Kojic Acid Derivative as an Antimitotic Agent That Selectively Kills Tumour Cells
Abstract
:1. Introduction
2. Results
2.1. Investigating the L1 Mechanism of Action
2.1.1. Light and Electron Microscopy Investigations
2.1.2. Next Generation Sequencing (NGS) Investigation
2.2. Investigation of Mitotic Exit into Apoptosis
2.3. Studies of L1 Selectivity Versus Tumour Cells
2.3.1. Light Microscopy Investigation of L1 Selectivity
2.3.2. Investigation of L1 Selectivity Using Next Generation Sequencing (NGS)
2.3.3. Investigation of Selective Cell Cycle Arrest Using Fluorescence
2.4. Bioavailability and Toxicity Studies of L1 in Different Cell Lines
3. Discussion
4. Materials and Methods
4.1. Reagents
4.2. Molecules Synthesis and Characterisation
4.3. Cell Cultures
4.4. Cytotoxic Activity
4.4.1. Trypan Blue Staining
4.4.2. MTT Assay
4.5. Determining L1 Bioavailability in the Cells
4.6. Microscopy
4.6.1. Light Microscopy
Hematoxylin and Eosin (H&E) Staining
Fluorescence Microscopy and Tubulin Staining
Toluidine Blue Staining
4.6.2. Electron Microscopy
Transmission Electron Microscopy (TEM)
Scanning Electron Microscopy (SEM)
4.7. Analysis of Cell Cycle Phases
Dose–Response Analysis
4.8. Next Generation Sequencing (NGS)
4.9. Apoptosis/Necrosis Analysis
4.10. Caspase-3 Activity Assay
5. Conclusions
6. Patents
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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External Gene Name | External Gene Source | Description | Base Mean | log2 Fold Change | lfcSE | Stat | p-Value | Padj |
---|---|---|---|---|---|---|---|---|
TUBB2B | HGNC Symbol | tubulin beta 2B class IIb[Source:HGNCSymbol;Acc:HGNC:30829] | 4300 | 1.2 | 0.05 | 23 | 8.70 × 10−119 | 1.20 × 10−114 |
INSIG1 | HGNC Symbol | insulin induced gene 1[Source:HGNCSymbol;Acc:HGNC:6083] | 2300 | 1.3 | 0.063 | 21 | 6.10 × 10−95 | 4.30 × 10−91 |
IDI1 | HGNC Symbol | isopentenyl-diphosphatedelta isomerase 1[Source:HGNCSymbol;Acc:HGNC:5387] | 7700 | 0.78 | 0.04 | 20 | 1.10 × 10−86 | 5.00 × 10−83 |
PNRC1 | HGNC Symbol | proline rich nuclearreceptor coactivator 1[Source:HGNCSymbol;Acc:HGNC:17278] | 2700 | 0.93 | 0.052 | 18 | 8.00 × 10−71 | 2.80 × 10−67 |
HERPUD1 | HGNC Symbol | homocysteine inducible ERprotein with ubiquitin likedomain 1 [Source:HGNCSymbol;Acc:HGNC:13744] | 4800 | 0.83 | 0.047 | 18 | 9.80 × 10−70 | 2.80 × 10−66 |
TP53INP2 | HGNC Symbol | tumour protein p53inducible nuclear protein 2[Source:HGNCSymbol;Acc:HGNC:16104] | 2000 | 1.2 | 0.067 | 17 | 1.40 × 10−66 | 3.20 × 10−63 |
TOB1 | HGNC Symbol | transducer of ERBB2, 1[Source:HGNCSymbol;Acc:HGNC:11979] | 8700 | 0.66 | 0.039 | 17 | 5.10 × 10−66 | 1.00 × 10−62 |
JUN | HGNC Symbol | Jun proto-oncogene, AP-1transcription factorsubunit [Source:HGNCSymbol;Acc:HGNC:6204] | 1700 | 1.2 | 0.072 | 17 | 6.40 × 10−65 | 1.10 × 10−61 |
SAT1 | HGNC Symbol | spermidine/spermine N1-acetyltransferase 1[Source:HGNCSymbol;Acc:HGNC:10540] | 3800 | 0.79 | 0.047 | 17 | 1.40 × 10−64 | 2.20 × 10−61 |
TRIB1 | HGNC Symbol | tribbles pseudokinase 1[Source:HGNCSymbol;Acc:HGNC:16891] | 2000 | 1.1 | 0.066 | 17 | 2.90 × 10−62 | 4.20 × 10−59 |
External Gene Name | External Gene Source | Description | Base Mean | log2 Fold Change | lfcSE | Stat | p-Value | Padj |
---|---|---|---|---|---|---|---|---|
TUBB | HGNC Symbol | tubulin beta class I[Source:HGNCSymbol;Acc:HGNC:20778] | 42,000 | −2.1 | 0.072 | −29 | 3.00 × 10−191 | 4.10 × 10−187 |
TUBA1B | HGNC Symbol | tubulin alpha 1b[Source:HGNCSymbol;Acc:HGNC:18809] | 73,000 | −1.9 | 0.074 | −25 | 4.40 × 10−142 | 3.00 × 10−138 |
TUBB4B | HGNC Symbol | tubulin beta 4B class IVb[Source:HGNCSymbol;Acc:HGNC:20771] | 24,000 | −1.8 | 0.076 | −23 | 9.40 × 10−122 | 4.30 × 10−118 |
ANKRD1 | HGNC Symbol | ankyrin repeat domain 1[Source:HGNCSymbol;Acc:HGNC:15819] | 6700 | 2.1 | 0.1 | 20 | 3.70 × 10−93 | 1.30 × 10−89 |
TAGLN | HGNC Symbol | transgelin [Source:HGNCSymbol;Acc:HGNC:11553] | 14,000 | 1.9 | 0.094 | 20 | 1.30 × 10−91 | 3.60 × 10−88 |
ITGA2 | HGNC Symbol | integrin subunit alpha 2[Source:HGNCSymbol;Acc:HGNC:6137] | 3400 | 1.9 | 0.095 | 20 | 3.70 × 10−88 | 8.50 × 10−85 |
TUBB2B | HGNC Symbol | tubulin beta 2B class IIb[Source:HGNCSymbol;Acc:HGNC:30829] | 4800 | −1.4 | 0.094 | −15 | 1.20 × 10−51 | 2.30 × 10−48 |
LAMA1 | HGNC Symbol | laminin subunit alpha 1[Source:HGNCSymbol;Acc:HGNC:6481] | 18,000 | −1.1 | 0.074 | −15 | 2.00 × 10−50 | 3.40 × 10−47 |
TUBA1C | HGNC Symbol | tubulin alpha 1c[Source:HGNCSymbol;Acc:HGNC:20768] | 27,000 | −1.2 | 0.082 | −15 | 5.60 × 10−49 | 8.50 × 10−46 |
DKK1 | HGNC Symbol | dickkopf WNT signalingpathway inhibitor 1[Source:HGNCSymbol;Acc:HGNC:2891] | 16,000 | 1 | 0.077 | 13 | 4.60 × 10−39 | 6.40 × 10−36 |
External_gene_name | External_gene_source | Description | BaseMean | log2FoldChange | lfcSE | Stat | p-Value | Padj |
---|---|---|---|---|---|---|---|---|
TUBB | HGNC Symbol | tubulin beta class I[Source:HGNCSymbol;Acc:HGNC:20778] | 56,000 | −1.9 | 0.057 | −33 | 1.4 × 10−243 | 1.7 × 10−239 |
TUBA1B | HGNC Symbol | tubulin alpha 1b[Source:HGNCSymbol;Acc:HGNC:18809] | 70,000 | −1.7 | 0.057 | −30 | 3.6 × 10−195 | 2.2 × 10−191 |
FLNA | HGNC Symbol | filamin A [Source:HGNCSymbol;Acc:HGNC:3754] | 45,000 | 1.3 | 0.057 | 23 | 1.3 × 10−116 | 5.1 × 10−113 |
IRS4 | HGNC Symbol | insulin receptor substrate4 [Source:HGNCSymbol;Acc:HGNC:6128] | 23,000 | −1.4 | 0.063 | −22 | 3.7 × 10−103 | 1.1 × 10−99 |
AL035425.2 | Clone-based (Ensembl)gene | insulin receptor substrate4 [Source:NCBIgene;Acc:8471] | 9800 | −1.7 | 0.084 | −20 | 4.8 × 10−93 | 1.2 × 10−89 |
AMOT | HGNC Symbol | angiomotin [Source:HGNCSymbol;Acc:HGNC:17810] | 51,000 | −1.1 | 0.057 | −20 | 3.4 × 10−88 | 6.8 × 10−85 |
TPM4 | HGNC Symbol | tropomyosin 4[Source:HGNCSymbol;Acc:HGNC:12013] | 11,000 | 1.2 | 0.073 | 17 | 1.1 × 10−63 | 1.9 × 10−60 |
GLA | HGNC Symbol | galactosidase alpha[Source:HGNCSymbol;Acc:HGNC:4296] | 10,000 | −1.3 | 0.076 | −17 | 2.1 × 10−62 | 3.2 × 10−59 |
TUBB4B | HGNC Symbol | tubulin beta 4B class IVb[Source:HGNCSymbol;Acc:HGNC:20771] | 16,000 | −1.2 | 0.072 | −16 | 5.8 × 10−60 | 7.8 × 10−57 |
JUN | HGNC Symbol | Jun proto-oncogene, AP-1transcription factorsubunit [Source:HGNCSymbol;Acc:HGNC:6204] | 9500 | 1.2 | 0.076 | 15 | 8.8 × 10−53 | 1.1 × 10−49 |
External_gene_name | External_gene_source | Description | BaseMean | log2FoldChange | lfcSE | Stat | p-Value | Padj |
---|---|---|---|---|---|---|---|---|
IRS4 | HGNC Symbol | insulin receptor substrate4 [Source:HGNCSymbol;Acc:HGNC:6128] | 23,000 | −0.69 | 0.032 | −22 | 8.8 × 10−106 | 1.2 × 10−101 |
NEFM | HGNC Symbol | neurofilament medium[Source:HGNCSymbol;Acc:HGNC:7734] | 15,000 | −0.61 | 0.035 | −18 | 2.4 × 10−70 | 1.7 × 10−66 |
BMP2 | HGNC Symbol | bone morphogeneticprotein 2 [Source:HGNCSymbol;Acc:HGNC:1069] | 4100 | −0.88 | 0.051 | −17 | 6.8 × 10−66 | 3.1 × 10−62 |
AL035425.2 | Clone-based (Ensembl)gene | insulin receptor substrate4 [Source:NCBIgene;Acc:8471] | 9400 | −0.86 | 0.055 | −16 | 6.3 × 10−55 | 2.2 × 10−51 |
ID2 | HGNC Symbol | inhibitor of DNA binding2 [Source:HGNCSymbol;Acc:HGNC:5361] | 7200 | −0.74 | 0.048 | −16 | 2.9 × 10−54 | 8 × 10−51 |
FAM84B | HGNC Symbol | family with sequencesimilarity 84 member B[Source:HGNCSymbol;Acc:HGNC:24166] | 4500 | −0.86 | 0.059 | −15 | 1 × 10−48 | 2.3 × 10−45 |
DFFA | HGNC Symbol | DNA fragmentation factorsubunit alpha[Source:HGNCSymbol;Acc:HGNC:2772] | 12,000 | −0.54 | 0.037 | −14 | 2.2 × 10−47 | 4.3 × 10−44 |
TFRC | HGNC Symbol | transferrin receptor[Source:HGNCSymbol;Acc:HGNC:11763] | 15,000 | 0.5 | 0.037 | 14 | 8.7 × 10−42 | 1.5 × 10−38 |
AMOT | HGNC Symbol | angiomotin[Source:HGNCSymbol;Acc:HGNC:17810] | 56,000 | −0.34 | 0.026 | −13 | 1 × 10−40 | 1.6 × 10−37 |
CA2 | HGNC Symbol | carbonic anhydrase 2[Source:HGNCSymbol;Acc:HGNC:1373] | 15,000 | −0.5 | 0.038 | −13 | 6 × 10−38 | 8.3 × 10−35 |
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Pichiri, G.; Piludu, M.; Congiu, T.; Grandi, N.; Coni, P.; Piras, M.; Jaremko, M.; Lachowicz, J.I. Kojic Acid Derivative as an Antimitotic Agent That Selectively Kills Tumour Cells. Pharmaceuticals 2025, 18, 11. https://doi.org/10.3390/ph18010011
Pichiri G, Piludu M, Congiu T, Grandi N, Coni P, Piras M, Jaremko M, Lachowicz JI. Kojic Acid Derivative as an Antimitotic Agent That Selectively Kills Tumour Cells. Pharmaceuticals. 2025; 18(1):11. https://doi.org/10.3390/ph18010011
Chicago/Turabian StylePichiri, Giuseppina, Marco Piludu, Terenzio Congiu, Nicole Grandi, Pierpaolo Coni, Monica Piras, Mariusz Jaremko, and Joanna Izabela Lachowicz. 2025. "Kojic Acid Derivative as an Antimitotic Agent That Selectively Kills Tumour Cells" Pharmaceuticals 18, no. 1: 11. https://doi.org/10.3390/ph18010011
APA StylePichiri, G., Piludu, M., Congiu, T., Grandi, N., Coni, P., Piras, M., Jaremko, M., & Lachowicz, J. I. (2025). Kojic Acid Derivative as an Antimitotic Agent That Selectively Kills Tumour Cells. Pharmaceuticals, 18(1), 11. https://doi.org/10.3390/ph18010011