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Rajan SS, Merlin JPJ, Abrahamse H. Breaking the Resistance: Photodynamic Therapy in Cancer Stem Cell-Driven Tumorigenesis. Pharmaceutics 2025; 17:559. [PMID: 40430852 PMCID: PMC12115314 DOI: 10.3390/pharmaceutics17050559] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2025] [Revised: 04/11/2025] [Accepted: 04/21/2025] [Indexed: 05/29/2025] Open
Abstract
Cancer stem cells (CSCs) are essential for the growth of malignancies because they encourage resistance to cancer therapy and make metastasis and relapse easier. To effectively tackle the obstacles presented by CSCs, novel therapeutic approaches are required. Photodynamic therapy (PDT) is a promising treatment option for cancer cells, which uses light-sensitive medications that are activated by light wavelengths. This review investigates the use of PDT to overcome malignancies driven by CSCs that have innate resistance mechanisms. PDT works by causing tumor cells to accumulate photosensitizers (PSs) selectively. The reactive oxygen species (ROS), which kill cells, are released by these PSs when they are stimulated by light. According to recent developments in PDT, its efficacy may go beyond traditional tumor cells, providing a viable remedy for the resistance shown by CSCs. Researchers want to improve the targeted elimination and selective targeting of CSCs by combining PDT with new PSs and customized delivery systems. Studies emphasize how PDT affects CSCs as well as bulk tumor cells. According to studies, PDT not only limits CSC growth but also modifies their microenvironment, which lowers the possibility of recovery. Additionally, studies are being conducted on the utilization of PDT and immunotherapeutic techniques to improve treatment efficacy and overcome inherent resistance of CSCs. In conclusion, PDT is a viable strategy for treating carcinogenesis driven by CSCs. By applying the most recent advancements in PDT technologies and recognizing how it interacts with CSCs, this treatment has the potential to surpass traditional resistance mechanisms and improve the future of cancer patients. Clinical and preclinical studies highlight that combining PDT with CSC-targeted approaches has the potential to overcome current therapy limitations. Future efforts should focus on clinical validation, optimizing light delivery and PS use, and developing effective combination strategies to target CSCs.
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Affiliation(s)
- Sheeja S. Rajan
- Laser Research Centre, Faculty of Health Sciences, University of Johannesburg, Doornfontein, P.O. Box 17011, Johannesburg 2028, South Africa; (J.P.J.M.); (H.A.)
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2
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Spring BQ, Watanabe K, Ichikawa M, Mallidi S, Matsudaira T, Timerman D, Swain JWR, Mai Z, Wakimoto H, Hasan T. Red light-activated depletion of drug-refractory glioblastoma stem cells and chemosensitization of an acquired-resistant mesenchymal phenotype. Photochem Photobiol 2025; 101:215-229. [PMID: 38922889 PMCID: PMC11664018 DOI: 10.1111/php.13985] [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: 05/08/2024] [Accepted: 06/09/2024] [Indexed: 06/28/2024]
Abstract
Glioblastoma stem cells (GSCs) are potent tumor initiators resistant to radiochemotherapy, and this subpopulation is hypothesized to re-populate the tumor milieu due to selection following conventional therapies. Here, we show that 5-aminolevulinic acid (ALA) treatment-a pro-fluorophore used for fluorescence-guided cancer surgery-leads to elevated levels of fluorophore conversion in patient-derived GSC cultures, and subsequent red light-activation induces apoptosis in both intrinsically temozolomide chemotherapy-sensitive and -resistant GSC phenotypes. Red light irradiation of ALA-treated cultures also exhibits the ability to target mesenchymal GSCs (Mes-GSCs) with induced temozolomide resistance. Furthermore, sub-lethal light doses restore Mes-GSC sensitivity to temozolomide, abrogating GSC-acquired chemoresistance. These results suggest that ALA is not only useful for fluorescence-guided glioblastoma tumor resection, but that it also facilitates a GSC drug-resistance agnostic, red light-activated modality to mop up the surgical margins and prime subsequent chemotherapy.
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Affiliation(s)
- Bryan Q. Spring
- Wellman Center for Photomedicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
- Department of Physics, Northeastern University, Boston, MA 02115, USA
| | - Kohei Watanabe
- Wellman Center for Photomedicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
- Healthcare Optics Research Laboratory, Canon USA, Inc., Cambridge MA 02139, USA
| | - Megumi Ichikawa
- Wellman Center for Photomedicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
| | - Srivalleesha Mallidi
- Wellman Center for Photomedicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
- Department of Biomedical Engineering, Tufts University, Medford, MA 02155, USA
| | - Tatsuyuki Matsudaira
- Wellman Center for Photomedicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
| | - Dmitriy Timerman
- Wellman Center for Photomedicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
| | - Joseph W. R. Swain
- Wellman Center for Photomedicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
| | - Zhiming Mai
- Wellman Center for Photomedicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
| | - Hiroaki Wakimoto
- Brain Tumor Research Center and Molecular Neurosurgery Laboratory, Department of Neurosurgery, 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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Aebisher D, Woźnicki P, Czarnecka-Czapczyńska M, Dynarowicz K, Szliszka E, Kawczyk-Krupka A, Bartusik-Aebisher D. Molecular Determinants for Photodynamic Therapy Resistance and Improved Photosensitizer Delivery in Glioma. Int J Mol Sci 2024; 25:8708. [PMID: 39201395 PMCID: PMC11354549 DOI: 10.3390/ijms25168708] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2024] [Revised: 08/02/2024] [Accepted: 08/06/2024] [Indexed: 09/02/2024] Open
Abstract
Gliomas account for 24% of all the primary brain and Central Nervous System (CNS) tumors. These tumors are diverse in cellular origin, genetic profile, and morphology but collectively have one of the most dismal prognoses of all cancers. Work is constantly underway to discover a new effective form of glioma therapy. Photodynamic therapy (PDT) may be one of them. It involves the local or systemic application of a photosensitive compound-a photosensitizer (PS)-which accumulates in the affected tissues. Photosensitizer molecules absorb light of the appropriate wavelength, initiating the activation processes leading to the formation of reactive oxygen species and the selective destruction of inappropriate cells. Research focusing on the effective use of PDT in glioma therapy is already underway with promising results. In our work, we provide detailed insights into the molecular changes in glioma after photodynamic therapy. We describe a number of molecules that may contribute to the resistance of glioma cells to PDT, such as the adenosine triphosphate (ATP)-binding cassette efflux transporter G2, glutathione, ferrochelatase, heme oxygenase, and hypoxia-inducible factor 1. We identify molecular targets that can be used to improve the photosensitizer delivery to glioma cells, such as the epithelial growth factor receptor, neuropilin-1, low-density lipoprotein receptor, and neuropeptide Y receptors. We note that PDT can increase the expression of some molecules that reduce the effectiveness of therapy, such as Vascular endothelial growth factor (VEGF), glutamate, and nitric oxide. However, the scientific literature lacks clear data on the effects of PDT on many of the molecules described, and the available reports are often contradictory. In our work, we highlight the gaps in this knowledge and point to directions for further research that may enhance the efficacy of PDT in the treatment of glioma.
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Affiliation(s)
- David Aebisher
- Department of Photomedicine and Physical Chemistry, Medical College of The Rzeszów University, 35-310 Rzeszów, Poland
| | - Paweł Woźnicki
- English Division Science Club, Medical College of The Rzeszów University, 35-310 Rzeszów, Poland;
| | - Magdalena Czarnecka-Czapczyńska
- Department of Internal Medicine, Angiology and Physical Medicine, Center for Laser Diagnostics and Therapy, Medical University of Silesia, Batorego 15 Street, 41-902 Bytom, Poland;
| | - Klaudia Dynarowicz
- Center for Innovative Research in Medical and Natural Sciences, Medical College of The University of Rzeszów, 35-310 Rzeszów, Poland;
| | - Ewelina Szliszka
- Department of Microbiology and Immunology, Medical University of Silesia, Poniatowskiego 15, 40-055 Katowice, Poland;
| | - Aleksandra Kawczyk-Krupka
- Department of Internal Medicine, Angiology and Physical Medicine, Center for Laser Diagnostics and Therapy, Medical University of Silesia, Batorego 15 Street, 41-902 Bytom, Poland;
| | - Dorota Bartusik-Aebisher
- Department of Biochemistry and General Chemistry, Medical College of The Rzeszów University, 35-310 Rzeszów, Poland;
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Oezen G, Kraus L, Schentarra EM, Bolten JS, Huwyler J, Fricker G. Aluminum and ABC transporter activity. ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY 2024; 108:104451. [PMID: 38648870 DOI: 10.1016/j.etap.2024.104451] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/12/2024] [Revised: 04/06/2024] [Accepted: 04/16/2024] [Indexed: 04/25/2024]
Abstract
Aluminum is the third most common element on Earth´s crust and despite its wide use in our workaday life it has been associated with several health risks after overexposure. In the present study the impact of aluminum salts upon ABC transporter activity was studied in the P-GP-expressing human blood-brain barrier cell line hCMEC/D3, in MDCKII cells overexpressing BCRP and MRP2, respectively, and in freshly isolated, functionally intact kidney tubules from Atlantic killifish (Fundulus heteroclitus), which express the analog ABC transporters, P-gp, Bcrp and Mrp2. In contrast to previous findings with heavy metals salts (cadmium(II) chloride or mercury(II) chloride), which have a strong inhibitory effect on ABC transporter activity, or zinc(II) chloride and sodium arsenite, which have a stimulatory effect upon ABC transport function, the results indicate no modulatory effect of aluminum salts on the efflux activity of the human ABC transporters P-GP, BCRP and MRP2 nor on the analog transporters P-gp, Bcrp and Mrp2.
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Affiliation(s)
- Goezde Oezen
- Institute of Pharmacy and Molecular Biotechnology, Ruprecht-Karls University, Heidelberg 69120, Germany; Mount Desert Island Biological Laboratory, Salisbury Cove, ME 04672, United States
| | - Lisa Kraus
- Institute of Pharmacy and Molecular Biotechnology, Ruprecht-Karls University, Heidelberg 69120, Germany; Mount Desert Island Biological Laboratory, Salisbury Cove, ME 04672, United States
| | - Eva-Maria Schentarra
- Institute of Pharmacy and Molecular Biotechnology, Ruprecht-Karls University, Heidelberg 69120, Germany; Mount Desert Island Biological Laboratory, Salisbury Cove, ME 04672, United States
| | - Jan Stephan Bolten
- Mount Desert Island Biological Laboratory, Salisbury Cove, ME 04672, United States; Department of Pharmaceutical Sciences, University of Basel, Basel 4056, Switzerland
| | - Joerg Huwyler
- Mount Desert Island Biological Laboratory, Salisbury Cove, ME 04672, United States; Department of Pharmaceutical Sciences, University of Basel, Basel 4056, Switzerland
| | - Gert Fricker
- Institute of Pharmacy and Molecular Biotechnology, Ruprecht-Karls University, Heidelberg 69120, Germany; Mount Desert Island Biological Laboratory, Salisbury Cove, ME 04672, United States.
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Ibarra AMC, Aguiar EMG, Ferreira CBR, Siqueira JM, Corrêa L, Nunes FD, Franco ALDS, Cecatto RB, Hamblin MR, Rodrigues MFSD. Photodynamic therapy in cancer stem cells - state of the art. Lasers Med Sci 2023; 38:251. [PMID: 37919479 DOI: 10.1007/s10103-023-03911-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Accepted: 10/14/2023] [Indexed: 11/04/2023]
Abstract
Despite significant efforts to control cancer progression and to improve oncology treatment outcomes, recurrence and tumor resistance are frequently observed in cancer patients. These problems are partly related to the presence of cancer stem cells (CSCs). Photodynamic therapy (PDT) has been developed as a therapeutic approach for solid tumors; however, it remains unclear how this therapy can affect CSCs. In this review, we focus on the effects of PDT on CSCs and the possible changes in the CSC population after PDT exposure. Tumor response to PDT varies according to the photosensitizer and light parameters employed, but most studies have reported the successful elimination of CSCs after PDT. However, some studies have reported that CSCs were more resistant to PDT than non-CSCs due to the increased efflux of photosensitizer molecules and the action of autophagy. Additionally, using different PDT approaches to target the CSCs resulted in increased sensitivity, reduction of sphere formation, invasiveness, stem cell phenotype, and improved response to chemotherapy. Lastly, although mainly limited to in vitro studies, PDT, combined with targeted therapies and/or chemotherapy, could successfully target CSCs in different solid tumors and promote the reduction of stemness, suggesting a promising therapeutic approach requiring evaluation in robust pre-clinical studies.
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Affiliation(s)
- Ana Melissa C Ibarra
- Postgraduate Program in Biophotonics Applied to Health Sciences, Nove de Julho University - UNINOVE, São Paulo, Brazil
| | | | - Cássia B R Ferreira
- Postgraduate Program in Biophotonics Applied to Health Sciences, Nove de Julho University - UNINOVE, São Paulo, Brazil
| | | | - Luciana Corrêa
- School of Dentistry, University of São Paulo - FOUSP, São Paulo, Brazil
| | - Fabio D Nunes
- School of Dentistry, University of São Paulo - FOUSP, São Paulo, Brazil
| | | | - Rebeca B Cecatto
- Postgraduate Program in Biophotonics Applied to Health Sciences, Nove de Julho University - UNINOVE, São Paulo, Brazil
| | - Michael R Hamblin
- Laser Research Centre, Faculty of Health Science, University of Johannesburg, Johannesburg, South Africa
| | - Maria Fernanda S D Rodrigues
- Postgraduate Program in Biophotonics Applied to Health Sciences, Nove de Julho University - UNINOVE, São Paulo, Brazil.
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Ancheta LR, Shramm PA, Bouajram R, Higgins D, Lappi DA. Streptavidin-Saporin: Converting Biotinylated Materials into Targeted Toxins. Toxins (Basel) 2023; 15:toxins15030181. [PMID: 36977072 PMCID: PMC10059012 DOI: 10.3390/toxins15030181] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Revised: 02/12/2023] [Accepted: 02/19/2023] [Indexed: 03/02/2023] Open
Abstract
Streptavidin-Saporin can be considered a type of ‘secondary’ targeted toxin. The scientific community has taken advantage of this conjugate in clever and fruitful ways using many kinds of biotinylated targeting agents to send saporin into a cell selected for elimination. Saporin is a ribosome-inactivating protein that causes inhibition of protein synthesis and cell death when delivered inside a cell. Streptavidin-Saporin, mixed with biotinylated molecules to cell surface markers, results in powerful conjugates that are used both in vitro and in vivo for behavior and disease research. Streptavidin-Saporin harnesses the ‘Molecular Surgery’ capability of saporin, creating a modular arsenal of targeted toxins used in applications ranging from the screening of potential therapeutics to behavioral studies and animal models. The reagent has become a well-published and validated resource in academia and industry. The ease of use and diverse functionality of Streptavidin-Saporin continues to have a significant impact on the life science industry.
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7
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Raghav PK, Mann Z. Cancer stem cells targets and combined therapies to prevent cancer recurrence. Life Sci 2021; 277:119465. [PMID: 33831426 DOI: 10.1016/j.lfs.2021.119465] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Revised: 03/01/2021] [Accepted: 03/26/2021] [Indexed: 12/12/2022]
Abstract
Cancer stem cells (CSCs) control the dynamics of tumorigenesis by self-renewal ability and differentiation potential. These properties contribute towards tumor malignancy, metastasis, cellular heterogeneity, and immune escape, which are regulated by multiple signaling pathways. The CSCs are chemoresistant and cause cancer recurrence, generally recognized as a small side-population that eventually leads to tumor relapse. Despite many treatment options available, none can be considered entirely efficient due to a lack of specificity and dose limitation. This review primarily highlights the processes involved in CSCs development and maintenance. Secondly, the current effective therapies based on stem cells, cell-free therapies that involve exosomes and miRNAs, and photodynamic therapy have been discussed. Also, the inhibitors that specifically target various signaling pathways, which can be used in combination to control CSCs kinetics have been highlighted. Conclusively, this comprehensive review is a detailed study of recently developed novel treatment strategies that will facilitate in coming up with better-targeted approaches against CSCs.
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Affiliation(s)
| | - Zoya Mann
- Independent Researcher, New Delhi, India
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8
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Wong JJW, Selbo PK. High aldehyde dehydrogenase activity does not protect colon cancer cells against TPCS 2a-sensitized photokilling. Photochem Photobiol Sci 2020; 19:308-312. [PMID: 32108197 DOI: 10.1039/c9pp00453j] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Aldehyde dehydrogenases (ALDH) are detoxifying enzymes that are upregulated in cancer stem cells (CSCs) and may cause chemo- and ionizing radiation (IR) therapy resistance. By using the ALDEFLUOR assay, CD133 + human colon cancer cells HT-29, were FACSorted into three populations: ALDHbright, ALDHdim and unsorted (bulk) and treated with chemo-, radio- or photodynamic therapy (PDT) using the clinical relevant photosensitizer disulfonated tetraphenyl chlorin (TPCS2a/fimaporfin). Here we show that there is no difference in cytotoxic responses to TPCS2a-PDT in ALHDbright, ALDHdim or bulk cancer cells. Likewise, both 5-FU and oxaliplatin chemotherapy efficacy was not reduced in ALDHbright as compared to ALDHdim cancer cells. However, we found that ALHDbright HT-29 cells are significantly less sensitive to ionizing radiation compared to ALDHdim cells. This study demonstrates that the cytotoxic response to PDT (using TPCS2a as photosensitizer) is independent of ALDH activity in HT-29 cancer cells. Our results further strengthen the use of TPCS2a to target CSCs.
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Affiliation(s)
- Judith Jing Wen Wong
- Department of Radiation Biology, Institute for Cancer Research, The Norwegian Radium Hospital Oslo University Hospital Montebello, 0379, Oslo, Norway
| | - Pål Kristian Selbo
- Department of Radiation Biology, Institute for Cancer Research, The Norwegian Radium Hospital Oslo University Hospital Montebello, 0379, Oslo, Norway
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9
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Olsen CE, Cheung LH, Weyergang A, Berg K, Vallera DA, Rosenblum MG, Selbo PK. Design, Characterization, and Evaluation of scFvCD133/rGelonin: A CD133-Targeting Recombinant Immunotoxin for Use in Combination with Photochemical Internalization. J Clin Med 2019; 9:jcm9010068. [PMID: 31888091 PMCID: PMC7019722 DOI: 10.3390/jcm9010068] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2019] [Revised: 12/17/2019] [Accepted: 12/22/2019] [Indexed: 01/02/2023] Open
Abstract
The objective of this study was to develop and explore a novel CD133-targeting immunotoxin (IT) for use in combination with the endosomal escape method photochemical internalization (PCI). scFvCD133/rGelonin was recombinantly constructed by fusing a gene (scFvCD133) encoding the scFv that targets both non-glycosylated and glycosylated forms of both human and murine CD133/prominin-1 to a gene encoding the ribosome-inactivating protein (RIP) gelonin (rGelonin). RIP-activity was assessed in a cell-free translation assay. Selective binding and intracellular accumulation of scFvCD133/rGelonin was evaluated by flow cytometry and fluorescence microscopy. PCI of scFvCD133/rGelonin was explored in CD133high and CD133low cell lines and a CD133neg cell line, where cytotoxicity was evaluated by the MTT assay. scFvCD133/rGelonin exhibited superior binding to and a higher accumulation in CD133high cells compared to CD133low cells. No cytotoxic responses were detected in either CD133high or CD133low cells after 72 h incubation with <100 nM scFvCD133/rGelonin. Despite a severe loss in RIP-activity of scFvCD133/rGelonin compared to free rGelonin, PCI of scFvCD133/rGelonin induced log-fold reduction of viability compared to PCI of rGelonin. Strikingly, PCI of scFvCD133/rGelonin exceeded the cytotoxicity of PCI of rGelonin also in CD133low cells. In conclusion, PCI promotes strong cytotoxic activity of the per se non-toxic scFvCD133/rGelonin in both CD133high and CD133low cancer cells.
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Affiliation(s)
- Cathrine Elisabeth Olsen
- Department of Radiation Biology, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, N-0310 Oslo, Norway; (C.E.O.); (A.W.); (K.B.)
| | - Lawrence H. Cheung
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (L.H.C.); (M.G.R.)
| | - Anette Weyergang
- Department of Radiation Biology, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, N-0310 Oslo, Norway; (C.E.O.); (A.W.); (K.B.)
| | - Kristian Berg
- Department of Radiation Biology, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, N-0310 Oslo, Norway; (C.E.O.); (A.W.); (K.B.)
| | - Daniel A. Vallera
- Department of Therapeutic Radiology-Radiation Oncology, University of Minnesota, Masonic Cancer Center, Minneapolis, MN 55455, USA;
| | - Michael G. Rosenblum
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (L.H.C.); (M.G.R.)
| | - Pål Kristian Selbo
- Department of Radiation Biology, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, N-0310 Oslo, Norway; (C.E.O.); (A.W.); (K.B.)
- Correspondence: ; Tel.: +47-22781469
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10
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Khot MI, Downey CL, Armstrong G, Svavarsdottir HS, Jarral F, Andrew H, Jayne DG. The role of ABCG2 in modulating responses to anti-cancer photodynamic therapy. Photodiagnosis Photodyn Ther 2019; 29:101579. [PMID: 31639455 DOI: 10.1016/j.pdpdt.2019.10.014] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2019] [Revised: 10/03/2019] [Accepted: 10/11/2019] [Indexed: 01/10/2023]
Abstract
The ATP-binding cassette (ABC) superfamily G member 2 (ABCG2) transmembrane protein transporter is known for conferring resistance to treatment in cancers. Photodynamic therapy (PDT) is a promising anti-cancer method involving the use of light-activated photosensitisers to precisely induce oxidative stress and cell death in cancers. ABCG2 can efflux photosensitisers from out of cells, reducing the capacity of PDT and limiting the efficacy of treatment. Many studies have attempted to elucidate the relationship between the expression of ABCG2 in cancers, its effect on the cellular retention of photosensitisers and its impact on PDT. This review looks at the studies which investigate the effect of ABCG2 on a range of different photosensitisers in different pre-clinical models of cancer. This work also evaluates the approaches that are being investigated to address the role of ABCG2 in PDT with an outlook on potential clinical validation.
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Affiliation(s)
- M Ibrahim Khot
- School of Medicine, St James's University Hospital, University of Leeds, Leeds, UK.
| | - Candice L Downey
- School of Medicine, St James's University Hospital, University of Leeds, Leeds, UK
| | - Gemma Armstrong
- School of Medicine, St James's University Hospital, University of Leeds, Leeds, UK
| | | | - Fazain Jarral
- School of Medicine, St James's University Hospital, University of Leeds, Leeds, UK
| | - Helen Andrew
- School of Medicine, St James's University Hospital, University of Leeds, Leeds, UK
| | - David G Jayne
- School of Medicine, St James's University Hospital, University of Leeds, Leeds, UK
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Adigbli DK, Pye H, Seebaluck J, Loizidou M, MacRobert AJ. The intracellular redox environment modulates the cytotoxic efficacy of single and combination chemotherapy in breast cancer cells using photochemical internalisation. RSC Adv 2019; 9:25861-25874. [PMID: 35530074 PMCID: PMC9070005 DOI: 10.1039/c9ra04430b] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2019] [Accepted: 08/09/2019] [Indexed: 12/27/2022] Open
Abstract
The redox environment modulates photochemical internalization of an entrapped cytotoxic agent. Administration of light depicted by jagged arrow.
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Affiliation(s)
- Derick K. Adigbli
- Division of Surgery and Interventional Science
- University College London
- London
- UK
| | - Hayley Pye
- Division of Surgery and Interventional Science
- University College London
- London
- UK
| | - Jason Seebaluck
- Division of Surgery and Interventional Science
- University College London
- London
- UK
| | - Marilena Loizidou
- Division of Surgery and Interventional Science
- University College London
- London
- UK
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12
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Hadi LM, Yaghini E, Stamati K, Loizidou M, MacRobert AJ. Therapeutic enhancement of a cytotoxic agent using photochemical internalisation in 3D compressed collagen constructs of ovarian cancer. Acta Biomater 2018; 81:80-92. [PMID: 30267880 DOI: 10.1016/j.actbio.2018.09.041] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2018] [Revised: 09/17/2018] [Accepted: 09/25/2018] [Indexed: 01/19/2023]
Abstract
Photochemical internalisation (PCI) is a method for enhancing delivery of drugs to their intracellular target sites of action. In this study we investigated the efficacy of PCI using a porphyrin photosensitiser and a cytotoxic agent on spheroid and non-spheroid compressed collagen 3D constructs of ovarian cancer versus conventional 2D culture. The therapeutic responses of two human carcinoma cell lines (SKOV3 and HEY) were compared using a range of assays including optical imaging. The treatment was shown to be effective in non-spheroid constructs of both cell lines causing a significant and synergistic reduction in cell viability measured at 48 or 96 h post-illumination. In the larger spheroid constructs, PCI was still effective but required higher saporin and photosensitiser doses. Moreover, in contrast to the 2D and non-spheroid experiments, where comparable efficacy was found for the two cell lines, HEY spheroid constructs were found to be more susceptible to PCI and a lower dose of saporin could be used. PCI treatment was observed to induce death principally by apoptosis in the 3D constructs compared to the mostly necrotic cell death caused by PDT. At low oxygen levels (1%) both PDT and PCI were significantly less effective in the constructs. STATEMENT OF SIGNIFICANCE: Assessment of new drugs or delivery systems for cancer therapy prior to conducting in vivo studies often relies on the use of conventional 2D cell culture, however 3D cancer constructs can provide more physiologically relevant information owing to their 3D architecture and the presence of an extracellular matrix. This study investigates the efficacy of Photochemical Internalisation mediated drug delivery in 3D constructs. In 3D cultures, both oxygen and drug delivery to the cells are limited by diffusion through the extracellular matrix unlike 2D models, and in our model we have used compressed collagen constructs where the density of collagen mimics physiological values. These 3D constructs are therefore well suited to studying drug delivery using PCI. Our study highlights the potential of these constructs for identifying differences in therapeutic response to PCI of two ovarian carcinoma lines.
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13
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Eng MS, Kaur J, Prasmickaite L, Engesæter BØ, Weyergang A, Skarpen E, Berg K, Rosenblum MG, Mælandsmo GM, Høgset A, Ferrone S, Selbo PK. Enhanced targeting of triple-negative breast carcinoma and malignant melanoma by photochemical internalization of CSPG4-targeting immunotoxins. Photochem Photobiol Sci 2018; 17:539-551. [PMID: 29565434 PMCID: PMC8728892 DOI: 10.1039/c7pp00358g] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2017] [Accepted: 03/05/2018] [Indexed: 08/10/2023]
Abstract
Triple-negative breast cancer (TNBC) and malignant melanoma are highly aggressive cancers that widely express the cell surface chondroitin sulfate proteoglycan 4 (CSPG4/NG2). CSPG4 plays an important role in tumor cell growth and survival and promotes chemo- and radiotherapy resistance, suggesting that CSPG4 is an attractive target in cancer therapy. In the present work, we applied the drug delivery technology photochemical internalization (PCI) in combination with the novel CSPG4-targeting immunotoxin 225.28-saporin as an efficient and specific strategy to kill aggressive TNBC and amelanotic melanoma cells. Light-activation of the clinically relevant photosensitizer TPCS2a (fimaporfin) and 225.28-saporin was found to act in a synergistic manner, and was superior to both PCI of saporin and PCI-no-drug (TPCS2a + light only) in three TNBC cell lines (MDA-MB-231, MDA-MB-435 and SUM149) and two BRAFV600E mutated malignant melanoma cell lines (Melmet 1 and Melmet 5). The cytotoxic effect was highly dependent on the light dose and expression of CSPG4 since no enhanced cytotoxicity of PCI of 225.28-saporin compared to PCI of saporin was observed in the CSPG4-negative MCF-7 cells. The PCI of a smaller, and clinically relevant CSPG4-targeting toxin (scFvMEL-rGel) validated the CSPG4-targeting concept in vitro and induced a strong inhibition of tumor growth in the amelanotic melanoma xenograft A-375 model. In conclusion, the combination of the drug delivery technology PCI and CSPG4-targeting immunotoxins is an efficient, specific and light-controlled strategy for the elimination of aggressive cells of TNBC and malignant melanoma origin. This study lays the foundation for further preclinical evaluation of PCI in combination with CSPG4-targeting.
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Affiliation(s)
- M S Eng
- Department of Radiation Biology, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.
| | - J Kaur
- Department of Radiation Biology, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.
| | - L Prasmickaite
- Department of Tumor Biology, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
| | - B Ø Engesæter
- Department of Tumor Biology, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
| | - A Weyergang
- Department of Radiation Biology, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.
| | - E Skarpen
- Department of Core Facilities, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
| | - K Berg
- Department of Radiation Biology, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.
| | - M G Rosenblum
- Department of Experimental Therapeutics, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA
| | - G M Mælandsmo
- Department of Tumor Biology, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
| | | | - S Ferrone
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - P K Selbo
- Department of Radiation Biology, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.
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Cheng CC, Shi LH, Wang XJ, Wang SX, Wan XQ, Liu SR, Wang YF, Lu Z, Wang LH, Ding Y. Stat3/Oct-4/c-Myc signal circuit for regulating stemness-mediated doxorubicin resistance of triple-negative breast cancer cells and inhibitory effects of WP1066. Int J Oncol 2018; 53:339-348. [PMID: 29750424 DOI: 10.3892/ijo.2018.4399] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2018] [Accepted: 04/11/2018] [Indexed: 01/06/2023] Open
Abstract
Doxorubicin (Dox) is widely used in the treatment of triple-negative breast cancer cells (TNBCs), however resistance limits its effectiveness. Cancer stem cells (CSCs) are associated with Dox resistance in MCF-7 estrogen receptor positive breast cancer cells. Signal transducer and activator of transcription 3 (Stat3) may functionally shift non-CSCs towards CSCs. However, whether Stat3 drives the formation of CSCs during the development of resistance in TNBC, and whether a Stat3 inhibitor reverses CSC-mediated Dox resistance, remains to be elucidated. In the present study, human MDA-MB-468 and murine 4T1 mammary carcinoma cell lines with the typical characteristics of TNBCs, were compared with estrogen receptor-positive MCF-7 cells as a model system. The MTT assay was used to detect cytotoxicity of Dox. In addition, the expression levels of CSC-specific markers and transcriptional factors were measured by western blotting, immunofluorescence staining and flow cytometry. The mammosphere formation assay was used to detect stem cell activity. Under long-term continuous treatment with Dox at a low concentration, TNBC cultures not only exhibited a drug-resistant phenotype, but also showed CSC properties. These Dox-resistant TNBC cells showed activation of Stat3 and high expression levels of pluripotency transcription factors octamer-binding transcription factor-4 (Oct-4) and c-Myc, which was different from the high expression of superoxide dismutase 2 (Sox2) in Dox-resistant MCF-7 cells. WP1066 inhibited the phosphorylation of Stat3, and decreased the expression of Oct-4 and c-Myc, leading to a reduction in the CD44-positive cell population, and restoring the sensitivity of the cells to Dox. Taken together, a novel signal circuit of Stat3/Oct-4/c-Myc was identified for regulating stemness-mediated Dox resistance in TNBC. The Stat3 inhibitor WP1066 was able to overcome the resistance to Dox through decreasing the enrichment of CSCs, highlighting the therapeutic potential of WP1066 as a novel sensitizer of Dox-resistant TNBC.
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Affiliation(s)
- Cong-Cong Cheng
- Laboratory of Molecular Oncology, Weifang Medical College, Weifang, Shandong 261053, P.R. China
| | - Li-Hong Shi
- Laboratory of Molecular Oncology, Weifang Medical College, Weifang, Shandong 261053, P.R. China
| | - Xue-Jian Wang
- Laboratory of Molecular Oncology, Weifang Medical College, Weifang, Shandong 261053, P.R. China
| | - Shu-Xiao Wang
- Department of Pharmacology, Weifang Medical College, Weifang, Shandong 261053, P.R. China
| | - Xiao-Qing Wan
- Laboratory of Molecular Oncology, Weifang Medical College, Weifang, Shandong 261053, P.R. China
| | - Shu-Rong Liu
- Laboratory of Molecular Oncology, Weifang Medical College, Weifang, Shandong 261053, P.R. China
| | - Yi-Fei Wang
- Laboratory of Molecular Oncology, Weifang Medical College, Weifang, Shandong 261053, P.R. China
| | - Zhong Lu
- Laboratory of Molecular Oncology, Weifang Medical College, Weifang, Shandong 261053, P.R. China
| | - Li-Hua Wang
- Laboratory of Molecular Oncology, Weifang Medical College, Weifang, Shandong 261053, P.R. China
| | - Yi Ding
- Laboratory of Molecular Oncology, Weifang Medical College, Weifang, Shandong 261053, P.R. China
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15
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Olsen CE, Weyergang A, Edwards VT, Berg K, Brech A, Weisheit S, Høgset A, Selbo PK. Development of resistance to photodynamic therapy (PDT) in human breast cancer cells is photosensitizer-dependent: Possible mechanisms and approaches for overcoming PDT-resistance. Biochem Pharmacol 2017; 144:63-77. [DOI: 10.1016/j.bcp.2017.08.002] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2017] [Accepted: 08/03/2017] [Indexed: 10/19/2022]
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Abstract
Glioblastoma multiforme (GBM) are extremely lethal and still poorly treated primary brain tumors, characterized by the presence of highly tumorigenic cancer stem cell (CSC) subpopulations, considered responsible for tumor relapse. In order to successfully eradicate GBM growth and recurrence, new anti-cancer strategies selectively targeting CSCs should be designed. CSCs might be eradicated by targeting some of their cell surface markers and transporters, inducing their differentiation, impacting their hyper-glycolytic metabolism, inhibiting CSC-related signaling pathways and/or by targeting their microenvironmental niche. In this regard, phytocompounds such as curcumin, isothiocyanates, resveratrol and epigallocatechin-3-gallate have been shown to prevent or reverse cancer-related epigenetic dysfunctions, reducing tumorigenesis, preventing metastasis and/or increasing chemotherapy and radiotherapy efficacy. However, the actual bioavailability and metabolic processing of phytocompounds is generally unknown, and the presence of the blood brain barrier often represents a limitation to glioma treatments. Nowadays, nanoparticles (NPs) can be loaded with therapeutic compounds such as phytochemicals, improving their bioavailability and their targeted delivery within the GBM tumor bulk. Moreover, NPs can be designed to increase their tropism and specificity toward CSCs by conjugating their surface with antibodies specific for CSC antigens, with ligands or with glucose analogues. Here we discuss the use of phytochemicals as anti-glioma agents and the applicability of phytochemical-loaded NPs as drug delivery systems to target GBM. Additionally, we provide some examples on how NPs can be specifically formulated to improve CSC targeting.
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Rapozzi V, Varchi G, Della Pietra E, Ferroni C, Xodo LE. A photodynamic bifunctional conjugate for prostate cancer: an in vitro mechanistic study. Invest New Drugs 2016; 35:115-123. [PMID: 27726093 DOI: 10.1007/s10637-016-0396-x] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2016] [Accepted: 09/28/2016] [Indexed: 01/12/2023]
Abstract
Photodynamic therapy (PDT) has drawn considerable attention for its efficacy against certain types of cancers. It shows however limits in the case of deep cancers, favoring tumor recurrence under suboptimal conditions. More insight into the molecular mechanisms of PDT-induced cytotoxicity and cytoprotection is essential to extend and strengthen this therapeutic modality. As PDT induces iNOS/NO in both tumor and microenvironment, we examined the role of nitric oxide (NO) in cytotoxicity and cytoprotection. Our findings show that NO mediates its cellular effects by acting on the NF-κB/YY1/RKIP loop, which controls cell growth and apoptosis. The cytoprotective effect of PDT-induced NO is observed at low NO levels, which activate the pro-survival/anti-apoptotic NF-κB and YY1, while inhibiting the anti-survival/pro-apoptotic and metastasis suppressor RKIP. In contrast, high PDT-induced NO levels inhibit NF-κB and YY1 and induce RKIP, resulting in significant anti-tumor activity. These findings reveal a critical role played by NO in PDT and suggest that the use of bifunctional PDT agents composed of a photosensitizer and a NO-donor could enhance the photo-treatment effect. A successful application of NO in anticancer therapy requires control of its concentration in the target tissue. To address this issue we propose as PDT agent, a bimolecular conjugate called DR2, composed of a photosensitizer (Pheophorbide a) and a non-steroidal anti-androgen molecule capable of releasing NO under the exclusive control of light. The mechanism of action of DR2 in prostate cancer cells is reported and discussed.
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Affiliation(s)
- Valentina Rapozzi
- Department of Medical and Biological Sciences, University of Udine, Piazzale Kolbe 4, 33100, Udine, Italy.
| | - Greta Varchi
- Institute of Organic Synthesis and Photoreactivity, Italian National Research Council, Via P. Gobetti 101, 40129, Bologna, Italy
| | - Emilia Della Pietra
- Department of Medical and Biological Sciences, University of Udine, Piazzale Kolbe 4, 33100, Udine, Italy
| | - Claudia Ferroni
- Institute of Organic Synthesis and Photoreactivity, Italian National Research Council, Via P. Gobetti 101, 40129, Bologna, Italy
| | - Luigi E Xodo
- Department of Medical and Biological Sciences, University of Udine, Piazzale Kolbe 4, 33100, Udine, Italy
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18
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Sultan AA, Jerjes W, Berg K, Høgset A, Mosse CA, Hamoudi R, Hamdoon Z, Simeon C, Carnell D, Forster M, Hopper C. Disulfonated tetraphenyl chlorin (TPCS2a)-induced photochemical internalisation of bleomycin in patients with solid malignancies: a phase 1, dose-escalation, first-in-man trial. Lancet Oncol 2016; 17:1217-29. [PMID: 27475428 DOI: 10.1016/s1470-2045(16)30224-8] [Citation(s) in RCA: 80] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2016] [Revised: 05/25/2016] [Accepted: 06/02/2016] [Indexed: 12/12/2022]
Abstract
BACKGROUND Photochemical internalisation, a novel minimally invasive treatment, has shown promising preclinical results in enhancing and site-directing the effect of anticancer drugs by illumination, which initiates localised chemotherapy release. We assessed the safety and tolerability of a newly developed photosensitiser, disulfonated tetraphenyl chlorin (TPCS2a), in mediating photochemical internalisation of bleomycin in patients with advanced and recurrent solid malignancies. METHODS In this phase 1, dose-escalation, first-in-man trial, we recruited patients (aged ≥18 to <85 years) with local recurrent, advanced, or metastatic cutaneous or subcutaneous malignancies who were clinically assessed as eligible for bleomycin chemotherapy from a single centre in the UK. Patients were given TPCS2a on day 0 by slow intravenous injection, followed by a fixed dose of 15 000 IU/m(2) bleomycin by intravenous infusion on day 4. After 3 h, the surface of the target tumour was illuminated with 652 nm laser light (fixed at 60 J/cm(2)). The TPCS2a starting dose was 0·25 mg/kg and was then escalated in successive dose cohorts of three patients (0·5, 1·0, and 1·5 mg/kg). The primary endpoints were safety and tolerability of TPCS2a; other co-primary endpoints were dose-limiting toxicity and maximum tolerated dose. The primary analysis was per protocol. This study is registered with ClinicalTrials.gov, number NCT00993512, and has been completed. FINDINGS Between Oct 3, 2009, and Jan 14, 2014, we recruited 22 patients into the trial. 12 patients completed the 3-month follow-up period. Adverse events related to photochemical internalisation were either local, resulting from the local inflammatory process, or systemic, mostly as a result of the skin-photosensitising effect of TPCS2a. The most common grade 3 or worse adverse events were unexpected higher transient pain response (grade 3) localised to the treatment site recorded in nine patients, and respiratory failure (grade 4) noted in two patients. One dose-limiting toxicity was reported in the 1·0 mg/kg cohort (skin photosensitivity [grade 2]). Dose-limiting toxicities were reported in two of three patients at a TPCS2a dose of 1·5 mg/kg (skin photosensitivity [grade 3] and wound infection [grade 3]); thus, the maximum tolerated dose of TPCS2a was 1·0 mg/kg. Administration of TPCS2a was found to be safe and tolerable by all patients. No deaths related to photochemical internalisation treatment occurred. INTERPRETATION TPCS2a-mediated photochemical internalisation of bleomycin is safe and tolerable. We identified TPCS2a 0·25 mg/kg as the recommended treatment dose for future trials. FUNDING PCI Biotech.
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Affiliation(s)
- Ahmed A Sultan
- Academic Unit of Oral and Maxillofacial Surgery, UCL Eastman Dental Institute, London, UK
| | - Waseem Jerjes
- Division of Surgery and Interventional Science, University College London, London, UK
| | - Kristian Berg
- Department of Radiation Biology, Oslo University Hospital, Oslo, Norway
| | | | - Charles A Mosse
- Division of Surgery and Interventional Science, University College London, London, UK
| | - Rifat Hamoudi
- Division of Surgery and Interventional Science, University College London, London, UK
| | - Zaid Hamdoon
- Academic Unit of Oral and Maxillofacial Surgery, UCL Eastman Dental Institute, London, UK
| | - Celia Simeon
- Cancer Clinical Trials Unit, University College London Hospitals, London, UK
| | - Dawn Carnell
- Head and Neck Unit, University College London Hospitals, London, UK
| | - Martin Forster
- Head and Neck Unit, University College London Hospitals, London, UK; UCL Cancer Institute, London, UK
| | - Colin Hopper
- Academic Unit of Oral and Maxillofacial Surgery, UCL Eastman Dental Institute, London, UK; Head and Neck Unit, University College London Hospitals, London, UK; UCL Cancer Institute, London, UK.
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19
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Shegokar R, Sawant S, Al Shaal L. Applications of Cell-Based Drug Delivery Systems: Use of Single Cell Assay. SERIES IN BIOENGINEERING 2016. [DOI: 10.1007/978-3-662-49118-8_12] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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20
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Westover D, Li F. New trends for overcoming ABCG2/BCRP-mediated resistance to cancer therapies. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2015; 34:159. [PMID: 26714461 PMCID: PMC4696234 DOI: 10.1186/s13046-015-0275-x] [Citation(s) in RCA: 64] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 11/25/2015] [Accepted: 12/17/2015] [Indexed: 12/18/2022]
Abstract
ATP-binding cassette (ABC) transporters make up a superfamily of transmembrane proteins that play a critical role in the development of drug resistance. This phenomenon is especially important in oncology, where superfamily member ABCG2 (also called BCRP - breast cancer resistance protein) is known to interact with dozens of anti-cancer agents that are ABCG2 substrates. In addition to the well-studied and well-reviewed list of cytotoxic and targeted agents that are substrates for the ABCG2 transporter, a growing body of work links ABCG2 to multiple photodynamic therapy (PDT) agents, and there is a limited body of evidence suggesting that ABCG2 may also play a role in resistance to radiation therapy. In addition, the focus of ABC transporter research in regards to therapeutic development has begun to shift in the past few years. The shift has been away from using pump inhibitors for reversing resistance, toward the development of therapeutic agents that are poor substrates for these efflux pump proteins. This approach may result in the development of drug regimens that circumvent ABC transporter-mediated resistance entirely. Here, it is our intention to review: 1) recent discoveries that further characterize the role of ABCG2 in oncology, and 2) advances in reversing and circumventing ABC transporter-mediated resistance to anti-cancer therapies.
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Affiliation(s)
- David Westover
- Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY, 14263, USA.
| | - Fengzhi Li
- Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY, 14263, USA.
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21
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Spring BQ, Rizvi I, Xu N, Hasan T. The role of photodynamic therapy in overcoming cancer drug resistance. Photochem Photobiol Sci 2015; 14:1476-91. [PMID: 25856800 PMCID: PMC4520758 DOI: 10.1039/c4pp00495g] [Citation(s) in RCA: 236] [Impact Index Per Article: 23.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2015] [Accepted: 03/10/2015] [Indexed: 12/19/2022]
Abstract
Many modalities of cancer therapy induce mechanisms of treatment resistance and escape pathways during chronic treatments, including photodynamic therapy (PDT). It is conceivable that resistance induced by one treatment might be overcome by another treatment. Emerging evidence suggests that the unique mechanisms of tumor cell and microenvironment damage produced by PDT could be utilized to overcome cancer drug resistance, to mitigate the compensatory induction of survival pathways and even to re-sensitize resistant cells to standard therapies. Approaches that capture the unique features of PDT, therefore, offer promising factors for increasing the efficacy of a broad range of therapeutic modalities. Here, we highlight key preclinical findings utilizing PDT to overcome classical drug resistance or escape pathways and thus enhance the efficacy of many pharmaceuticals, possibly explaining the clinical observations of the PDT response to otherwise treatment-resistant diseases. With the development of nanotechnology, it is possible that light activation may be used not only to damage and sensitize tumors but also to enable controlled drug release to inhibit escape pathways that may lead to resistance or cell proliferation.
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Affiliation(s)
- Bryan Q Spring
- Wellman Center for Photomedicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
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22
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Rapozzi V, Ragno D, Guerrini A, Ferroni C, della Pietra E, Cesselli D, Castoria G, Di Donato M, Saracino E, Benfenati V, Varchi G. Androgen Receptor Targeted Conjugate for Bimodal Photodynamic Therapy of Prostate Cancer in Vitro. Bioconjug Chem 2015; 26:1662-71. [PMID: 26108715 DOI: 10.1021/acs.bioconjchem.5b00261] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Prostate cancer (PC) represents the most common type of cancer among males and is the second leading cause of cancer death in men in Western society. Current options for PC therapy remain unsatisfactory, since they often produce uncomfortable long-term side effects, such as impotence (70%) and incontinence (5-20%) even in the first stages of the disease. Light-triggered therapies, such as photodynamic therapy, have the potential to provide important advances in the treatment of localized and partially metastasized prostate cancer. We have designed a novel molecular conjugate (DR2) constituted of a photosensitizer (pheophorbide a, Pba), connected to a nonsteroidal anti-androgen molecule through a small pegylated linker. This study aims at investigating whether DR2 represents a valuable approach for PC treatment based on light-induced production of single oxygen and nitric oxide (NO) in vitro. Besides being able to efficiently bind the androgen receptor (AR), the 2-trifluoromethylnitrobenzene ring on the DR2 backbone is able to release cytotoxic NO under the exclusive control of light, thus augmenting the general photodynamic effect. Although DR2 is similarly internalized in cells expressing different levels of androgen receptor, the AR ligand prevents its efflux through the ABCG2-pump. In vitro phototoxicity experiments demonstrated the ability of DR2 to kill cancer cells more efficiently than Pba, while no dark toxicity was observed. Overall, the presented approach is very promising for further development of AR-photosensitizer conjugates in the multimodal photodynamic treatment of prostate cancer.
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Affiliation(s)
- Valentina Rapozzi
- ‡Department of Medical and Biological Sciences University of Udine, Piazzale Kolbe, 4, 33100 Udine, Italy
| | - Daniele Ragno
- ∥Department of Chemistry University of Ferrara, Via Fossato di Mortara, 17, 44121 Ferrara, Italy
| | - Andrea Guerrini
- †Institute of the Organic Synthesis and Photoreactivity Italian National Research Council, Via P. Gobetti, 101, 40129 Bologna, Italy
| | - Claudia Ferroni
- †Institute of the Organic Synthesis and Photoreactivity Italian National Research Council, Via P. Gobetti, 101, 40129 Bologna, Italy
| | - Emilia della Pietra
- ‡Department of Medical and Biological Sciences University of Udine, Piazzale Kolbe, 4, 33100 Udine, Italy
| | - Daniela Cesselli
- ‡Department of Medical and Biological Sciences University of Udine, Piazzale Kolbe, 4, 33100 Udine, Italy
| | - Gabriella Castoria
- §Department of Biochemistry, Biophysics and General Pathology - II University of Naples , Via L. De Crecchio, 7, 80138 Naples, Italy
| | - Marzia Di Donato
- §Department of Biochemistry, Biophysics and General Pathology - II University of Naples , Via L. De Crecchio, 7, 80138 Naples, Italy
| | - Emanuela Saracino
- ⊥Institute for the Study of Nanostructured Materials, Italian National Research Council, Via P. Gobetti, 101, 40129 Bologna, Italy
| | - Valentina Benfenati
- †Institute of the Organic Synthesis and Photoreactivity Italian National Research Council, Via P. Gobetti, 101, 40129 Bologna, Italy
| | - Greta Varchi
- †Institute of the Organic Synthesis and Photoreactivity Italian National Research Council, Via P. Gobetti, 101, 40129 Bologna, Italy
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Effect of FosPeg® mediated photoactivation on P-gp/ABCB1 protein expression in human nasopharyngeal carcinoma cells. JOURNAL OF PHOTOCHEMISTRY AND PHOTOBIOLOGY B-BIOLOGY 2015; 148:82-87. [PMID: 25900553 DOI: 10.1016/j.jphotobiol.2015.03.019] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/11/2014] [Revised: 03/17/2015] [Accepted: 03/24/2015] [Indexed: 11/24/2022]
Abstract
Multidrug resistance (MDR) refers to the ability of cancer cells to develop cross resistance to a range of anticancer drugs which are structurally and functionally unrelated. P-glycoprotein (P-gp) is the best studied MDR phenotype in photodynamic therapy (PDT) treated cells. Our pervious study demonstrated that FosPeg® mediated PDT is effective to NPC cell line models. In this in vitro study, the expression of MDR1 gene and its product P-gp in undifferentiated, poorly differentiated and well differentiated human nasopharyngeal carcinoma (NPC) cells were investigated. The influence of P-gp efflux activities on photosensitizer FosPeg® was also examined. Regardless of the differentiation status, PDT tested NPC cell lines all expressed P-gp protein. Results indicated that FosPeg® photoactivation could heighten the expression of MDR1 gene and P-gp transporter protein in a dose dependent manner. Up to 2-fold increase of P-gp protein expression were seen in NPC cells after FosPeg® mediated PDT. Interestingly, our finding demonstrated that FosPeg® mediated PDT efficiency is independent to the MDR1 gene and P-gp protein expression in NPC cells. FosPeg® itself is not the substrate of P-gp transporter protein and no efflux of FosPeg® were observed in NPC cells. Therefore, the PDT efficiency would not be affected even though FosPeg® mediated PDT could induce MDR1 gene and P-gp protein expression in NPC cells. FosPeg® mediated PDT could be a potential therapeutic approach for MDR cancer patients.
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24
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Park W, Park SJ, Lee J, Na K. Recent advances in utilization of photochemical internalization (PCI) for efficient nano carrier mediated drug delivery. BIOMATERIALS AND BIOMECHANICS IN BIOENGINEERING 2015. [DOI: 10.12989/bme.2015.2.1.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
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Martinez de Pinillos Bayona A, Moore CM, Loizidou M, MacRobert AJ, Woodhams JH. Enhancing the efficacy of cytotoxic agents for cancer therapy using photochemical internalisation. Int J Cancer 2015; 138:1049-57. [PMID: 25758607 PMCID: PMC4973841 DOI: 10.1002/ijc.29510] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2014] [Accepted: 02/26/2015] [Indexed: 12/22/2022]
Abstract
Photochemical internalisation (PCI) is a technique for improving cellular delivery of certain bioactive agents which are prone to sequestration within endolysosomes. There is a wide range of agents suitable for PCI‐based delivery including toxins, oligonucleotides, genes and immunoconjugates which demonstrates the versatility of this technique. The basic mechanism of PCI involves triggering release of the agent from endolysosomes within the target cells using a photosensitiser which is selectively retained with the endolysosomal membranes. Excitation of the photosensitiser by visible light leads to disruption of the membranes via photooxidative damage thereby releasing the agent into the cytosol. This treatment enables the drugs to reach their intended subcellular target more efficiently and improves their efficacy. In this review we summarise the applications of this technique with the main emphasis placed on cancer chemotherapy.
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Affiliation(s)
| | - Caroline M Moore
- UCL Division of Surgery and Interventional Sciences, University College London, London, United Kingdom
| | - Marilena Loizidou
- UCL Division of Surgery and Interventional Sciences, University College London, London, United Kingdom
| | - Alexander J MacRobert
- UCL Division of Surgery and Interventional Sciences, University College London, London, United Kingdom
| | - Josephine H Woodhams
- UCL Division of Surgery and Interventional Sciences, University College London, London, United Kingdom
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26
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Bostad M, Olsen CE, Peng Q, Berg K, Høgset A, Selbo PK. Light-controlled endosomal escape of the novel CD133-targeting immunotoxin AC133-saporin by photochemical internalization - A minimally invasive cancer stem cell-targeting strategy. J Control Release 2015; 206:37-48. [PMID: 25758331 DOI: 10.1016/j.jconrel.2015.03.008] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2015] [Revised: 03/05/2015] [Accepted: 03/06/2015] [Indexed: 01/13/2023]
Abstract
The cancer stem cell (CSC) marker CD133 is an attractive target to improve antitumor therapy. We have used photochemical internalization (PCI) for the endosomal escape of the novel CD133-targeting immunotoxin AC133-saporin (PCIAC133-saporin). PCI employs an endocytic vesicle-localizing photosensitizer, which generates reactive oxygen species upon light-activation causing a rupture of the vesicle membranes and endosomal escape of entrapped drugs. Here we show that AC133-saporin co-localizes with the PCI-photosensitizer TPCS2a, which upon light exposure induces cytosolic release of AC133-saporin. PCI of picomolar levels of AC133-saporin in colorectal adenocarcinoma WiDr cells blocked cell proliferation and induced 100% inhibition of cell viability and colony forming ability at the highest light doses, whereas no cytotoxicity was obtained in the absence of light. Efficient PCI-based CD133-targeting was in addition demonstrated in the stem-cell-like, triple negative breast cancer cell line MDA-MB-231 and in the aggressive malignant melanoma cell line FEMX-1, whereas no enhanced targeting was obtained in the CD133-negative breast cancer cell line MCF-7. PCIAC133-saporin induced mainly necrosis and a minimal apoptotic response based on assessing cleavage of caspase-3 and PARP, and the TUNEL assay. PCIAC133-saporin resulted in S phase arrest and reduced LC3-II conversion compared to control treatments. Notably, co-treatment with Bafilomycin A1 and PCIAC133-saporin blocked LC3-II conversion, indicating a termination of the autophagic flux in WiDr cells. For the first time, we demonstrate laser-controlled targeting of CD133 in vivo. After only one systemic injection of AC133-saporin and TPCS2a, a strong anti-tumor response was observed after PCIAC133-saporin. The present PCI-based endosomal escape technology represents a minimally invasive strategy for spatio-temporal, light-controlled targeting of CD133+ cells in localized primary tumors or metastasis.
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Affiliation(s)
- Monica Bostad
- Department of Radiation Biology, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway; Cancer Stem Cell Innovation Center (SFI-CAST), Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
| | - Cathrine Elisabeth Olsen
- Department of Radiation Biology, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway; Cancer Stem Cell Innovation Center (SFI-CAST), Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
| | - Qian Peng
- Department of Pathology, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
| | - Kristian Berg
- Department of Radiation Biology, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
| | - Anders Høgset
- Cancer Stem Cell Innovation Center (SFI-CAST), Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway; PCI Biotech AS, Lysaker, Norway
| | - Pål Kristian Selbo
- Department of Radiation Biology, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway; Cancer Stem Cell Innovation Center (SFI-CAST), Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.
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Preliminary analysis of stem cell-like cells in human neuroblastoma. World J Pediatr 2015; 11:54-60. [PMID: 25431041 DOI: 10.1007/s12519-014-0529-2] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2013] [Accepted: 06/19/2014] [Indexed: 10/24/2022]
Abstract
BACKGROUND Neuroblastoma is an embryonic neoplasm originating from the neural crest with cellular heterogeneity as one of its oncobiological characteristics. This study was undertaken to determine whether human neuroblastoma contains stem cell-like cells. METHODS Twenty patients with neuroblastoma who have been treated in our hospital since January 2005 were divided into pre-operative chemotherapy (10 patients) and non-chemotherapy (10) groups. Tumor specimens of the patients were taken and paraffin sections were made. The expressions of stem cell markers CD133, ABCG2, CD117 and nestin were immunohistochemically detected in the specimens. Neuroblastoma cells were stained with Hoechst 33342 and PI. The side population (SP) cells were analyzed by the fluorescence-activated cell sorter. The disparity drug resistance to cisplatin (DDP) of SP and non-SP cells was measured with MTT colorimetric assay. The oncogenicity of SP and non-SP cells was identified in nude mice. RESULTS There was no significant difference in the expression intensity of CD117 and nestin between the two groups of specimens (P>0.05). There was a significant difference between the two groups in terms of the expression intensity of CD133 and ABCG2 (P<0.05). The SP cells accounted for 0.2%-1.3% of the total human neuroblastoma cells and were decreased to 0.1%-0.5% after verapamil treatment. The SP and non-SP cells showed disparity in cell growth experiment and drug resistance to DDP. Oncogenicity experiment revealed that nude mice could erupt tumor by an injection of l×10(6) SHSY5Y and WIV SP cells. However, the nude mice could not form tumor by an injection of l×10(6) non-SP cells. CONCLUSION Neuroblastoma might contain cancer stem cell-like cells.
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Weyergang A, Berstad MEB, Bull-Hansen B, Olsen CE, Selbo PK, Berg K. Photochemical activation of drugs for the treatment of therapy-resistant cancers. Photochem Photobiol Sci 2015; 14:1465-75. [DOI: 10.1039/c5pp00029g] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Resistance to chemotherapy, molecular targeted therapy as well as radiation therapy is a major obstacle for cancer treatment.
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Affiliation(s)
- Anette Weyergang
- Department of Radiation Biology
- Institute for Cancer Research
- The Norwegian Radium Hospital
- Oslo University Hospital
- Montebello
| | - Maria E. B. Berstad
- Department of Radiation Biology
- Institute for Cancer Research
- The Norwegian Radium Hospital
- Oslo University Hospital
- Montebello
| | - Bente Bull-Hansen
- Department of Radiation Biology
- Institute for Cancer Research
- The Norwegian Radium Hospital
- Oslo University Hospital
- Montebello
| | - Cathrine E. Olsen
- Department of Radiation Biology
- Institute for Cancer Research
- The Norwegian Radium Hospital
- Oslo University Hospital
- Montebello
| | - Pål K. Selbo
- Department of Radiation Biology
- Institute for Cancer Research
- The Norwegian Radium Hospital
- Oslo University Hospital
- Montebello
| | - Kristian Berg
- Department of Radiation Biology
- Institute for Cancer Research
- The Norwegian Radium Hospital
- Oslo University Hospital
- Montebello
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Selbo PK, Bostad M, Olsen CE, Edwards VT, Høgset A, Weyergang A, Berg K. Photochemical internalisation, a minimally invasive strategy for light-controlled endosomal escape of cancer stem cell-targeting therapeutics. Photochem Photobiol Sci 2015; 14:1433-50. [DOI: 10.1039/c5pp00027k] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Despite progress in radio-, chemo- and photodynamic-therapy (PDT) of cancer, treatment resistance still remains a major problem for patients with aggressive tumours.
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Affiliation(s)
- Pål Kristian Selbo
- Department of Radiation Biology
- Institute for Cancer Research
- The Norwegian Radium Hospital
- Oslo University Hospital
- Montebello
| | - Monica Bostad
- Department of Radiation Biology
- Institute for Cancer Research
- The Norwegian Radium Hospital
- Oslo University Hospital
- Montebello
| | - Cathrine Elisabeth Olsen
- Department of Radiation Biology
- Institute for Cancer Research
- The Norwegian Radium Hospital
- Oslo University Hospital
- Montebello
| | - Victoria Tudor Edwards
- Department of Radiation Biology
- Institute for Cancer Research
- The Norwegian Radium Hospital
- Oslo University Hospital
- Montebello
| | - Anders Høgset
- Cancer Stem Cell Innovation Center (SFI-CAST)
- Institute for Cancer Research
- Norwegian Radium Hospital
- Oslo University Hospital
- Oslo
| | - Anette Weyergang
- Department of Radiation Biology
- Institute for Cancer Research
- The Norwegian Radium Hospital
- Oslo University Hospital
- Montebello
| | - Kristian Berg
- Department of Radiation Biology
- Institute for Cancer Research
- The Norwegian Radium Hospital
- Oslo University Hospital
- Montebello
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Lamberti MJ, Vittar NBR, Rivarola VA. Breast cancer as photodynamic therapy target: Enhanced therapeutic efficiency by overview of tumor complexity. World J Clin Oncol 2014; 5:901-907. [PMID: 25493228 PMCID: PMC4259952 DOI: 10.5306/wjco.v5.i5.901] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2013] [Revised: 04/04/2014] [Accepted: 07/15/2014] [Indexed: 02/06/2023] Open
Abstract
Photodynamic therapy is a minimally invasive and clinically approved procedure for eliminating selected malignant cells with specific light activation of a photosensitizer agent. Whereas interstitial and intra-operative approaches have been investigated for the ablation of a broad range of superficial or bulky solid tumors such as breast cancer, the majority of approved photodynamic therapy protocols are for the treatment of superficial lesions of skin and luminal organs. This review article will discuss recent progress in research focused mainly on assessing the efficacies of various photosensitizers used in photodynamic therapy, as well as the combinatory strategies of various therapeutic modalities for improving treatments of parenchymal and/or stromal tissues of breast cancer solid tumors. Cytotoxic agents are used in cancer treatments for their effect on rapidly proliferating cancer cells. However, such therapeutics often lack specificity, which can lead to toxicity and undesirable side effects. Many approaches are designed to target tumors. Selective therapies can be established by focusing on distinctive intracellular (receptors, apoptotic pathways, multidrug resistance system, nitric oxide-mediated stress) and environmental (glucose, pH) differences between tumor and healthy tissue. A rational design of effective combination regimens for breast cancer treatment involves a better understanding of the mechanisms and molecular interactions of cytotoxic agents that underlie drug resistance and sensitivity.
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31
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Park H, Park W, Na K. Doxorubicin loaded singlet-oxygen producible polymeric micelle based on chlorine e6 conjugated pluronic F127 for overcoming drug resistance in cancer. Biomaterials 2014; 35:7963-9. [DOI: 10.1016/j.biomaterials.2014.05.063] [Citation(s) in RCA: 91] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2014] [Accepted: 05/22/2014] [Indexed: 12/20/2022]
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32
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Bostad M, Kausberg M, Weyergang A, Olsen CE, Berg K, Høgset A, Selbo PK. Light-Triggered, Efficient Cytosolic Release of IM7-Saporin Targeting the Putative Cancer Stem Cell Marker CD44 by Photochemical Internalization. Mol Pharm 2014; 11:2764-76. [DOI: 10.1021/mp500129t] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
| | | | | | | | | | - Anders Høgset
- PCI Biotech
AS, Strandveien 55, N-1366 Lysaker, Norway
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34
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Yang CF, Peng LX, Huang TJ, Yang GD, Chu QQ, Liang YY, Cao X, Xie P, Zheng LS, Huang HB, Cai MD, Huang JL, Liu RY, Zhu ZY, Qian CN, Huang BJ. Cancer stem-like cell characteristics induced by EB virus-encoded LMP1 contribute to radioresistance in nasopharyngeal carcinoma by suppressing the p53-mediated apoptosis pathway. Cancer Lett 2014; 344:260-271. [PMID: 24262659 DOI: 10.1016/j.canlet.2013.11.006] [Citation(s) in RCA: 66] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2013] [Revised: 11/02/2013] [Accepted: 11/10/2013] [Indexed: 12/26/2022]
Abstract
Emerging evidence confirms that cancer stem cells (CSCs) are responsible for the chemoradioresistance of malignancies. EBV-encoded latent membrane protein 1 (LMP1) is associated with tumor relapse and poor prognosis of nasopharyngeal carcinoma (NPC). However, whether LMP1 induces the development of CSCs and the mechanism by which this rare cell subpopulation leads to radioresistance in NPC remain unclear. In the present study, LMP1-transformed NPC cells showed significant radioresistance compared to the empty vector control. We found that LMP1 up-regulated the expression of several stemness-related genes, increased the cell number of side population (SP) by flow cytometry analysis, enhanced the self-renewal properties of the cells in a spherical culture and enhanced the in vivo tumor initiation ability. We also found that LMP1 positively regulated the expression of the CSC marker CD44. The CD44(+/High) subpopulation of the LMP1-transformed NPC cells displayed more significant CSC characteristics than the CD44(-/Low) subpopulation of the LMP1-transformed NPC cells; these characteristics included the upregulation of stemness-related genes, in vitro self-renewal and in vivo tumor initiation ability. Importantly, the CD44(+/High) subpopulation displayed more radioresistance than the CD44(-/Low) subpopulation. Our results also demonstrated that phosphorylation of the DNA damage response (DDR) proteins, ATM, Chk1, Chk2 and p53, was inactivated in the LMP1-induced CD44(+/High) cells in response to DNA damage, and this was accompanied by a downregulation of the p53-targeted proapoptotic genes, which suggested that the inactivation of the p53-mediated apoptosis pathway was responsible for the radioresistance in the CD44(+/High) cells. Taken together, we found that LMP1 induced an increase in CSC-like CD44(+/High) cells, and we determined the molecular mechanism underlying the radioresistance of the LMP1-activated CSCs, highlighting the need of CSC-targeted radiotherapy in EBV-positive NPC.
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Affiliation(s)
- Chang-Fu Yang
- Department of Cancer Chemotherapy, The People's Hospital of Gaozhou, Guangdong Province, China
| | - Li-Xia Peng
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China; Department of Experimental Research, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Tie-Jun Huang
- Department of Nuclear Medicine, The Second People's Hospital of Shenzhen, Shenzhen, China
| | - Guang-Da Yang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China; Department of Experimental Research, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Qiao-Qiao Chu
- School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China
| | - Ying-Ying Liang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China; Department of Experimental Research, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Xue Cao
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China; Department of Experimental Research, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Ping Xie
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China; Department of Experimental Research, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Li-Sheng Zheng
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China; Department of Experimental Research, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Hong-Bing Huang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Mao-De Cai
- Department of Cancer Chemotherapy, The People's Hospital of Gaozhou, Guangdong Province, China
| | - Jia-Ling Huang
- Department of Medicine, Division of Infectious Diseases, University of Pennsylvania School of Medicine, Philadelphia, USA
| | - Ran-Yi Liu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Zhen-Yu Zhu
- Department of Biochemistry & Molecular Biology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China
| | - Chao-Nan Qian
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China; Department of Nasopharyngeal Carcinoma, Sun Yat-Sen University Cancer Center, Guangzhou, China.
| | - Bi-Jun Huang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China; Department of Experimental Research, Sun Yat-Sen University Cancer Center, Guangzhou, China.
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Olsen CE, Berg K, Selbo PK, Weyergang A. Circumvention of resistance to photodynamic therapy in doxorubicin-resistant sarcoma by photochemical internalization of gelonin. Free Radic Biol Med 2013; 65:1300-1309. [PMID: 24076428 DOI: 10.1016/j.freeradbiomed.2013.09.010] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2013] [Revised: 09/16/2013] [Accepted: 09/17/2013] [Indexed: 12/14/2022]
Abstract
A wide range of anti-cancer therapies have been shown to induce resistance upon repetitive treatment and such adapted resistance may also cause cross-resistance to other treatment modalities. We here show that MES-SA/Dx5 cells with adapted resistance to doxorubicin (DOX) are cross-resistant to photodynamic therapy (PDT). A DOX-induced increased expression of the reactive oxygen species (ROS)-scavenging proteins glutathione peroxidase (GPx) 1 and GPx4 in MES-SA/Dx5 cells was indicated as the mechanism of resistance to PDT in line with the reduction in PDT-generated ROS observed in this cell line. ROS-induced p38 activation was, in addition, shown to be reduced to one-third of the signal of the parental MES-SA cells 2h after PDT, and addition of the p38 inhibitor SB203580 confirmed p38 activation as a death signal after PDT in the MES-SA cells. The MES-SA/Dx5 cells were also cross-resistant to ionizing radiation in agreement with the increased GPx1 and GPx4 expression. Surprisingly, PDT-induced endo/lysosomal release of the ribosome-inactivating protein gelonin (photochemical internalization (PCI)) was more effective in the PDT-resistant MES-SA/Dx5 cells, as measured by synergy calculations in both cell lines. Analysis of death-inducing signaling indicated a low activation of caspase-3 and a strong PARP I cleavage after PDT and PCI in both cell lines. The PARP I activation was, however, stronger after PCI than after PDT in the MES-SA cells, but not in the MES-SA/Dx5 cells, and therefore cannot explain the strong PCI effect in the MES-SA/Dx5 cells. In conclusion PCI of recombinant gelonin circumvents ROS resistance in an apoptosis-independent manner.
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Affiliation(s)
- Cathrine Elisabeth Olsen
- Department of Radiation Biology, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Norway.
| | - Kristian Berg
- Department of Radiation Biology, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Norway
| | - Pål Kristian Selbo
- Department of Radiation Biology, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Norway
| | - Anette Weyergang
- Department of Radiation Biology, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Norway
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Diving through Membranes: Molecular Cunning to Enforce the Endosomal Escape of Antibody-Targeted Anti-Tumor Toxins. Antibodies (Basel) 2013. [DOI: 10.3390/antib2020209] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
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37
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Photochemical internalization (PCI) of immunotoxins targeting CD133 is specific and highly potent at femtomolar levels in cells with cancer stem cell properties. J Control Release 2013; 168:317-26. [PMID: 23567040 DOI: 10.1016/j.jconrel.2013.03.023] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2013] [Revised: 03/22/2013] [Accepted: 03/24/2013] [Indexed: 12/17/2022]
Abstract
CD133 is a putative cancer stem cell (CSC) marker for a number of different cancers and is suggested to be a therapeutic target. Since also normal stem cells express CD133 it is of paramount importance that targeting strategies provide a specific and efficient delivery of cytotoxic drugs in only CD133-positive CSCs. In this study, we have employed photochemical internalization (PCI), a minimally invasive method for light-controlled, specific delivery of membrane-impermeable macromolecules from endocytic vesicles to the cytosol, to specifically target CD133-positive cancer cells. We demonstrate that PCI increases the cytotoxic effect of an immunotoxin (IT) targeting CD133-expressing cancer cells of colon (WiDr and HCT116) and pancreas (BxPC-3) origin. The IT consisted of the mAb CD133/1 (AC133) bound to the ribosome inactivating plant toxin saporin (anti-CD133/1-sap). We show that TPCS2a-PCI of anti-CD133/1-sap is specific, and highly cytotoxic at femto-molar concentrations. Specific binding and uptake of CD133/1, was shown by fluorescence microscopy and co-localization with TPCS2a in endosomes/lysosomes was determined by confocal microscopy. CD133(high) WiDr cells, isolated by fluorescence activated cell sorting, had a 7-fold higher capacity to initiate spheroids than CD133(low) cells (P<0.001) and were resistant to photodynamic therapy (PDT). However, PDT-resistance was bypassed by the PCI strategy. Tumor initiation and aggressive growth in athymic nude mice was obtained with only 10 CD133(high) cells in contrast to CD133(low) cells where substantially higher cell numbers were needed. The excellent high efficacy and selectivity of eliminating CD133-expressing cells by PCI warrant further pre-clinical evaluations of this novel therapeutic approach.
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Thakur M, Mergel K, Weng A, von Mallinckrodt B, Gilabert-Oriol R, Dürkop H, Melzig MF, Fuchs H. Targeted tumor therapy by epidermal growth factor appended toxin and purified saponin: an evaluation of toxicity and therapeutic potential in syngeneic tumor bearing mice. Mol Oncol 2012; 7:475-83. [PMID: 23298730 DOI: 10.1016/j.molonc.2012.12.004] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2012] [Revised: 12/12/2012] [Accepted: 12/12/2012] [Indexed: 10/27/2022] Open
Abstract
Targeted toxin-based therapeutics are hindered by poor intracellular uptake, limited stability and non-specific immune stimulation. To address these problems, ligand-targeted toxins in combination with low dose saponin mixtures have been adapted and tested in vivo in the past, however, undefined saponin raw mixtures are not suitable for use in clinical development. In the present work we therefore used a targeted toxin (Sap3-EGF, i.e. saporin fused to epidermal growth factor) in combination with a structurally defined isolated saponin m/z 1861 (SO-1861). In vitro evaluation confirmed a 6900-fold enhancement in the cytotoxic efficacy of Sap3-EGF against TSA-EGFR target cells. The required dose of the targeted toxin was appreciably reduced and there was a highly synergistic effect observed. An ex vivo hemolysis assay showed no or very less hemolysis up to 10 μg/mL of SO-1861. In the acute toxicity studies SO-1861 was found to be non-toxic up to a dose of 100 μg/treatment. The enzymes aspartate aminotransferase, alanine aminotransferase, and glutamate dehydrogenase did not show any statistically significant liver damage, which was further confirmed by histological examination. Additionally, creatinine was also similar to the control group thus ruling out damage to kidney. In vivo studies in a syngeneic BALB/c tumor model characterized by EGFR overexpression were done by applying 30 μg SO-1861 and 0.1 μg Sap3-EGF per treatment. A more than 90% reduction (p < 0.05) in the average tumor volume was observed by this combined therapy.
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Affiliation(s)
- Mayank Thakur
- Institut für Laboratoriumsmedizin, Klinische Chemie und Pathobiochemie, Charité - Universitätsmedizin Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, D-12200 Berlin, Germany.
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