Necroptosis activation is associated with greater methylene blue-photodynamic therapy-induced cytotoxicity in human pancreatic ductal adenocarcinoma cells (original) (raw)
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BMC cancer, 2017
Breast cancer is the main cause of mortality among women. The disease presents high recurrence mainly due to incomplete efficacy of primary treatment in killing all cancer cells. Photodynamic therapy (PDT), an approach that causes tissue destruction by visible light in the presence of a photosensitizer (Ps) and oxygen, appears as a promising alternative therapy that could be used adjunct to chemotherapy and surgery for curing cancer. However, the efficacy of PDT to treat breast tumours as well as the molecular mechanisms that lead to cell death remain unclear. In this study, we assessed the cell-killing potential of PDT using methylene blue (MB-PDT) in three breast epithelial cell lines that represent non-malignant conditions and different molecular subtypes of breast tumours. Cells were incubated in the absence or presence of MB and irradiated or not at 640 nm with 4.5 J/cm(2). We used a combination of imaging and biochemistry approaches to assess the involvement of classical autop...
Scientific reports, 2017
Cell death triggered by photodynamic therapy can occur through different mechanisms: apoptosis, necrosis or autophagy. However, recent studies have demonstrated the existence of other mechanisms with characteristics of both necrosis and apoptosis. These new cell death pathways, collectively termed regulated necrosis, include a variety of processes triggered by different stimuli. In this study, we evaluated the cell death mechanism induced by photodynamic treatments with two photosensitizers, meso-tetrakis (4-carboxyphenyl) porphyrin sodium salt (Na-H2TCPP) and its zinc derivative Na-ZnTCPP, in two human breast epithelial cell lines, a non-tumoral (MCF-10A) and a tumoral one (SKBR-3). Viability assays showed that photodynamic treatments with both photosensitizers induced a reduction in cell viability in a concentration-dependent manner and no dark toxicity was observed. The cell death mechanisms triggered were evaluated by several assays and cell line-dependent results were found. Mo...
An Efficient Photodynamic Therapy Treatment for Human Pancreatic Adenocarcinoma
Journal of Clinical Medicine
To date, pancreatic adenocarcinoma (ADKP) is a devastating disease for which the incidence rate is close to the mortality rate. The survival rate has evolved only 2–5% in 45 years, highlighting the failure of current therapies. Otherwise, the use of photodynamic therapy (PDT), based on the use of an adapted photosensitizer (PS) has already proved its worth and has prompted a growing interest in the field of oncology. We have developed a new photosensitizer (PS-FOL/PS2), protected by a recently published patent (WO2019 016397-A1, 24 January 2019). This photosensitizer is associated with an addressing molecule (folic acid) targeting the folate receptor 1 (FOLR1) with a high affinity. Folate binds to FOLR1, in a specific way, expressed in 100% of ADKP or over-expressed in 30% of cases. The first objective of this study is to evaluate the effectiveness of this PS2-PDT in four ADKP cell lines: Capan-1, Capan-2, MiapaCa-2, and Panc-1. For this purpose, we first evaluated the gene and prot...
Differential cell death response to photodynamic therapy is dependent on dose and cell type
British Journal of Cancer, 2001
Photodynamic therapy (PDT) may result in either apoptotic or necrotic cell death (Noodt et al, 1999). Many stimuli may trigger apoptosis: DNA damage, tumour necrosis factor, radiation, reactive oxygen species and elevated intracellular calcium levels. These stimuli interact with mitochondria, which are thought to be key regulators of apoptosis (Susin et al, 1998), by activation of the caspase cascade. Photodynamic therapy may interact with many of these pathways but it is unclear which is responsible for triggering apoptosis following PDT. The type of response may vary according to the cell type, the physical properties and intracellular localization of the sensitizer (Noodt et al, 1999) and the PDT dose (Kessel et al, 1995). The effect of PDT dose may reflect the fact that at low doses the cellular machinery for apoptosis is activated whereas at higher doses, the apoptotic machinery is itself damaged. The effect of cell type may depend on the genetics of the cell, as neoplastic cells often have mutations affecting the apoptotic machinery. MATERIALS AND METHODS Cell lines MCF 7, Human Mammary Carcinoma (ECACC, European collection of Animal Cell Cultures, Porton Down, UK). This cell line has a wild-type p53 gene (Sharma and Srikant, 1998), but a mutation in the caspase 3 gene (Janicke et al, 1998). T47D, Human Mammary Carcinoma (ECACC). This cell line contains a mutated p53 gene (Bonsing et al, 1997). HT1197, Human Bladder Carcinoma (ECACC). This cell line contains a mutated p53 gene (Cooper et al, 1994). WRC, Walker Rat Carcinoma. This cell line contains a wildtype p53 gene (Tang et al, 1996). MVECs, Human Microvascular Endothelial Cells, derived from human adipose tissue, by the method of Hewitt and Murray (1993). Cell culture techniques All of the cell types studied were cultured in their optimal media and maintained using standard tissue culture techniques. Cell death assay: dual staining for apoptosis and necrosis
International Journal of Oncology, 2004
In this study we describe photodamaging and photokilling effects of palladium(II)-tetraphenylporphycene (PdTPPo) (previously incorporated into dipalmitoylphosphatidylcholine liposomes) on the human lung adeno carcinoma A-549 cell line. No dark cytotoxicity was found when the drug was applied at 10 6 M or 5xl0 7 M for 1 or 18 h, respectively. After 1-h treatment with 10~7 M or 5xl0" 7 M PdTPPo followed by red light irradiation for variable times, dose-dependent lethal effects were observed in A-549 cells. Apoptosis was not found after the above photodynamic treatments or under even milder sublethal conditions. In contrast to HeLa cells subjected to PdTPPo photosensitization where either apoptosis or necrosis were induced, morpho logical analysis and electrophoretical DNA pattern of A-549 cells always revealed a clearly necrotic death mechanism. However, A-549 cells died by apoptosis after serum and Lglutamine deprivation, indicating that only the photodynamically induced apoptosis was inhibited. Immunofluorescent labeling revealed that microtubules and actin microfilaments were immediately and strongly damaged by photodynamic treatments with PdTPPo. No metaphase arrest and/or mitotic alterations were observed after phototreatments. Present results show that the cell type plays a fundamental role in relation to the apoptotic or necrotic response to photosensitization, and that cytoskeletal components are important targets implicated in cell death processes.
Cell Death Pathways Associated with Photodynamic Therapy: An Update
Photochemistry and photobiology, 2018
Photodynamic therapy (PDT) has the potential to make a significant impact on cancer treatment. PDT can sensitize malignant tissues to light, leading to a highly selective effect if an appropriate light dose can be delivered. Variations in light distribution and drug delivery, along with impaired efficacy in hypoxic regions, can reduce the overall tumor response. There is also evidence that malignant cells surviving PDT may become more aggressive than the initial tumor population. Promotion of more effective direct tumor eradication is therefore an important goal. While a list of properties for the "ideal" photosensitizing agent often includes formulation, pharmacologic and photophysical elements, we propose that subcellular targeting is also an important consideration. Perspectives relating to optimizing PDT efficacy are offered here. These relate to death pathways initiated by photodamage to particular subcellular organelles.
… and Photodynamic therapy, 2005
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.
Photochemical & Photobiological Sciences, 2007
Photodynamic therapy (PDT) represents a new rapidly-developing anticancer approach based on administration of a non-or weakly-toxic photosensitizer and its activation with light of appropriate wavelength. Hypericin, one of the promising photosensitizers, is known to induce apoptosis with high efficiency in various cell line models. However, here we report the prevalence of necrosis accompanied by suppression of caspase-3 activation in colon adenocarcinoma HT-29 cells exposed to an extensive range of PDT doses evoked by variations in two variables-hypericin concentration and light dose. Necrosis was the principal mode of cell death despite different PDT doses and the absence of anti-apoptotic Bcl-2 expression, even if the same condition induced caspase-3 activity at similar toxicity in HeLa cells. Introduction of Bcl-2 into HT-29 cells invoked caspase-3 activation, changed the Bcl-X L expression pattern, increased the apoptosis ratio with no effect on overall toxicity, and supported arrest in the G 2 /M-phase of cell cycle. Since it is known that Bcl-2 suppression in HT-29 is reversible and linked to the over-expression of mutated p53 and also considering our data, we suggest that the mutation in p53 and events linked to this feature may play a role in cell death signalling in HT-29 colon cancer cells.
Apoptosis and associated phenomena as a determinants of the efficacy of photodynamic therapy
Photochemical & photobiological sciences : Official journal of the European Photochemistry Association and the European Society for Photobiology, 2015
Failure of neoplastic cells to respond to conventional chemotherapy is usually associated with factors that limit access of drugs to subcellular sites, differences in cell-cycle kinetics or mutations leading to loss of drug-activation pathways or other processes that govern response factors. For PDT, efficacy depends mainly on selective uptake of photosensitizers by neoplastic cells, oxygenation levels, the suitable direction of irradiation and the availability of pathways to cell death that are highly conserved among mammalian cell types. While it is possible to engineer PDT-resistant cell types, current evidence suggests that the major obstacles to cancer control relate to drug, light and oxygen distribution. This review discusses some of the factors that can govern PDT-induced cell death.