID: 28722126 DOI: 10.1111/jphp.12779] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2016] [Indexed: 01/04/2023]
Abstract
OBJECTIVES In this study, we investigate in human cervical epithelial HeLa cells the intracellular dynamics and the mutual interaction with the organelles of the poly-l-lactic acid nanoparticles (PLLA NPs) carrying the naturally occurring hydrophobic photosensitizer hypericin. METHODS Temporal and spatiotemporal image correlation spectroscopy was used for the assessment of the intracellular diffusion and directed motion of the nanocarriers by tracking the hypericin fluorescence. Using image cross-correlation spectroscopy and specific fluorescent labelling of endosomes, lysosomes and mitochondria, the NPs dynamics in association with the cell organelles was studied. Static colocalization experiments were interpreted according to the Manders' overlap coefficient. KEY FINDINGS Nanoparticles associate with a small fraction of the whole-organelle population. The organelles moving with NPs exhibit higher directed motion compared to those moving without them. The rate of the directed motion drops substantially after the application of nocodazole. The random component of the organelle motions is not influenced by the NPs. CONCLUSIONS Image correlation and cross-correlation spectroscopy are most appropriate to unravel the motion of the PLLA nanocarrier and to demonstrate that the rate of the directed motion of organelles is influenced by their interaction with the nanocarriers. Not all PLLA-hypericin NPs are associated with organelles.
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Affiliation(s)
- Rozhin Penjweini
- Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium.,NHLBI Laboratory of Molecular Biophysics, National Institutes of Health, Bethesda, MD, USA
| | - Sarah Deville
- Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium.,Environmental Risk and Health Unit, Flemish Institute for Technological Research, Mol, Belgium
| | - Omid Haji Maghsoudi
- Department of Bioengineering, School of Engineering, Temple University, Philadelphia, PA, USA
| | - Kristof Notelaers
- Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium.,Division of Nanoscopy, Maastricht University, Maastricht, The Netherlands
| | - Anitha Ethirajan
- Institute for Materials Research, IMO-IMOMEC, Hasselt University, Diepenbeek, Belgium
| | - Marcel Ameloot
- Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium
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18
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Conjugation of chlorins with spermine enhances phototoxicity to cancer cells in vitro. JOURNAL OF PHOTOCHEMISTRY AND PHOTOBIOLOGY B-BIOLOGY 2017; 168:175-184. [DOI: 10.1016/j.jphotobiol.2017.02.012] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/25/2016] [Accepted: 02/14/2017] [Indexed: 11/22/2022]
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van Straten D, Mashayekhi V, de Bruijn HS, Oliveira S, Robinson DJ. Oncologic Photodynamic Therapy: Basic Principles, Current Clinical Status and Future Directions. Cancers (Basel) 2017; 9:cancers9020019. [PMID: 28218708 PMCID: PMC5332942 DOI: 10.3390/cancers9020019] [Citation(s) in RCA: 603] [Impact Index Per Article: 75.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2016] [Revised: 02/10/2017] [Accepted: 02/12/2017] [Indexed: 12/12/2022] Open
Abstract
Photodynamic therapy (PDT) is a clinically approved cancer therapy, based on a photochemical reaction between a light activatable molecule or photosensitizer, light, and molecular oxygen. When these three harmless components are present together, reactive oxygen species are formed. These can directly damage cells and/or vasculature, and induce inflammatory and immune responses. PDT is a two-stage procedure, which starts with photosensitizer administration followed by a locally directed light exposure, with the aim of confined tumor destruction. Since its regulatory approval, over 30 years ago, PDT has been the subject of numerous studies and has proven to be an effective form of cancer therapy. This review provides an overview of the clinical trials conducted over the last 10 years, illustrating how PDT is applied in the clinic today. Furthermore, examples from ongoing clinical trials and the most recent preclinical studies are presented, to show the directions, in which PDT is headed, in the near and distant future. Despite the clinical success reported, PDT is still currently underutilized in the clinic. We also discuss the factors that hamper the exploration of this effective therapy and what should be changed to render it a more effective and more widely available option for patients.
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Affiliation(s)
- Demian van Straten
- Cell Biology, Department of Biology, Science Faculty, Utrecht University, Utrecht 3584 CH, The Netherlands.
| | - Vida Mashayekhi
- Cell Biology, Department of Biology, Science Faculty, Utrecht University, Utrecht 3584 CH, The Netherlands.
| | - Henriette S de Bruijn
- Center for Optical Diagnostics and Therapy, Department of Otolaryngology-Head and Neck Surgery, Erasmus Medical Center, Postbox 204, Rotterdam 3000 CA, The Netherlands.
| | - Sabrina Oliveira
- Cell Biology, Department of Biology, Science Faculty, Utrecht University, Utrecht 3584 CH, The Netherlands.
- Pharmaceutics, Department of Pharmaceutical Sciences, Science Faculty, Utrecht University, Utrecht 3584 CG, The Netherlands.
| | - Dominic J Robinson
- Center for Optical Diagnostics and Therapy, Department of Otolaryngology-Head and Neck Surgery, Erasmus Medical Center, Postbox 204, Rotterdam 3000 CA, The Netherlands.
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20
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Immobilized phthalocyanines of magnesium, aluminum, and zinc in photodynamic treatment of mesenchymal stromal cells. Russ Chem Bull 2016. [DOI: 10.1007/s11172-016-1297-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
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21
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Chen JJ, Gao LJ, Liu TJ. Photodynamic therapy with a novel porphyrin-based photosensitizer against human gastric cancer. Oncol Lett 2015; 11:775-781. [PMID: 26870283 DOI: 10.3892/ol.2015.3953] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2014] [Accepted: 10/02/2015] [Indexed: 12/26/2022] Open
Abstract
The objective of the present study was to evaluate the effects of novel porphyrin-based photosensitizer meso-5-[ρ-diethylene triamine pentaacetic acid- aminophenyl]-10,15,20-triphenyl-porphyrin (DTP)-mediated photodynamic therapy (PDT) on the HGC27 and SNU-1 human gastric cancer cell lines. The absorption spectrum of DTP was analyzed using a microplate spectrophotometer. The HGC27 or SNU-1 cells were incubated with DTP and exposed to illumination by a 650-nm laser. The experiments were divided into four groups: A blank control, cells treated with DTP without light, cells exposed to laser light without DTP and cells treated with a combination of DTP and light together. The phototoxicity of DTP was analyzed by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide assay. Cell apoptosis was detected by flow cytometry and Hoechst 33342 staining. In addition, the intracellular distribution of DTP was investigated by laser scanning confocal microscopy. DTP-PDT demonstrated marked phototoxicity towards HGC27- and SNU-1 cells. The rate of cell death increased significantly in a DTP concentration-dependent and light dose-dependent manner, with maximum mortality rates of 74.14 and 67.76%, respectively. There were significant differences between the therapeutic and control groups (P<0.01). In addition, the growth of cells treated with DTP or laser light alone was not inhibited. Further evaluation revealed that, following DTP-PDT, HGC27 and SNU-1 cells demonstrated notable apoptotic changes, including condensed chromatin, fragmented nuclei and apoptotic bodies, and the percentage of apoptotic cells was significantly higher than that of the control groups (P<0.01). Furthermore, confocal laser scanning microscopy revealed that DTP localized to the lysosomes but not mitochondria in the two types of tumor cell. In conclusion, significant phototoxicity and reduced cytotoxicity in dark conditions make the novel photosensitizer DTP a promising potential PDT drug for future use in the treatment of human gastric cancer.
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Affiliation(s)
- Jing-Jing Chen
- Department of Pharmacology of Changzhi Medical College, Changzhi, Shanxi 046000, P.R. China
| | - Li-Jing Gao
- Department of Physiology, Changzhi Medical College, Changzhi, Shanxi 046000, P.R. China
| | - Tian-Jun Liu
- Institute of Biomedical Engineering, Peking Union Medical College and Chinese Academy of Medical Sciences, Tianjin 300192, P.R. China
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22
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Vera RE, Lamberti MJ, Rivarola VA, Rumie Vittar NB. Developing strategies to predict photodynamic therapy outcome: the role of melanoma microenvironment. Tumour Biol 2015; 36:9127-36. [PMID: 26419592 DOI: 10.1007/s13277-015-4059-x] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2015] [Accepted: 09/04/2015] [Indexed: 02/07/2023] Open
Abstract
Melanoma is among the most aggressive and treatment-resistant human skin cancer. Photodynamic therapy (PDT), a minimally invasive therapeutic modality, is a promising approach to treating melanoma. It combines a non-toxic photoactivatable drug called photosensitizer with harmless visible light to generate reactive oxygen species which mediate the antitumor effects. The aim of this review was to compile the available data about PDT on melanoma. Our comparative analysis revealed a disconnection between several hypotheses generated by in vitro therapeutic studies and in vivo and clinical assays. This fact led us to highlight new preclinical experimental platforms that mimic the complexity of tumor biology. The tumor and its stromal microenvironment have a dynamic and reciprocal interaction that plays a critical role in tumor resistance, and these interactions can be exploited for novel therapeutic targets. In this sense, we review two strategies used by photodynamic researchers: (a) developing 3D culture systems which mimic tumor architecture and (b) heterotypic cultures that resemble tumor microenvironment to favor therapeutic regimen design. After this comprehensive review of the literature, we suggest that new complementary preclinical models are required to better optimize the clinical outcome of PDT on skin melanoma.
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Affiliation(s)
- Renzo Emanuel Vera
- Biología Molecular, Universidad Nacional de Río Cuarto, Ruta 36 Km 601, Río Cuarto, 5800, Córdoba, Argentina
| | - María Julia Lamberti
- Biología Molecular, Universidad Nacional de Río Cuarto, Ruta 36 Km 601, Río Cuarto, 5800, Córdoba, Argentina
| | - Viviana Alicia Rivarola
- Biología Molecular, Universidad Nacional de Río Cuarto, Ruta 36 Km 601, Río Cuarto, 5800, Córdoba, Argentina
| | - Natalia Belén Rumie Vittar
- Biología Molecular, Universidad Nacional de Río Cuarto, Ruta 36 Km 601, Río Cuarto, 5800, Córdoba, Argentina.
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23
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Chen JJ, Hong G, Gao LJ, Liu TJ, Cao WJ. In vitro and in vivo antitumor activity of a novel porphyrin-based photosensitizer for photodynamic therapy. J Cancer Res Clin Oncol 2015; 141:1553-61. [PMID: 25609073 DOI: 10.1007/s00432-015-1918-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2014] [Accepted: 01/12/2015] [Indexed: 01/09/2023]
Abstract
PURPOSE Photodynamic therapy (PDT) is a promising treatment in cancer therapy, based on the use of a photosensitizer activated by visible light in the presence of oxygen. Nowadays significant research efforts have been focused on finding a new photosensitizer. In the present paper, the antitumor effects of a novel porphyrin-based photosensitizer, {Carboxymethyl-[2-(carboxymethyl-{[4-(10,15,20-triphenylporphyrin-5-yl)-phenylcarbamoyl]-methyl}-amino)-ethyl]-amino}-acetic acid (ATPP-EDTA) on two types of human malignant tumor cells in vitro and a gastric cancer model in nude mice, were evaluated. METHODS The PDT efficacy with ATPP-EDTA in vitro was assessed by MTT assay. The intracellular accumulation was detected with fluorescence spectrometer, and the intracellular distribution was determined by laser scanning confocal microscopy. The mode of cell death was investigated by Hoechst 33342 staining and flow cytometer. BGC823-derived xenograft tumor model was established to explore the in vivo antitumor effects of ATPP-EDTA. RESULTS ATPP-EDTA exhibited intense phototoxicity on both cell lines in vitro in concentration- and light dose-dependent manners meanwhile imposing minimal dark cytotoxicity. The accumulation of ATPP-EDTA in two malignant cell lines was time-dependent and prior compared to normal cells. It was mainly localized at lysosomes, but induced cell death by apoptotic pathway. ATPP-EDTA significantly inhibited the growth of BGC823 tumors in nude mice (160 mW/cm(2), 100 J/cm(2)). CONCLUSIONS Present studies suggest that ATPP-EDTA is an effective photosensitizer for PDT to tumors. It distributed in lysosomes and caused cell apoptosis. ATPP-EDTA, as a novel photosensitizer, has a great potential for human gastric cancer treatment in PDT and deserves further investigations.
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Affiliation(s)
- Jing-Jing Chen
- Central Laboratory of Heping Hospital, Changzhi Medical College, Changzhi City, 046000, Shanxi Province, People's Republic of China
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Castano AP, Demidova TN, Hamblin MR. Mechanisms in photodynamic therapy: part two-cellular signaling, cell metabolism and modes of cell death. Photodiagnosis Photodyn Ther 2014; 2:1-23. [PMID: 25048553 DOI: 10.1016/s1572-1000(05)00030-x] [Citation(s) in RCA: 503] [Impact Index Per Article: 45.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2005] [Revised: 03/09/2005] [Accepted: 03/09/2005] [Indexed: 12/29/2022]
Abstract
Photodynamic therapy (PDT) has been known for over a hundred years, but is only now becoming widely used. Originally developed as a tumor therapy, some of its most successful applications are for non-malignant disease. In the second of a series of three reviews, we will discuss the mechanisms that operate in PDT on a cellular level. In Part I [Castano AP, Demidova TN, Hamblin MR. Mechanism in photodynamic therapy: part one-photosensitizers, photochemistry and cellular localization. Photodiagn Photodyn Ther 2004;1:279-93] it was shown that one of the most important factors governing the outcome of PDT, is how the photosensitizer (PS) interacts with cells in the target tissue or tumor, and the key aspect of this interaction is the subcellular localization of the PS. PS can localize in mitochondria, lysosomes, endoplasmic reticulum, Golgi apparatus and plasma membranes. An explosion of investigation and explorations in the field of cell biology have elucidated many of the pathways that mammalian cells undergo when PS are delivered in tissue culture and subsequently illuminated. There is an acute stress response leading to changes in calcium and lipid metabolism and production of cytokines and stress proteins. Enzymes particularly, protein kinases, are activated and transcription factors are expressed. Many of the cellular responses are centered on mitochondria. These effects frequently lead to induction of apoptosis either by the mitochondrial pathway involving caspases and release of cytochrome c, or by pathways involving ceramide or death receptors. However, under certain circumstances cells subjected to PDT die by necrosis. Although there have been many reports of DNA damage caused by PDT, this is not thought to be an important cell-death pathway. This mechanistic research is expected to lead to optimization of PDT as a tumor treatment, and to rational selection of combination therapies that include PDT as a component.
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Affiliation(s)
- Ana P Castano
- BAR314B, Wellman Center for Photomedicine, Massachusetts General Hospital, 50 Blossom Street, Bartlett 3, Boston, MA 02114, USA; Department of Dermatology, Harvard Medical School, USA
| | - Tatiana N Demidova
- BAR314B, Wellman Center for Photomedicine, Massachusetts General Hospital, 50 Blossom Street, Bartlett 3, Boston, MA 02114, USA; Department of Cellular, Molecular and Developmental Biology, Tufts University, USA
| | - Michael R Hamblin
- BAR314B, Wellman Center for Photomedicine, Massachusetts General Hospital, 50 Blossom Street, Bartlett 3, Boston, MA 02114, USA; Department of Dermatology, Harvard Medical School, USA
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25
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Castano AP, Demidova TN, Hamblin MR. Mechanisms in photodynamic therapy: part one-photosensitizers, photochemistry and cellular localization. Photodiagnosis Photodyn Ther 2014; 1:279-93. [PMID: 25048432 DOI: 10.1016/s1572-1000(05)00007-4] [Citation(s) in RCA: 1375] [Impact Index Per Article: 125.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2004] [Revised: 01/11/2005] [Accepted: 01/27/2005] [Indexed: 10/25/2022]
Abstract
The use of non-toxic dyes or photosensitizers (PS) in combination with harmless visible light that is known as photodynamic therapy (PDT) has been known for over a hundred years, but is only now becoming widely used. Originally developed as a tumor therapy, some of its most successful applications are for non-malignant disease. In a series of three reviews we will discuss the mechanisms that operate in the field of PDT. Part one discusses the recent explosion in discovery and chemical synthesis of new PS. Some guidelines on how to choose an ideal PS for a particular application are presented. The photochemistry and photophysics of PS and the two pathways known as Type I (radicals and reactive oxygen species) and Type II (singlet oxygen) photochemical processes are discussed. To carry out PDT effectively in vivo, it is necessary to ensure sufficient light reaches all the diseased tissue. This involves understanding how light travels within various tissues and the relative effects of absorption and scattering. The fact that most of the PS are also fluorescent allows various optical imaging and monitoring strategies to be combined with PDT. The most important factor governing the outcome of PDT is how the PS interacts with cells in the target tissue or tumor, and the key aspect of this interaction is the subcellular localization of the PS. Examples of PS that localize in mitochondria, lysosomes, endoplasmic reticulum, Golgi apparatus and plasma membranes are given. Finally the use of 5-aminolevulinic acid as a natural precursor of the heme biosynthetic pathway, stimulates accumulation of the PS protoporphyrin IX is described.
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Affiliation(s)
- Ana P Castano
- Wellman Center for Photomedicine, Massachusetts General Hospital, 40 Blossom Street, Bartlett 3, Boston, MA 02114, USA; Department of Dermatology, Harvard Medical School, USA
| | - Tatiana N Demidova
- Wellman Center for Photomedicine, Massachusetts General Hospital, 40 Blossom Street, Bartlett 3, Boston, MA 02114, USA; Department of Cellular, Molecular and Developmental Biology, Tufts University, USA
| | - Michael R Hamblin
- Wellman Center for Photomedicine, Massachusetts General Hospital, 40 Blossom Street, Bartlett 3, Boston, MA 02114, USA; Department of Dermatology, Harvard Medical School, USA
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26
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Udartseva OO, Andreeva ER, Buravkova LB. Effects of photodynamic treatment on mesenchymal stromal cells. DOKLADY BIOLOGICAL SCIENCES : PROCEEDINGS OF THE ACADEMY OF SCIENCES OF THE USSR, BIOLOGICAL SCIENCES SECTIONS 2013; 450:185-8. [PMID: 23821063 DOI: 10.1134/s0012496613030174] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/05/2013] [Indexed: 11/23/2022]
Affiliation(s)
- O O Udartseva
- Institute of Biomedical Problems, Russian Academy of Sciences, Moscow, Russia
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Novel nanostructural photosensitizers for photodynamic therapy: in vitro studies. Int J Pharm 2012; 430:129-40. [PMID: 22525077 DOI: 10.1016/j.ijpharm.2012.04.016] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2011] [Revised: 03/16/2012] [Accepted: 04/05/2012] [Indexed: 11/22/2022]
Abstract
Photosensitizing properties of 5,10,15,20-tetrakis(4-hydroxyphenyl)porphyrin (p-THPP) functionalized by covalent attachment of one chain of poly(ethylene glycol) (PEG) with a molecular weight of 350, 2000, or 5000 Da (p-THPP-PEG(350), p-THPP-PEG(2000), p-THPP-PEG(5000)) were studied in vitro. Dark and photo cytotoxicity of these photosensitizers delivered in solution or embedded in liposomes were evaluated on two cell lines: a human colorectal carcinoma cell line (HCT 116) and a prostate cancer cell line (DU 145), and compared with these treated with free p-THPP. The attachment of PEG chains results in the pronounced reduction of the dark cytotoxicity of the parent porphyrin. Cell viability tests have demonstrated that the phototoxicity of pegylated porphyrins is dependent on the length of PEG chain and p-THPP-PEG(2000) exhibited the highest photodynamic efficacy for both cell lines. The encapsulation into liposomes did not improve the PDT effect. However, the liposomal formulation of p-THPP-PEG(2000) showed a greater tendency to induce apoptosis in both cell lines than the parent or pegylated porphyrin delivered in solution. The colocalization of p-THPP, p-THPP-PEG(2000) and p-THPP-PEG(2000) enclosed in liposomes with fluorescent markers for lysosomes, mitochondria, endoplasmatic reticulum (ER) and Golgi apparatus (GA) was determined in the HCT 116 line. The p-THPP exhibited ubiquitous intracellular distribution with a preference for membranes: mitochondria, ER, GA, lysosomes and plasma membrane. Fluorescence of p-THPP-PEG(2000) was observed within the cytoplasm, with a stronger signal detected in membranous organelle: mitochondria, ER, GA and lysosomes. In contrast, p-THPP-PEG(2000) delivered in liposomes gave a distinct lysosomal pattern of localization.
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Indocyanine green-based photodynamic therapy with 785nm light emitting diode for oral squamous cancer cells. Photodiagnosis Photodyn Ther 2011; 8:337-42. [DOI: 10.1016/j.pdpdt.2011.06.002] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2010] [Revised: 06/11/2011] [Accepted: 06/14/2011] [Indexed: 11/23/2022]
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Carneiro ZA, de Moraes JCB, Rodrigues FP, de Lima RG, Curti C, da Rocha ZN, Paulo M, Bendhack LM, Tedesco AC, Formiga ALB, da Silva RS. Photocytotoxic activity of a nitrosyl phthalocyanine ruthenium complex — A system capable of producing nitric oxide and singlet oxygen. J Inorg Biochem 2011; 105:1035-43. [DOI: 10.1016/j.jinorgbio.2011.04.011] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2011] [Revised: 04/22/2011] [Accepted: 04/25/2011] [Indexed: 12/14/2022]
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Mroz P, Yaroslavsky A, Kharkwal GB, Hamblin MR. Cell death pathways in photodynamic therapy of cancer. Cancers (Basel) 2011; 3:2516-39. [PMID: 23914299 PMCID: PMC3729395 DOI: 10.3390/cancers3022516] [Citation(s) in RCA: 449] [Impact Index Per Article: 32.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2011] [Revised: 04/26/2011] [Accepted: 05/03/2011] [Indexed: 02/06/2023] Open
Abstract
Photodynamic therapy (PDT) is an emerging cancer therapy that uses the combination of non-toxic dyes or photosensitizers (PS) and harmless visible light to produce reactive oxygen species and destroy tumors. The PS can be localized in various organelles such as mitochondria, lysosomes, endoplasmic reticulum, Golgi apparatus and plasma membranes and this sub-cellular location governs much of the signaling that occurs after PDT. There is an acute stress response that leads to changes in calcium and lipid metabolism and causes the production of cytokines and stress response mediators. Enzymes (particularly protein kinases) are activated and transcription factors are expressed. Many of the cellular responses center on mitochondria and frequently lead to induction of apoptosis by the mitochondrial pathway involving caspase activation and release of cytochrome c. Certain specific proteins (such as Bcl-2) are damaged by PDT-induced oxidation thereby increasing apoptosis, and a build-up of oxidized proteins leads to an ER-stress response that may be increased by proteasome inhibition. Autophagy plays a role in either inhibiting or enhancing cell death after PDT.
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Affiliation(s)
- Pawel Mroz
- Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, MA 02114, USA; E-Mails: (A.Y.); (G.K.); (M.R.H.)
- Department of Dermatology, Harvard Medical School, Boston, MA 02114, USA
| | - Anastasia Yaroslavsky
- Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, MA 02114, USA; E-Mails: (A.Y.); (G.K.); (M.R.H.)
- Boston University College of Engineering, Boston, MA 02114, USA
| | - Gitika B Kharkwal
- Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, MA 02114, USA; E-Mails: (A.Y.); (G.K.); (M.R.H.)
- Department of Dermatology, Harvard Medical School, Boston, MA 02114, USA
| | - Michael R. Hamblin
- Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, MA 02114, USA; E-Mails: (A.Y.); (G.K.); (M.R.H.)
- Department of Dermatology, Harvard Medical School, Boston, MA 02114, USA
- Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA 02139, USA
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Parent N, Scherer M, Liebisch G, Schmitz G, Bertrand R. Protein kinase C-δ isoform mediates lysosome labilization in DNA damage-induced apoptosis. Int J Oncol 2010; 38:313-24. [PMID: 21174057 DOI: 10.3892/ijo.2010.881] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2010] [Accepted: 11/05/2010] [Indexed: 11/05/2022] Open
Abstract
A lysosomal pathway, characterized by the partial rupture or labilization of lysosomal membranes (LLM) and cathepsin release into the cytosol, is evoked during the early events of 20-S-camptothecin lactone (CPT)-induced apoptosis in human cancer cells, including human histiocytic lymphoma U-937 cells. These lysosomal events begin rapidly and simultaneously with mitochondrial permeabilization and caspase activation within 3 h after drug treatment. Recently, in a comparative proteomics analysis performed on highly-enriched lysosomal extracts, we identified proteins whose translocation to lysosomes correlated with LLM induction after CPT treatment, including protein kinase C-δ (PKC-δ). In this study, we show that the PKC-δ translocation to lysosomes is required for LLM, as silencing its expression with RNA interference or suppressing its activity with the inhibitor, rottlerin, prevents CPT-induced LLM. PKC-δ translocation to lysosomes is associated with lysosomal acidic sphingomyelinase (ASM) phosphorylation and activation, which in turn leads to an increase in ceramide (CER) content in lysosomes. The accumulation of endogenous CER in lysosomes is a critical event for CPT-induced LLM as suppressing PKC-δ or ASM activity reduces both the CPT-mediated CER generation in lysosomes and CPT-induced LLM. These findings reveal a novel mechanism by which PKC-δ mediates ASM phosphorylation/activation and CER accumulation in lysosomes in CPT-induced LLM, rapidly activating the lysosomal pathway of apoptosis after CPT treatment.
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Affiliation(s)
- Nicolas Parent
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Hôpital Notre-Dame and Institut du Cancer de Montréal, Montreal, QC H2L 4M1, Canada
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Combating melanoma: the use of photodynamic therapy as a novel, adjuvant therapeutic tool. Cancer Treat Rev 2010; 37:465-75. [PMID: 21168280 DOI: 10.1016/j.ctrv.2010.11.007] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2010] [Revised: 11/23/2010] [Accepted: 11/24/2010] [Indexed: 11/21/2022]
Abstract
Metastatic malignant melanoma remains one of the most dreaded skin cancers worldwide. Numerous factors contribute to its resistance to hosts of treatment regimes and despite significant scientific advances over the last decade in the field of chemotherapeutics and melanocytic targets, there still remains the need for improved therapeutic modalities. Photodynamic therapy, a minimally invasive therapeutic modality has been shown to be effective in a number of oncologic and non-oncologic conditions. Using second-generation stable, lipophilic photosensitizers with optimised wavelengths, PDT may be a promising tool for adjuvant therapy in combating melanoma. Potential targets for PDT in melanoma eradication include cell proliferation inhibition, activation of cell death and reduction in pro-survival autophagy and a decrease in the cellular melanocytic antioxidant system. This review highlights the current knowledge with respect to these characteristics and suggests that PDT be considered as a good candidate for adjuvant treatment in post-resected malignant metastatic melanoma. Furthermore, it suggests that primary consideration must be given to organelle-specific destruction in melanoma specifically targeting the melanosomes - the one organelle that is specific to cells of the melanocytic lineage that houses the toxic compound, melanin. We believe that using this combined knowledge may eventually lead to an effective therapeutic tool to combat this highly intractable disease.
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Ji ZY, Fan TL, Zhao LQ, Yang XJ, Qiu YB, Zhang JZ, Zhang YB, Sun Y, Qiu SL, Yang GR. Effects of subcellular localization pattern of PpIX on photodynamic efficiency in esophageal cancer cells. Shijie Huaren Xiaohua Zazhi 2009; 17:1602-1608. [DOI: 10.11569/wcjd.v17.i16.1602] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To study the effects of subcellular localization pattern of PpIX on photodynamic efficiency in esophageal cancer cell lines.
METHODS: KYSE-450, KYSE-70 and Het-1A cells were treated with ALA, exogenous PpIX and MitoTracker, respectively. The subcellular localization patterns of PpIX were observed using fluorescence microscopy. Mitochondrial transmembrane potential (ΔΨm) after ALA-PDT and PpIX-PDT was measured using JC-1 flow cytometry. The morphological study of mitochondria after ALA-PDT and PpIX-PDT was performed with electron microscopy. MTS was used to examine the cell survival rate.
RESULTS: The granular patterns and distribution of fluorescence in the extranuclear fraction of the cells were similar for both ALA-derived endogenous PpIX and the MitoTracker in all cell lines; however, exogenous PpIX was diffusely distributed in the whole cytoplasm of cells. After 12 h of ALA-based PDT, the percentages were increased to 22%, 52% and 33% in the KYSE-450, KYSE-70 and Het-1A cell lines, respectively; where only 15%, 14% and 18% of the depolarized cell fractions were seen following PDT with exogenous PpIX. As early as 1 h after photodynamic treatment, some of the mitochondria were already damaged by ALA-PDT with unclear cristae, vacuoles and swelling; while the mitochondrial ultrastructure was still well preserved 1 h later following PDT with exogenous PpIX. ALA-mediated PDT was significantly more efficient than PDT with exogenous PpIX in killing cells in all the 3 cell lines.
CONCLUSION: Different subcellular location of photosensitizer may affect the PDT efficacy. Mitochondria are more sensitive and may be important targets for PDT. This finding suggests that new photosensitizers with mitochondrially-localizing property may be designed for improvement of PDT effectiveness in the future.
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Vittar NBR, Prucca CG, Strassert C, Awruch J, Rivarola VA. Cellular inactivation and antitumor efficacy of a new zinc phthalocyanine with potential use in photodynamic therapy. Int J Biochem Cell Biol 2008; 40:2192-205. [DOI: 10.1016/j.biocel.2008.02.024] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2007] [Revised: 02/18/2008] [Accepted: 02/27/2008] [Indexed: 01/23/2023]
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Mitsunaga M, Tsubota A, Nariai K, Namiki Y, Sumi M, Yoshikawa T, Fujise K. Early apoptosis and cell death induced by ATX-S10Na (II)-mediated photodynamic therapy are Bax- and p53-dependent in human colon cancer cells. World J Gastroenterol 2007; 13:692-8. [PMID: 17278191 PMCID: PMC4066001 DOI: 10.3748/wjg.v13.i5.692] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the roles of Bax and p53 proteins in photosensitivity of human colon cancer cells by using lysosome-localizing photosensitizer, ATX-S10Na (II).
METHODS: HCT116 human colon cancer cells and Bax-null or p53-null isogenic derivatives were irradiated with a diode laser. Early apoptosis and cell death in response to photodynamic therapy were determined by MTT assays, annexin V assays, transmission electron microscopy assays, caspase assays and western blotting.
RESULTS: Induction of early apoptosis and cell death was Bax- and p53-dependent. Bax and p53 were required for caspase-dependent apoptosis. The levels of anti-apoptotic Bcl-2 family proteins, Bcl-2 and Bcl-xL, were decreased in Bax- and p53-independent manner.
CONCLUSION: Our results indicate that early apoptosis and cell death of human colon cancer cells induced by photodynamic therapy with lysosome-localizing photosensitizer ATX-S10Na (II) are mediated by p53-Bax network and low levels of Bcl-2 and Bcl-xL proteins. Our results might help in formulating new therapeutic approaches in photodynamic therapy.
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Affiliation(s)
- Makoto Mitsunaga
- Institute of Clinical Medicine and Research, Jikei University School of Medicine, 163-1 Kashiwa-shita, Kashiwa, Chiba 277-8567, Japan
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McLaughlin N, Annabi B, Lachambre MP, Kim KS, Bahary JP, Moumdjian R, Béliveau R. Combined low dose ionizing radiation and green tea-derived epigallocatechin-3-gallate treatment induces human brain endothelial cells death. J Neurooncol 2006; 80:111-21. [PMID: 16715350 DOI: 10.1007/s11060-006-9171-8] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2006] [Accepted: 03/30/2006] [Indexed: 12/31/2022]
Abstract
The microvasculature of brain tumors has been proposed as the primary target for ionizing radiation (IR)-induced apoptosis. However, the contribution of low dose IR-induced non-apoptotic cell death pathways has not been investigated. This study aimed to characterize the effect of IR on human brain microvascular endothelial cells (HBMEC) and to assess the combined effect of epigallocatechin-3-gallate (EGCg), a green tea-derived anti-angiogenic molecule. HBMEC were treated with EGCg, irradiated with a sublethal (< or =10 Gy) single dose. Cell survival was assessed 48 h later by nuclear cell counting and Trypan blue exclusion methods. Cell cycle distribution and DNA fragmentation were evaluated by flow cytometry (FC), cell death was assessed by fluorimetric caspase-3 activity, FC and immunoblotting for pro-apoptotic proteins. While low IR doses alone reduced cell survival by 30%, IR treatment was found more effective in EGCg pretreated-cells reaching 70% cell death. Analysis of cell cycle revealed that IR-induced cell accumulation in G2-phase. Expression of cyclin-dependent kinase inhibitors p21(CIP/Waf1) and p27(Kip) were increased by EGCg and IR. Although random DNA fragmentation increased by approximately 40% following combined EGCg/IR treatments, the synergistic reduction of cell survival was not related to increased pro-apoptotic caspase-3, caspase-9 and cytochrome C proteins. Cell necrosis increased 5-fold following combined EGCg/IR treatments while no changes in early or late apoptosis were observed. Our results suggest that the synergistic effects of combined EGCg/IR treatments may be related to necrosis, a non-apoptotic cell death pathway. Strategies sensitizing brain tumor-derived EC to IR may enhance the efficacy of radiotherapy and EGCg may represent such a potential agent.
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Affiliation(s)
- Nancy McLaughlin
- Laboratoire de Médecine Moléculaire, Centre de Cancérologie Charles-Bruneau, Hôpital Sainte-Justine-UQAM, Montréal, Québec, Canada
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Kramer-Marek G, Serpa C, Szurko A, Widel M, Sochanik A, Snietura M, Kus P, Nunes RMD, Arnaut LG, Ratuszna A. Spectroscopic properties and photodynamic effects of new lipophilic porphyrin derivatives: efficacy, localisation and cell death pathways. JOURNAL OF PHOTOCHEMISTRY AND PHOTOBIOLOGY B-BIOLOGY 2006; 84:1-14. [PMID: 16495073 DOI: 10.1016/j.jphotobiol.2005.12.011] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/26/2005] [Revised: 12/07/2005] [Accepted: 12/11/2005] [Indexed: 11/26/2022]
Abstract
Photodynamic therapy (PDT) and photodynamic diagnostics (PDD) of cancer are based on the use of non-toxic dyes (photosensitisers) in combination with harmless visible light. This paper reports physicochemical properties, cell uptake, localisation as well as photodynamic efficiency of two novel lipophilic porphyrin derivatives, suitable for use as PDT sensitisers. Both compounds are characterised by high quantum yield of singlet oxygen generation which was measured by time-resolved phosphorescence. Photodynamic in vitro studies were conducted on three cancer cell lines. Results of cell survival tests showed negligible dark cytotoxicity but high phototoxicity. The results also indicate that cell death is dependent on energy dose and time following light exposure. Using confocal laser scanning microscopy both compounds were found to localise in the cytoplasm around the nucleus of the tumour cells. The mode of cell death was evaluated based on the morphological changes after differential staining. In summary, good photostability, high quantum yield of singlet oxygen and biological effectiveness indicate that the examined lipophilic porphyrin derivatives offer quite interesting prospects of photodynamic therapy application.
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Affiliation(s)
- Gabriela Kramer-Marek
- A.Chelkowski Institute of Physics, University of Silesia, Uniwersytecka 4, 40-007 Katowice, Poland.
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Miyazawa S, Nishida K, Komiyama T, Nakae Y, Takeda K, Yorimitsu M, Kitamura A, Kunisada T, Ohtsuka A, Inoue H. Novel transdermal photodynamic therapy using ATX-S10·Na(II) induces apoptosis of synovial fibroblasts and ameliorates collagen antibody-induced arthritis in mice. Rheumatol Int 2005; 26:717-25. [PMID: 16220291 DOI: 10.1007/s00296-005-0052-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2005] [Accepted: 08/18/2005] [Indexed: 10/25/2022]
Abstract
We aimed to test the effect of transdermal photodynamic therapy (PDT) on synovial proliferation in vitro and in vivo, using a novel photosensitizer, ATX-S10.Na(II). Synovial fibroblasts were obtained from patients with RA (RASF). Cell viability with or without PDT was determined by MTT assay. Cell morphology was examined by light and transmission electron microscopy. DNA fragmentation was labeled by TUNEL stain. Collagen antibody-induced arthritis (CAIA) was induced in DBA/1 mice, and the effects of transdermal PDT were evaluated by clinical and histological examination. PDT showed drug concentration-dependent and laser dose-dependent cytotoxicity on RASF. TUNEL stain and TEM study revealed the induction of apoptotic cell death of RASF. Transdermal PDT significantly reduced clinical arthritis and synovial inflammation in this model of arthritis. These results suggest that transdermal PDT using ATX-S10.Na(II) might be a novel less invasive treatment strategy for small joint arthritis and tenosynovitis.
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Affiliation(s)
- S Miyazawa
- Department of Orthopaedic Surgery, Science of Functional Recovery and Reconstruction, Okayama University Graduate School of Medicine and Dentistry, 2-5-1 Shikata-cho, 700-8558, Okayama University Hospital, Japan
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Córdoba F, Braathen LR, Weissenberger J, Vallan C, Kato M, Nakashima I, Weis J, von Felbert V. 5-aminolaevulinic acid photodynamic therapy in a transgenic mouse model of skin melanoma. Exp Dermatol 2005; 14:429-37. [PMID: 15885078 DOI: 10.1111/j.0906-6705.2005.00303.x] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Photodynamic therapy (PDT) is widely used to treat preneoplastic skin lesions and non-melanoma skin tumours. Studies analyzing the effects of PDT on malignant melanoma have yielded conflicting results. On the one hand, melanoma cell lines in culture as well as cell lines transplanted into experimental animals were sensitive to PDT. On the other hand, spontaneous melanomas of human patients responded poorly to most PDT regimens tested so far. Here, we analyzed effects of 5-aminolaevulinic acid (5-ALA)-based PDT on melanoma cell lines and on experimental melanomas. To mimic the clinical situation as closely as possible, metallothionein-I/ret (MT-ret) mice, a transgenic model of skin melanoma development, were used. Optimal doses of 5-ALA as well as energy doses and power densities were determined in vitro using a cell line (Mel25) established by us from a melanoma of an MT-ret transgenic mouse as well as commercially available human and mouse melanoma cell lines. Treatment with light irradiation alone had no effect. In combination with 5-ALA, however, this illumination readily induced the death of all mouse and human melanoma cell lines examined. Still, 5-ALA PDT caused only minor focal regressive changes including haemorrhages and fibrosis of MT-ret melanomas in vivo and did not significantly delay tumour growth. These results show that, even though MT-ret melanoma cells are vulnerable to 5-ALA PDT in vitro, malignant MT-ret melanomas in vivo are quite resistant to this type of therapy at doses which are highly effective in vitro.
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Affiliation(s)
- F Córdoba
- Division of Neuropathology, Institute of Pathology, University of Bern, Murtenstrasse, Bern, Switzerland
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