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Photodiagnosis and Photodynamic Therapy Feb 2024Photodynamic Therapy (PDT) is a clinically approved cancer treatment. Sex hormones, the key drivers for the development of female hormonal dependent cancers, might...
BACKGROUND
Photodynamic Therapy (PDT) is a clinically approved cancer treatment. Sex hormones, the key drivers for the development of female hormonal dependent cancers, might affect cancer treatment. There are seldom studies to evaluate the effect of sex hormones mimicked the menstrual cycle on the PDT mediated by prodrug 5-aminolevulinic acid (ALA) and its ester derivatives to the hormonal dependent cancers.
AIMS
To evaluate the efficacy of sex hormones on Hexyl-ALA-PDT in hormonal dependent cancers and the effect of the sex hormones on heme biosynthetic pathway.
METHODS
Cell culture system that mimicked the fluctuation of sex hormones 17β-estradiol (E2) and progesterone (PG) in the menstrual cycle was developed. Two pairs of hormonal-independent and hormonal dependent uterine sarcoma and breast cancer cell lines were used as cell models. Hexyl-ALA induced PpIX production and intracellular localization were examined. Key enzymes for PpIX synthesis were analysed. Hexyl-ALA-PDT mediated phototoxicity was evaluated.
RESULTS
The PpIX generation was increased in the hormonal-dependent cells (28-50 %) when cultured in the hormonal microenvironment with long incubation of Hexyl-ALA for 15 and 24 h compared to that cultured without hormones; whereas only slight difference in PpIX generation in their hormonal-independent counterpart. The PpIX generation was in a time-dependent manner. The CPOX, PPOX and FECH expressions were significantly enhanced by Hexyl-ALA-PDT in uterine sarcoma cells in hormonal microenvironment. Hexyl-ALA-PDT triggered significant increase of PPOX expression in breast cancer cells in hormonal microenvironment. The Hexyl-ALA-PDT phototoxicity was enhanced by 18-40 % in cells cultured in the hormonal system in a dose-dependent manner.
CONCLUSION
The PpIX generation and the efficacy of Hexyl-ALA-PDT in both uterine sarcoma and breast cancer cells was significantly enhanced by the sex hormones via cultured in the hormonal microenvironment.
Topics: Female; Humans; Photochemotherapy; Photosensitizing Agents; Sarcoma; Soft Tissue Neoplasms; Aminolevulinic Acid; Dermatitis, Phototoxic; Gonadal Steroid Hormones; Breast Neoplasms; Tumor Microenvironment; Flavoproteins; Mitochondrial Proteins; Protoporphyrinogen Oxidase
PubMed: 38316340
DOI: 10.1016/j.pdpdt.2024.103998 -
BioRxiv : the Preprint Server For... Jan 2024Being able to quantify the phototoxicity of dyes and drugs in live cells allows biologists to better understand cell responses to exogenous stimuli during imaging. This...
UNLABELLED
Being able to quantify the phototoxicity of dyes and drugs in live cells allows biologists to better understand cell responses to exogenous stimuli during imaging. This capability further helps to design fluorescent labels with lower phototoxicity and drugs with better efficacy. Conventional ways to evaluate cellular phototoxicity rely on late-stage measurements of individual or different populations of cells. Here, we developed a quantitative method using intracellular microtubule polymerization as a rapid and sensitive marker to quantify early-stage phototoxicity. Implementing this method, we assessed the photosensitization induced by organelle dyes illuminated with different excitation wavelengths. Notably, fluorescent markers targeting mitochondria, nuclei, and endoplasmic reticulum exhibited diverse levels of phototoxicity. Furthermore, leveraging a real-time precision opto-control technology allowed us to evaluate the synergistic effect of light and dyes on specific organelles. Studies in hypoxia revealed enhanced phototoxicity of Mito-Tracker Red CMXRos that is not correlated with the generation of reactive oxygen species but a different deleterious pathway in low oxygen conditions.
TEASER
Microtubule dynamics in live cells allow quantification of cellular phototoxicity of fluorescent dyes in various conditions.
PubMed: 38293099
DOI: 10.1101/2024.01.17.576021 -
Journal of Medicinal Chemistry Feb 2024One approach to reduce the side effects of chemotherapy in cancer treatment is photodynamic therapy (PDT), which allows spatiotemporal control of the cytotoxicity. We...
One approach to reduce the side effects of chemotherapy in cancer treatment is photodynamic therapy (PDT), which allows spatiotemporal control of the cytotoxicity. We have used the strategy of coordinating π-expansive ligands to increase the excited state lifetimes of Ir(III) half-sandwich complexes in order to facilitate the generation of O. We have obtained derivatives of formulas [Cp*Ir(CN)Cl] and [Cp*Ir(CN)L]BF with different degrees of π-expansion in the CN ligands. Complexes with the more π-expansive ligand are very effective photosensitizers with phototoxic indexes PI > 2000. Furthermore, PI values of 63 were achieved with red light. Time-dependent density functional theory (TD-DFT) calculations nicely explain the effect of the π-expansion. The complexes produce reactive oxygen species (ROS) at the cellular level, causing mitochondrial membrane depolarization, cleavage of DNA, nicotinamide adenine dinucleotide (NADH) oxidation, as well as lysosomal damage. Consequently, cell death by apoptosis and secondary necrosis is activated. Thus, we describe the first class of half-sandwich iridium cyclometalated complexes active in PDT.
Topics: Photosensitizing Agents; Antineoplastic Agents; Ligands; Photochemotherapy; Cell Line, Tumor; Iridium
PubMed: 38291666
DOI: 10.1021/acs.jmedchem.3c01276 -
International Journal of Molecular... Jan 2024(St. John's wort) has been described to be beneficial for the treatment of Alzheimer's disease (AD). Different extractions have demonstrated efficiency in mice and...
(St. John's wort) has been described to be beneficial for the treatment of Alzheimer's disease (AD). Different extractions have demonstrated efficiency in mice and humans, esp. extracts with a low hypericin and hyperforin content to reduce side effects such as phototoxicity. In order to systematically elucidate the therapeutic effects of extracts with different polarities, APP-transgenic mice were treated with a total ethanol extract (TE), a polar extract obtained from TE, and an apolar supercritical CO (scCO) extract. The scCO extract was formulated with silicon dioxide (SiO) for better oral application. APP-transgenic mice were treated with several extracts (total, polar, apolar) at different concentrations. We established an early treatment paradigm from the age of 40 days until the age of 80 days, starting before the onset of cerebral β-amyloid (Aβ) deposition at 45 days of age. Their effects on intracerebral soluble and insoluble Aβ were analyzed using biochemical analyses. Our study confirms that the scCO formulation shows better biological activity against Aβ-related pathological effects than the TE or polar extracts. Clinically, the treatment resulted in a dose-dependent improvement in food intake with augmentation of the body weight, and, biochemically, it resulted in a significant reduction in both soluble and insoluble Aβ (-27% and -25%, respectively). We therefore recommend apolar extracts for the early oral treatment of patients with mild cognitive impairment or early AD.
Topics: Humans; Mice; Animals; Infant; Plant Extracts; Phytotherapy; Hypericum; Alzheimer Disease; Silicon Dioxide; Amyloid beta-Peptides; Mice, Transgenic
PubMed: 38279301
DOI: 10.3390/ijms25021301 -
Frontiers in Pharmacology 2023Coumarins are naturally occuring metabolites from plants and a few micro-organisms. They have been widely used in the food and drug industry in their natural or... (Review)
Review
Coumarins are naturally occuring metabolites from plants and a few micro-organisms. They have been widely used in the food and drug industry in their natural or synthetic forms. Numerous coumarins possess several biological activities such as anti-inflammatory, anti-ulcers, anti-tumour, anti-microbial, anti-coagulant. The aim of this study was to assess the bioactivity, and toxicity of coumarins from African medicinal plants. We searched online databases and search engines such as PubMed, Google Scholar and Web of Science for key terms such as coumarins, toxicity, bioavailability, bioactivity with appropriate Boolean operators. Only full-length research articles published in English between 1956 to 2023 were reviewed. We recorded 22 coumarins from 15 plant species from Africa. Most of the plant species (33%) were from North Africa. These were followed by East Africa at 21%, then West, and Central Africa at 18.2% each. Most of the coumarins (21.3%) were isolated from the entire plant and the leaves (19.1%) and most of them (46.7%) had some antimicrobial activity. Five coumarins viz osthole, pseudocordatolide C & calanolide, chartreusin and esculetin had either antitumor or anticancer activity. Six coumarins had varying levels and types of toxicity ranging from inhibiting blood clotting as anticoagulants, to cytotoxic effects, causing hyperventilation, tremor, & photophobia, pulmonary haemorrhage, carcinogenic activity, severe neurotoxicity, hepato- and phototoxicity. Several African medicinal plants are sources of various coumarins that possess several biological activities as well as toxicities. This calls for more research into their safety and efficacy because of their wide spread applications as therapeutic agents.
PubMed: 38273831
DOI: 10.3389/fphar.2023.1231006 -
Research (Washington, D.C.) 2024Photodynamic therapy (PDT) has emerged as a promising approach for squamous cell carcinoma treatment but hindered by tumor hypoxia, acquired resistance, phototoxicity,...
Photodynamic therapy (PDT) has emerged as a promising approach for squamous cell carcinoma treatment but hindered by tumor hypoxia, acquired resistance, phototoxicity, and so on. To address these issues, we developed a smart strategy utilizing activable photosensitizers delivered by an aptamer-functionalized DNA probe (ADP). The ADP incorporated an AS1411 aptamer for tumor targeting and a linear antisense oligonucleotide (ASO) for recognition of Survivin mRNA. In the absence of the target, PDT remained quenched, thereby avoiding phototoxicity during circulation and nonselective distribution. With the aid of the aptamer, ADP achieved selective targeting of tumors. Upon internalization, ADP targeted recognized Survivin mRNA, triggering PDT activation, and releasing ASO to down-regulate Survivin expression and reverse tumor resistance. Consequently, the activable photosensitizers exhibited an "AND" logic gate, combining tumor-targeting delivery and tumor-related gene activation, thus enhancing its specificity. Additionally, the incorporation of hemin into the ADP provided catalase activity, converting tumor-abundant HO into O, thereby ameliorating tumor hypoxia. The resulting functionalized G-quadruplex/hemin-DNA probe complex demonstrated targeted delivery and activation, minimized side effects, and enhanced PDT efficacy in both xenograft tumor-bearing mice and patient-derived xenograft models. This study offers a unique and promising platform for efficient and safe PDT, thus holding great potential for future clinical translation and improved cancer therapy.
PubMed: 38269029
DOI: 10.34133/research.0295 -
Pharmaceutics Dec 2023In 2020, there were 377,713 new oral and lip cancer diagnoses and 177,757 deaths. Oral cancer is a malignancy of the head and neck region, and 90% of cases are squamous...
In 2020, there were 377,713 new oral and lip cancer diagnoses and 177,757 deaths. Oral cancer is a malignancy of the head and neck region, and 90% of cases are squamous cell carcinomas (OSCCs). One of the alternative methods of treating pre-cancerous lesions and oral cancer is photodynamic therapy (PDT). In addition to the cytotoxic effect, an important mechanism of PDT action is the immunomodulatory effect. This study used the OSCC (SCC-25) cell line and the healthy gingival fibroblast (HGF-1) line. A compound of natural origin-hypericin (HY)-was used as the photosensitizer (PS). The HY concentrations of 0-1 µM were used. After two hours of incubation with PS, the cells were irradiated with light doses of 0-20 J/cm. The MTT test determined sublethal doses of PDT. Cell supernatants subjected to sublethal PDT were assessed for interleukin 6 (IL-6), soluble IL-6 receptor alpha (sIL-6Ralfa), sIL-6Rbeta, IL-8, IL-10, IL-11 IL-20, IL-32, and Pentraxin-3 using the Bio-Plex Pro Assay. The phototoxic effect was observed starting with a light dose of 5 J/cm and amplified with increasing HY concentration and a light dose. HY-PDT affected the SCC-25 cell secretion of sIL-6Rbeta, IL-20, and Pentraxin-3. HY alone increased IL-8 secretion. In the case of HGF-1, the effect of HY-PDT on the secretion of IL-8 and IL-32 was found.
PubMed: 38258051
DOI: 10.3390/pharmaceutics16010042 -
The Study on Timolol and Its Potential Phototoxicity Using Chemical, In Silico and In Vitro Methods.Pharmaceuticals (Basel, Switzerland) Jan 2024Timolol (TIM) is a non-selective ß-adrenergic receptor antagonist used orally for the treatment of hypertension and heart attacks, and topically for treating glaucoma;...
Timolol (TIM) is a non-selective ß-adrenergic receptor antagonist used orally for the treatment of hypertension and heart attacks, and topically for treating glaucoma; lately, it has also been used in some specific dermatological problems. In the present study, its photodegradation and potential risk of phototoxicity were examined using chemical, in silico and in vitro methods. The UV/VIS irradiated solutions of TIM at pH 1-13 were subjected to LC-UV and UPLC-HRMS/MS analyses showing pseudo first-order kinetics of degradation and several degradation products. The structures of these photodegradants were elucidated by fragmentation path analysis based on high resolution (HR) fragmentation mass spectra, and then used for toxicity evaluation using OSIRIS Property Explorer and Toxtree. Potential risk of phototoxicity was also studied using chemical tests for detecting ROS under UV/VIS irradiation and in vitro tests on BALB/c 3T3 mouse fibroblasts (MTT, NRU and Live/Dead tests). TIM was shown to be potentially phototoxic because of its UV/VIS absorptive properties and generation ROS during irradiation. As was observed in the MTT and NRU tests, the co-treatment of fibroblasts with TIM and UV/VIS light inhibited cell viability, especially when concentrations of the drug were higher than 50 µg/mL.
PubMed: 38256931
DOI: 10.3390/ph17010098 -
Pharmaceuticals (Basel, Switzerland) Jan 2024The outcomes of unresectable gastric cancer (GC) are unfavorable even with chemotherapy; therefore, a new treatment modality is required. The combination of an oncolytic...
The outcomes of unresectable gastric cancer (GC) are unfavorable even with chemotherapy; therefore, a new treatment modality is required. The combination of an oncolytic virus and photodynamic therapy can be one of the promising modalities to overcome this. Mammalian orthoreovirus (MRV) is an oncolytic virus that has been used in clinical trials for several cancers. In this study, we developed and evaluated a recombinant MRV strain type 3 Dearing (T3D) that expresses membrane-targeting KillerRed (KRmem), a phototoxic fluorescent protein that produces cytotoxic reactive oxygen species upon light irradiation. KRmem was fused in-frame to the 3' end of the σ2 viral gene in the S2 segment using a 2A peptide linker, enabling the expression of multiple proteins from a single transcript. RNA electrophoresis, Western blotting, and immunofluorescence analyses confirmed functional insertion of KRmem into the recombinant virus. The growth activity of the recombinant virus was comparable to that of the wild-type MRV in a cultured cell line. The recombinant virus infected two GC cell lines (MKN45P and MKN7), and a significant cytocidal effect was observed in MKN45P cells infected with the recombinant virus after light irradiation. Thus, recombinant MRV-expressing KRmem has the potential to serve as a novel treatment tool for GC.
PubMed: 38256912
DOI: 10.3390/ph17010079 -
Pharmaceuticals (Basel, Switzerland) Dec 2023[Ru(bipy)(dpphen)]Cl (where bipy = 2,2'-bipyridine and dpphen = 2,9-diphenyl-1,10-phenanthroline) (complex ) is a sterically strained compound that exhibits promising in...
A Ru(II)-Strained Complex with 2,9-Diphenyl-1,10-phenanthroline Ligand Induces Selective Photoactivatable Chemotherapeutic Activity on Human Alveolar Carcinoma Cells via Apoptosis.
[Ru(bipy)(dpphen)]Cl (where bipy = 2,2'-bipyridine and dpphen = 2,9-diphenyl-1,10-phenanthroline) (complex ) is a sterically strained compound that exhibits promising in vitro photocytotoxicity on an array of cell lines. Since lung adenocarcinoma cancer remains the most common lung cancer and the leading cause of cancer deaths, the current study aims to evaluate the plausible effect and uptake of complex on human alveolar carcinoma cells (A549) and mesenchymal stem cells (MSC), and assess its cytotoxicity in vitro while considering its effect on cell morphology, membrane integrity and DNA damage. MSC and A549 cells showed similar rates of complex uptake with a plateau at 12 h. Upon photoactivation, complex exhibited selective, potent anticancer activity against A549 cells with phototoxicity index (PI) values of 16, 25 and 39 at 24, 48 and 72 h, respectively. This effect was accompanied by a significant increase in A549-cell rounding and detachment, loss of membrane integrity and DNA damage. Flow cytometry experiments confirmed that A549 cells undergo apoptosis when treated with complex followed by photoactivation. In conclusion, this present study suggests that complex might be a promising candidate for photochemotherapy with photoproducts that possess selective anticancer effects in vitro. These results are encouraging to probe the potential activity of this complex in vivo.
PubMed: 38256884
DOI: 10.3390/ph17010050