Antitumor activity and nucleic acid binding properties of dercitin, a new acridine alkaloid isolated from a marine Dercitus species sponge.

A new cytotoxic acridine alkaloid that exhibited antitumor activity in vivo was isolated from a marine Dercitus species sponge collected at a depth of 160 m in the Bahamas. This violet alkaloid, designated dercitin, inhibited the proliferation of cultured murine and human leukemia, lung, and colon tumor cells at nM concentrations (IC50 values of 63-150 nM) and prolonged the life of mice bearing ascitic P388 tumors (%T/C = 170, 5 mg/kg, i.p., QD1-9). Dercitin was also active against i.p. B16 melanoma and modestly inhibited the growth of s.c. Lewis lung carcinoma on the same schedule. DNA blocked the antiproliferative effects of the agent in culture, and incorporation studies indicated that dercitin disrupted DNA and RNA synthesis with less effects on protein synthesis, similar to the effects of known DNA intercalators. After 1-h exposure to 400 nM dercitin, the rates of incorporation of [3H]uridine, [3H]thymidine, and [3H]leucine by cultured P388 cells were inhibited 83, 61, and 23%, respectively. Equilibrium dialysis indicated that dercitin bound calf thymus DNA with an affinity of 3.1 microM and maximal binding of 0.20 mol dercitin/mol base pair. Binding involved intercalation as evidenced by ability to relax supercoiled phi X174 DNA (half maximal concentration for dercitin relaxation was 36 nM). The effects of dercitin on DNA mobility were reversible, and complete relaxation of DNA with topoisomerase I in the presence of dercitin followed by phenol extraction resulted in the appearance of supercoiled DNA. Dercitin, at microM concentrations, had a small effect in the K+-sodium dodecyl sulfate assay using cultured P388 cells, suggesting minimal inhibition of topoisomerase activity. But, dercitin completely inhibited DNA polymerase I/DNase nick translation of DNA at 1 microM. Relaxation of DNA at a given concentration was greater than inhibition of nick translation suggesting that the effects of dercitin on enzyme activity were secondary to changes in DNA conformation. Results indicate that dercitin is a new marine natural product that probably exerts its biological effects through intercalation into nucleic acids.