PubMed · 5107450
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T A Tromovitch. 1971-01-25. Cantharadin.. https://doi.org/10.1001/jama.1971.03180170074022
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Cantharidin is a natural toxin that has antitumor properties and causes leukocytosis as well as increasing sensitivity of tumor cells resistant to other chemotherapeutic agents. There is limited information, however, on the molecular pharmacological mechanisms of cantharidin on human cancer cells. We have used cDNA microarrays to identify gene expression changes in HL-60 promyeloid leukemia cells exposed to cantharidin. Cantharidin-treated cells not only decreased expression of genes coding for proteins involved in DNA replication (e.g., DNA polymerase delta), DNA repair (e.g., FANCG, ERCC), energy metabolism (e.g., isocitrate dehydrogenase alpha, ADP/ATP translocase), but also decreased expression of genes coding for proteins that have oncogenic activity (e.g., c-myc, GTPase) or show tumor-specific expression (e.g., phosphatidylinositol 3-kinase). In contrast, these treated cells overexpressed several genes that encode intracellular and secreted growth-inhibitory proteins (e.g., BTG2, MCP-3) as well as proapoptotic genes (e.g., ATL-derived PMA-responsive peptide). Our findings suggest that alterations in specific genes functionally related to cell proliferation or apoptosis may be responsible for cantharidin-mediated cytotoxicity. We also found that exposure of HL-60 cells to cantharidin resulted in the decreased expression of multidrug resistance-associated protein genes (e.g., ABCA3, MOAT-B), suggesting that cantharidin may be used as an oncotherapy sensitizer, and the increased expression of genes in modulating cytokine production and inflammatory response (e.g., NFIL-3, N-formylpeptide receptor), which may partly explain the stimulating effects on leukocytosis. Our data provide new insight into the molecular mechanisms of cantharidin.
The mass spectra of a series of N-substituted cantharidinimides were examined. The feature of this series compounds is a sequential double hydrogen transfer from the oxabicycloheptane unit to either the carbonyl group of the succinimide unit or the nitrogen atom of the pyridyl or thiazolyl substituent through space. The ability of the N-substituent to accept a hydrogen atom possibly leads to the different fragmentation pathway.
PURPOSE: Mammalian cells at mitosis contain chromatin in compacted form and are hypersensitive to ionizing radiation. Previous research had shown some chemicals that induce chromatin compaction within interphase cells act as radiosensitizers. Of these agents, cantharidin (LS-1), which is an inhibitor of protein phosphatases 1 (PP1) and 2A (PP2A), showed good radiosensitizing activity at non-toxic doses. Cantharidin and 13 additional structural analogues (LS-2-14) were tested for their radiosensitizing activity on tumour cells in vitro. MATERIALS AND METHODS: Twelve of the 14 cantharidin analogues were synthesized in the authors' laboratory. Various concentrations of the drugs were screened for toxicity and radiosensitizing effectiveness with asynchronous DU-145 (human prostate carcinoma) cells. More detailed radiobiological studies of the more potent agents were performed with HT-29 (human colon carcinoma) cells since they could be readily synchronized. The radiosensitization of G1 phase HT-29 cells was measured after a 2-h exposure to the more potent drugs and reductions of the surviving fraction after an acute dose of 2 Gy (SF2Gy) served to estimate their relative effectiveness. The increase in phosphorylation of histone 1 (H1) and histone 3 (H3) induced by these drug exposures was measured by Western blotting of protein extracts. Drug-induced change in chromatin morphology was visualized by electron microscopy, and the alkaline comet assay (which measures DNA single-strand breaks) was employed to measure the radiation sensitivity of cellular chromatin in the drug-treated cells. RESULTS: Of the 14 cantharidin analogues tested, LS-1, LS-2 and LS-5 at concentrations of 3-20 microM showed little or no toxicity, produced elevated levels of H1 and H3 phosphorylation, and effected significant radiosensitization at low radiation dose. The chromatin in tumour cells treated with LS-5 became visibly compacted and its DNA was about 1.6 times more sensitive to radiation-induced strand breakage relative to that of control cells. CONCLUSIONS: The results confirm the authors' earlier studies that showed an increase in tumour cell intrinsic radiosensitivity by exposure to agents that promote chromatin compaction. LS-5 was identified as the optimal radiosensitizing agent of this class of compounds. Radiosensitization was correlated with chromatin compaction and elevated phosphorylation of H1 and H3. The DNA in drug-treated cells exhibited an enhanced sensitivity to radiation-induced single-strand breakage.