Antitumor activity and mechanism of action of the novel marine natural products mycalamide-A and -B and onnamide

Abstract

Three novel heterocyclic compounds, mycalamide-A and -B and onnamide, were isolated from Mycale sp. and Theonella sp. sponges collected in New Zealand and Okinawan waters. Each exhibited potent in vitro toxicity and in vivo efficacy against murine and human tumor cells. Concentrations of each that inhibited replication of cultured murine lymphoma P388 cells by 50% were 5 nM or less. Mycalamide-A and -B were also potent inhibitors of HL-60, HT-29, and A549 human tumor cell replication (50% inhibitory concentration less than 5 nM), while values for onnamide were greater (50% inhibitory concentrations between 25 and 200 nM). Mycalamide-A (10 micrograms/kg) and -B (2.5 micrograms/kg) were moderately active against P388 leukemia (increase in life span, approximately 50%), while onnamide was inactive (40 micrograms/kg; increase in life span, 15%). Mycalamide-A was also active against B16 melanoma, Lewis lung carcinoma, M5076 ovarian sarcoma, colon 26 carcinoma, and the human MX-1, CX-1, and Burkitt's lymphoma tumor xenografts. Mechanism of action studies indicate that the three agents inhibited protein synthesis. For example, after 1-h exposures to 20 nM mycalamide-A and -B, the rates of [3H]leucine incorporation into acid-precipitable material of cultured P388 cells were inhibited 54 and 99%, while the effects on incorporation of [3H]uridine and [3H]thymidine were less. The relative effects of 20 to 2000 nM mycalamide-A on protein, RNA, and DNA synthesis were consistent with those observed during exposure of P388 cells to 1 microM emetine, a known inhibitor of protein synthesis. Also, the three agents inhibited translation of RNA into protein in a cell-free lysate of rabbit reticulocytes. Although mycalamide-A disrupted DNA metabolism, the agent apparently did not intercalate into DNA, and a mixture of four deoxynucleosides (250 microM each) did not decrease the antiproliferative effects of the agent. Collectively, these data indicate that this class of compounds represents novel antitumor agents which should be further evaluated to define their potential.