Intracellular and intratissular distribution of Foscan modulates apoptosis induced by photodynamic therapy
Bibliographic record
Abstract
Mechanisms of cell death triggered by photooxidatve stress are tightly related to the sites of photosensitizer accumulation. In this communication, we report the impact of intracellular or intratissular localisation of Foscan® on apoptosis induction following PDT. In vitro, the relationship between the subcellular localisation of Foscan® and intrinsic apoptotic pathway post Foscan®-PDT was investigated in the human mammary adenocarcinoma MCF-7 cell line. Apoptosis was analysed through mitochondria response (release of cytochrome c and membrane depolarisation) and activation of post mitochondrial caspase cascade, caspases -9 -7 (MCF-7 cells lack caspase-3) and -6. Short time (3h) of incubation with Foscan® revealed localisation mainly in Golgi apparatus and endoplasmic reticulum (ER). After photosensitization immediate mitochondria photodamage was observed followed by a mild activation of caspases. Increase in incubation time from 3h to 24 h with Foscan® showed a progressive leakage of Foscan® from Golgi apparatus. Cells incubated 24 hours with Foscan® and subjected to equitoxic light doses yielded fluence-dependent enhanced induction of the ER-resident glucose related protein 78 (Bip/GRP78) underlining the ER as the main site of photodamage. The analysis of apoptotic molecular events revealed a decrease in mitochondria response whereas caspase-7 activation was increased and strongly related to the expression of GRP78. Taken together, these results demonstrate that Foscan® localisation in ER improves the activation of a caspase-7 dependent pathway suggesting that apoptosis can be favoured by modulating the duration of photosensitiser contact with the tissue. In this context, in vivo apoptosis was evaluated in human colon adenocarcinoma HT29 xenografted tumour in nude mice subjected to Foscan® injected at different time (3h, 6h and 24h drug-light interval, DLI) before irradiation (30 mW cm-2, 10 J cm-2). Apoptosis was investigated in tumour sections by immunohistochemistry to active caspase-3. No significant apoptosis was observed at 3h DLI, whereas the number of apoptotic epithelial cells increased from 6h to 24h DLI. Co-labelling of caspase-3 with the vessel marker collagen IV displayed apoptosis in endothelial cells only at 6h DLI. These results demonstrate that DLI mediates vascular or tumour apoptotic response. In conclusion, applying protocols that elicit Foscan® accumulation in cellular targets prone to apoptosis could be an efficient strategy to improve clinical outcome.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.004 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".