Jadomycin B Acts Synergistically with NSAIDs to Produce Cytotoxic Effects in Human Breast Cancer Cells <i>in vitro</i>
Bibliographic record
Abstract
Background Breast cancer is the most prevalent cancer in North American women. Jadomycin B is a novel compound that is effective in killing triple negative human breast cancer cells that have become resistant to anthracycline and taxane chemotherapies. The mechanism through which jadomycin B exerts its cytotoxic effect remains to be fully characterized. A quantitative PCR (qPCR) array of cancer drug targets identified cyclooxygenase‐2 ( COX‐2 ) as a gene of interest in jadomycin B resistant breast cancer cells. Objective To explore the effects of COX‐2 signalling on jadomycin B cytotoxicity in MDA‐MB‐231 cells as a model of invasive triple‐negative, human breast cancer requiring more effective treatments. Methods and Results Control MDA‐MB‐231 (231‐CON) cells exposed to increasing concentrations of jadomycin B (0‐2.2 µM) over 7 months developed a 3‐fold resistance to jadomycin B as determined using methyl‐tetrazolium (MTT) cell viability assays. By qPCR, there was a significant increase in COX‐2 (40 fold, p < 0.05) but not cyclooxygenase‐1 ( COX‐1 ) ( 0.17 fold, p < 0.05 ), mRNA expression in jadomycin resistant (231‐JB) versus 231‐CON cells. A similar increase in COX‐ 2 was not observed in mitoxantrone resistant MDA‐MB‐231 cells (231‐MITX). We therefore hypothesized that inhibition of COX‐2 signalling would increase the susceptibility of breast cancer cells to jadomycin B. The 231‐CON and 231‐JB cells were treated with jadomycin B with or without the COX‐2 selective inhibitor celecoxib (CXB), or COX‐1/2 inhibitors ibuprofen (IBU) or Naproxen (NAP). The SynergyFinder 2.0 web application was used to analyze the cytotoxicity (MTT assays) of these combinations and calculate synergy scores using the Bliss model. IBU and NAP were found to act synergistically with jadomycin B in both control and jadomycin resistant cells, while CXB acted additively (Table 1). Conclusions Jadomycin B acts additively or synergistically with inhibitors of COX‐2 in vitro , resulting in increased cytotoxic effect. These results justify further investigation into the COX‐2 signaling pathway as a means to elucidate the mechanism of action of jadomycin B. Additionally, our research has the potential to contribute to an improved understanding of breast cancer relevant COX‐2 signalling, facilitating the use of COX‐2 inhibitors as chemosensitizers.
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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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
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".