The marine alkaloid naamidine A promotes caspase-dependent apoptosis in tumor cells.
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.
Department of Medicinal Chemistry University of Utah, Salt Lake City, UT 84112, USA.
Daniel V
DV
LaBarbera
Katarzyna
K
Modzelewska
Amanda I
AI
Glazar
Phillip D
PD
Gray
Manjinder
M
Kaur
Tong
T
Liu
Douglas
D
Grossman
Mary Kay
MK
Harper
Scott K
SK
Kuwada
Nadeem
N
Moghal
Chris M
CM
Ireland
D000470:Alkaloids / Q000302:isolation & purification / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000302:isolation & purification / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism*; D018929:Cell Culture Techniques; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007093:Imidazoles / Q000302:isolation & purification / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology; D011161:Porifera / Q000737:chemistry*; D016896:Treatment Outcome
D000470:Alkaloids; D000970:Antineoplastic Agents; D007093:Imidazoles; C114816:naamidine A; D020169:Caspases