CLU-502 is a polyisoprenylated benzophenone isolated from Clusia rosea, collected in Florida, USA. This novel substance was isolated from methanolic extracts of plant resins employing RP-HPLC techniques coupled to a photodiode array (PDA)-detector. Using the sulphorhodamine B (SRB) proliferation assay, CLU-502 has shown a potent cytotoxic activity in a panel of human tumor cell lines such as breast, colon, stomach, ovarian, neuroblastoma and leukemia lines. Both, wild-type cells and cells resistant to cytostatic therapy with doxorubicin (Adriamycin®), cis-platinum, etoposide (Vepesid®, VP-16), SN-38 (the active metabolite of CPT-11 (CAMPTOSAR®, Irinotecan), raltitrexed (Tomudex®) or 5-fluorouracil are highly sensitive to CLU-502. Interestingly, normal fibroblasts are more resistant to this compound than cancer cells. CLU-502 inhibits the unwinding activity of topoisomerase I in a relaxation of pBR322l plasmid, as well as the decatenation of kinetoplasmids by human topoisomerase II. In addition, after exposure of human colon carcinoma cells to CLU-502, the telomerase activity was inhibited dose-dependently. Further on, a drug-dependent effect on the phosphorylation of ERK1/2, the cytosolic downstream enzymes of the MAP-kinase pathway, was detected in Western blot analyses. The interaction of CLU-502 with PD98059, a specific inhibitor of ERK1/2 phosphorylation, results in a synergistic cytotoxic effect when both drugs are administered to human colon cancer cells simultaneously. The exposure of cell cultures to CLU-502 led to an arrest of the synthesis phase G1 in the cell cycle, measured by incorporation of propidium iodide and BrdU into the DNA. This G1 arrest should be a consequence of the induction of p21. Additionally, down-regulation of the N-myc proto-oncoprotein was observed in LAN-1 WT after the exposure to CLU-502. Finally, a dose dependent induction of DNA-damage in tumor cells was also observed. Finally, an apoptosis/DNA-damage in tumor cells was observed in agarose gels after the exposure of CLU-502 at different concentrations.

[Proc Amer Assoc Cancer Res, Volume 45, 2004]