A new pentacyclic guanidine alkaloid, monanchoxymycalin C (1) was isolated from a new collection of marine sponge Monanchora pulchra along with the known monanchoxymycalin A (2). The structure of 1 ...was elucidated on the basis of spectroscopic data. Monanchoxymycalin C exhibits cytotoxic activity against human cancer HeLa cells at low micromolar concentrations, induces apoptosis-related death of malignant cells and inhibits cancer cell colony formation. In addition, synergistic and additive effects have been observed in combination with cisplatin.
Background
Cisplatin-based chemotherapy is highly effective in metastasized germ cell tumours (GCT). However, 10–30 % of patients develop resistance to cisplatin, requiring salvage therapy. We ...investigated the in vitro activity of paclitaxel and the novel taxane cabazitaxel in cisplatin-sensitive and -resistant GCT cell lines.
Methods
In vitro activity of paclitaxel and cabazitaxel was determined by proliferation assays, and mode of action of cabazitaxel was assessed by western blotting and two screening approaches, i.e. whole proteome analysis and a human apoptosis array.
Results
Activity of paclitaxel and cabazitaxel was not affected by cisplatin resistance, suggesting that there is no cross-resistance between these agents in vitro. Cabazitaxel treatment showed a strong inhibitory effect on colony formation capacity. Cabazitaxel induced classical apoptosis in all cell lines, reflected by cleavage of PARP and caspase 3, without inducing specific changes in the cell cycle distribution. Using the proteomic and human apoptosis array screening approaches, differential regulation of several proteins, including members of the bcl-2 family, was found, giving first insights into the mode of action of cabazitaxel in GCT.
Conclusion
Cabazitaxel shows promising in vitro activity in GCT cells, independent of levels of cisplatin resistance.
Mycalamide A, a marine natural compound previously isolated from sponges, is known as a protein synthesis inhibitor with potent antitumor activity. However, the ability of this compound to prevent ...malignant transformation of cells has never been examined before. Here, for the first time, we report the isolation of mycalamide A from ascidian Polysincraton sp. as well as investigation of its cancer preventive properties. In murine JB6 Cl41 P+ cells, mycalamide A inhibited epidermal growth factor (EGF)-induced neoplastic transformation, and induced apoptosis at subnanomolar or nanomolar concentrations. The compound inhibited transcriptional activity of the oncogenic nuclear factors AP-1 and NF-κB, a potential mechanism of its cancer preventive properties. Induction of phosphorylation of the kinases MAPK p38, JNK, and ERK was also observed at high concentrations of mycalamide A. The drug shows promising potential for both cancer-prevention and cytotoxic therapy and should be further developed.
C11 cyclopentenone, 5-hydroxy-7-prop-2-en- (E)-ylidene-7,7a-dihydro-2H-cyclopentab pyran-6-one, isolated earlier from the sponges and ascidians, is known as a natural product possessing antimicrobial ...and cytotoxic properties. However, its cancer preventive activity has not been studied. Cancer preventive and proapoptotic properties of the compound as well as its effect on the main Mitogen- Activated Protein-Kinase (MAPK) signaling pathways were examined by the methods of epidermal growth factor- induced (EGFinduced) JB6 Cl41 P+ cell transformation in soft agar, flow cytometry, and MTS test of cell viability. Results: the compound inhibits EGFinduced neoplastic JB6 Cl41 P+ cell transformation in soft agar and induces apoptosis of HL-60 and THP-1 human leukemia cells. Jun N-terminal Kinase and p38 MAPK signaling pathways are involved in the cellular response to the treatment by the compound. Conclusions: 5-hydroxy-7-prop-2-en-(E)-ylidene- 7,7a-dihydro-2H-cyclopentabpyran-6- one and other related marine C11 cyclopentenones have potential for development of a new antitumor agent in cancer prophylactics and should be further investigated.
