Abstract
Thiocoraline, a new anticancer agent derived from the marine actinomycete Micromonospora marina, was found to induce profound perturbations of the cell cycle. On both LoVo and SW620 human colon cancer cell lines, thiocoraline caused an arrest in G1 phase of the cell cycle and a decrease in the rate of S phase progression towards G2/M phases, as assessed by using bromodeoxyuridine/DNA biparametric flow cytometric analysis. Thiocoraline does not inhibit DNA-topoisomerase II enzymes in vitro, nor does it induce DNA breakage in cells exposed to effective drug concentrations. The cell cycle effects observed after exposure to thiocoraline appear related to the inhibition of DNA replication. By using a primer extension assay it was found that thiocoraline inhibited DNA elongation by DNA polymerase α at concentrations that inhibited cell cycle progression and clonogenicity. These studies indicate that the new anticancer drug thiocoraline probably acts by inhibiting DNA polymerase α activity. © 1999 Cancer Research Campaign
Keywords: natural compound, thiocoraline, cell cycle, DNA polymerase α
Full Text
The Full Text of this article is available as a PDF (307.8 KB).
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Capranico G., Zunino F., Kohn K. W., Pommier Y. Sequence-selective topoisomerase II inhibition by anthracycline derivatives in SV40 DNA: relationship with DNA binding affinity and cytotoxicity. Biochemistry. 1990 Jan 16;29(2):562–569. doi: 10.1021/bi00454a033. [DOI] [PubMed] [Google Scholar]
- Catapano C. V., Perrino F. W., Fernandes D. J. Primer RNA chain termination induced by 9-beta-D-arabinofuranosyl-2-fluoroadenine 5'-triphosphate. A mechanism of DNA synthesis inhibition. J Biol Chem. 1993 Apr 5;268(10):7179–7185. [PubMed] [Google Scholar]
- Erba E., Mascellani E., Pifferi A., D'Incalci M. Comparison of cell-cycle phase perturbations induced by the DNA-minor-groove alkylator tallimustine and by melphalan in the SW626 cell line. Int J Cancer. 1995 Jul 17;62(2):170–175. doi: 10.1002/ijc.2910620211. [DOI] [PubMed] [Google Scholar]
- Erba E., Sen S., Sessa C., Vikhanskaya F. L., D'Incalci M. Mechanism of cytotoxicity of 5,10-dideazatetrahydrofolic acid in human ovarian carcinoma cells in vitro and modulation of the drug activity by folic or folinic acid. Br J Cancer. 1994 Feb;69(2):205–211. doi: 10.1038/bjc.1994.40. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Faretta M., Bergamaschi D., Taverna S., Ronzoni S., Pantarotto M., Mascellani E., Cappella P., Ubezio P., Erba E. Characterization of cyclin B1 expression in human cancer cell lines by a new three-parameter BrdUrd/cyclin B1/DNA analysis. Cytometry. 1998 Jan 1;31(1):53–59. [PubMed] [Google Scholar]
- Huberman J. A. New views of the biochemistry of eucaryotic DNA replication revealed by aphidicolin, an unusual inhibitor of DNA polymerase alpha. Cell. 1981 Mar;23(3):647–648. doi: 10.1016/0092-8674(81)90426-8. [DOI] [PubMed] [Google Scholar]
- Krishan A., Frei E., 3rd Effect of adriamycin on the cell cycle traverse and kinetics of cultured human lymphoblasts. Cancer Res. 1976 Jan;36(1):143–150. [PubMed] [Google Scholar]
- Perez Baz J., Cañedo L. M., Fernández Puentes J. L., Silva Elipe M. V. Thiocoraline, a novel depsipeptide with antitumor activity produced by a marine Micromonospora. II. Physico-chemical properties and structure determination. J Antibiot (Tokyo) 1997 Sep;50(9):738–741. doi: 10.7164/antibiotics.50.738. [DOI] [PubMed] [Google Scholar]
- Poddevin B., Riou J. F., Lavelle F., Pommier Y. Dual topoisomerase I and II inhibition by intoplicine (RP-60475), a new antitumor agent in early clinical trials. Mol Pharmacol. 1993 Oct;44(4):767–774. [PubMed] [Google Scholar]
- Pommier Y., Minford J. K., Schwartz R. E., Zwelling L. A., Kohn K. W. Effects of the DNA intercalators 4'-(9-acridinylamino)methanesulfon-m-anisidide and 2-methyl-9-hydroxyellipticinium on topoisomerase II mediated DNA strand cleavage and strand passage. Biochemistry. 1985 Nov 5;24(23):6410–6416. doi: 10.1021/bi00344a015. [DOI] [PubMed] [Google Scholar]
- Romero F., Espliego F., Pérez Baz J., García de Quesada T., Grávalos D., de la Calle F., Fernández-Puentes J. L. Thiocoraline, a new depsipeptide with antitumor activity produced by a marine Micromonospora. I. Taxonomy, fermentation, isolation, and biological activities. J Antibiot (Tokyo) 1997 Sep;50(9):734–737. doi: 10.7164/antibiotics.50.734. [DOI] [PubMed] [Google Scholar]
- Sheaff R., Ilsley D., Kuchta R. Mechanism of DNA polymerase alpha inhibition by aphidicolin. Biochemistry. 1991 Sep 3;30(35):8590–8597. doi: 10.1021/bi00099a014. [DOI] [PubMed] [Google Scholar]