The off-Patent Anti-Fungal Ciclopirox Olamine Displays Preclinical Activity in Leukemia and Myeloma.
Bibliographic record
Abstract
Abstract Off-patent drugs with previously unrecognized anti-cancer activity could be rapidly repurposed for this new indication given their prior testing for safety and toxicity. To identify such compounds, we developed, automated and conducted a cell-based chemical screen of 4800 off-patent drugs and chemicals. From this chemical screen, we identified the off-patent antimicrobial, ciclopirox olamine (CPX) that is currently used for the topical treatment of cutaneous fungal infections, but has not been previously evaluated as a systemic agent for the treatment of malignancy. As an anti-fungal agent, the mechanism of action of CPX is not well understood, but appears related to binding intracellular iron and inhibiting iron containing enzymes. To explore its efficacy and mechanism of action as an anticancer agent, leukemia, myeloma, and solid tumor cell lines were treated with increasing concentrations of CPX. 72 hours after incubation, cell viability was measured by the MTS assay. CPX decreased cell viability in 5/9 leukemia, 3/6 myeloma, and 3/5 solid tumor cells with an LD50 < 5 uM, a concentration that is pharmacologically achievable based on prior animal studies investigating CPX as an anti-fungal. Cell death was confirmed by the presence of a subG1 peak by flow cytometry after staining cells with propidium iodide. In contrast, CPX was less toxic to MRC 5, LF1, and GMO 5757 non malignant fibroblasts with an LD50 > 20 uM. Next, we evaluated CPX in combination with cytarabine and daunorubicin, standard chemotherapeutic agents used in the treatment of AML. In AML cell lines, CPX synergistically enhanced the cytotoxicity of cytarabine as determined by the median effect isobologram analysis. Specifically, the combination indices (CI) at the EC50, 75 and 90 were 0.18, 0.19, and 0.24, respectively, where a CI < 1 denotes synergy. In contrast, the addition of CPX to daunorubicin produced only additive effects. Given the effects in leukemia cells lines, we evaluated the effects of oral CPX in 3 mouse models of leukemia. Sublethally irradiated NOD-SCID mice were injected subcutaneously with OCI-AML2 or K562 human leukemia cells or intraperitoneally with MDAY-D2 murine leukemia cells. After tumor implantation, mice were treated with CPX (25mg/kg) in water or water alone by oral gavage. Oral CPX decreased tumor weight and volume in all 3 mouse models by up to 65% compared to control without evidence of weight loss or gross organ toxicity. Mechanistically, CPX arrested cells in the G1/S phase of the cell cycle and downregulated the expression of survivin, Cyclin D1, and the transcription factors YY1 and FTII-D prior to the onset of cell death. Consistent with effects as an anti-fungal, CPX bound intracellular iron in the malignant cells and its ability to bind intracellular iron was functionally important for its cytotoxicity. In contrast to CPX, deferoxamine, a more avid extracellular iron chelator, was not significantly cytotoxic with an IC25 > 10uM. The highest demand for intracellular iron occurs during the late G1 and S phases due, in part, to the activity of the iron-requiring enzyme ribonucleotide reductase. Therefore, we examined the effects of CPX on the activity of ribonucleotide reductase. By electron paramagnetic resonance (EPR), CPX inhibited ribonucleotide reductase at concentrations associated with cell death. Cell lines resistant to CPX-mediated inhibition of ribonucleotide reductase were also resistant to CPX-induced cell death, supporting a mechanism of action linked to ribonucleotide reductase. Thus, in summary, the off-patent anti-fungal agent CPX induces cell death through its ability to bind intracellular iron. Its ability to inhibit the iron-containing enzyme ribonucleotide reductase appears functionally important for its mechanism of action. CPX displays previously unrecognized anti-cancer activity at concentrations that are pharmacologically achievable. Thus, CPX could be rapidly repurposed for the treatment of malignancies including leukemia and myeloma.
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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 | 0.000 | 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) | 0.000 | 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".