Metabolic Manipulation of Glutathione as an Anticancer Therapeutic Target
Bibliographic record
Abstract
Many cancers rely on glycolysis rather than mitochondrial metabolism as their primary source of ATP. As such, altering this balance through forced mitochondrial activation has yielded promising results as anticancer therapies for specific cancers. In previous studies, stimulated mitochondrial activation through exposure to palmitoylcarnitine, a mitochondrial fatty-acid substrate, resulted in colon and prostate cancer-specific cell death, however, mitochondrial fatty-acid oxidation led to increased cervical cancer growth. The primary mechanism for promoting antineoplastic effects in response to palmitoylcarnitine is through oxidative stress, namely through production of superoxide and subsequently hydrogen peroxide (H2O2). However, H2O2 can be hormetic in nature, whereby elevated H2O2 can result in deleterious effects, yet modest H2O2 can promote growth. Therefore, the ability of the cell to regulate H2O2 is of apparent importance, highlighting glutathione, the most abundant intracellular antioxidant, as a potential determinant of cancer survival following palmitoylcarnitine. The purpose of this dissertation was to first determine the response of glutathione to palmitoylcarnitine within relation to cell survival. Following palmitoylcarnitine, glutathione responses seemingly dictated cell fate, whereby HT29 colorectal carcinoma cells displayed decreased cell survival, increased H2O2 and decreased glutathione. CCD 841 normal colon cells were insensitive to palmitoylcarnitine despite increased H2O2, yet maintained glutathione. HepG2 hepatocarcinoma cells, cells associated with fatty-acid stimulated disease progression, increased cell growth with coordinated increases in glutathione following palmitoylcarnitine. This dissertation considered recent evidence that suggests combined inhibition of glutathione and thioredoxin, another intracellular antioxidant, is required for anticancer effects in established tumours. Auranofin is a putative inhibitor of the thioredoxin system. HCT 116 p53-/- cells were resistant to auranofin at doses that HCT 116 p53+/+ cells were sensitive to, however concurrent exposure of auranofin and glutathione depletion through serine and glycine starvation sensitized HCT 116 p53-/- cells to decreased cell survival. This observation was repeated in a p53mutant cell line, HT29. Taken together, this thesis identifies glutathione as an important regulator in determining cell fate in response to palmitoylcarnitine, the dual role of glutathione and thioredoxin in influencing cell fate in relation to p53, and highlights the potential of redox-buffering systems as therapeutic targets for selective antineoplastic growth.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 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 source (direct Gemma or distilled Codex), 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".