The marine alkaloid naamidine A promotes caspase-dependent apoptosis in tumor cells

Abstract

Apoptosis is important for normal development and removal of damaged cells. Evasion of apoptosis by cancer cells is one of the key characteristics of many tumor types. Thus, discovering agents that promote apoptosis in tumor cells could have great therapeutic value. Marine natural products have demonstrated great potential as anticancer agents, and the proapoptotic activity of some of these products is emerging as a potentially useful property for cancer treatments. Using a tumor xenograft assay in rodents, we previously found that the marine alkaloid naamidine A is a potent antitumor agent. In this study, we further characterize the mechanism of action of naamidine A. In cultured tumor cells, we find that naamidine A induces cell death, which is accompanied with annexin V staining, disruption of the mitochondrial membrane potential, and cleavage and activation of caspases 3, 8, and 9, all of which are hallmarks of apoptosis. Furthermore, naamidine A-induced cell death is caspase dependent. We also find that under conditions where naamidine A inhibits tumor xenograft growth, it induces activation of caspase 3, suggesting that apoptosis is part of its antitumorigenic activity in vivo. Apoptosis is not dependent on extracellular signal-regulated kinase 1/2, previously characterized molecular targets of naamidine A, nor does it require functional p53. Our studies support the continued study of naamidine A and its target(s) for the potential development of better clinical treatments for cancer.

An Improved High Yield Total Synthesis and Cytotoxicity Study of the Marine Alkaloid Neoamphimedine: An ATP-Competitive Inhibitor of Topoisomerase IIα and Potent Anticancer Agent

“…Therefore, using fluorescence-activated cell sorter (FACS) analysis [58,59], we measured neo’s effect on the cell cycle and apoptosis using SW48 cells treated with 0.60 μM neo for 48 h (Figure 3). Propidium iodide staining followed by FACS indicated that the percentage of cells in the G1 phase of the cell cycle were the same for both neo treated and control cells.…”

“…Cell cycle and apoptosis experiments were conducted as previously reported with slight modification [59]. Briefly, SW48 cells (2 × 10 5 per well) were seeded into six-well plates and incubated for 24 h. Cells were treated with neo (0.6 μM) for 48 h, washed with PBS, and trypsinized with 0.5 mL of 0.25% trypsin.…”

Synthesis and Biological Evaluation of Novel 3-Alkylpyridine Marine Alkaloid Analogs with Promising Anticancer Activity

“…The results presented in Figure 6 indicate that Compounds 4c and 5c promoted apoptosis in RKO-AS-45-1 and HeLa cells, reducing the number of viable cells. The apoptotic behavior of isolated or synthetic alkaloids is associated with mitochondrial membrane depolarization [38], phosphatidylserine externalization [39] and alteration of the patterns of cytoskeleton polymerization [40]. …”

Total synthesis and cytotoxicity of Leucetta alkaloids

“…To date, only the biological activity of naamidine A ( 3 ) has been extensively investigated by the Ireland lab which has demonstrated that it promotes caspase-dependent apoptosis in cultured tumor cells. 8 An Australian team has reported a modest exploration of the SAR of the naamine/naamidine A framework. 9 More recently, the Looper lab 10 and our group 11 have begun to evaluate the biological activity of synthetic versions of various other family members, specifically the naphthimidazole group.…”