| The investigation of the molecular biology of cancer and the discovery of novel anticancer agents are mutually beneficial research topics. Understanding the biology of cancer leads to improved drug design and target selection while describing new drugs and mechanisms of action may result in an increased knowledge of the workings of cancer. Marine organisms continue to be a source of bioactive secondary metabolites.; Investigations of Lissoclinum patella, a marine ascidian, have yielded many interesting compounds. The patellazoles are a family of compounds in which the known natural products consist of a 24-member macrolide ring with a thiazole-epoxide tail. The opening of this epoxide does not greatly affect the bioactivity of these compounds, although the general cellular toxicity is generally decreased.; The patellazoles are extremely cytotoxic towards HCT 116 human colon tumor cells. Treatment with nanomolar amounts of these compounds results in immediate inhibition of protein synthesis and cell cycle arrest at G 1 and S phase. Interestingly, DNA synthesis is initially stimulated by patellazole treatment but the patellazoles do not interact with DNA. HCT 116 wild type cells underwent apoptosis after extended patellazole treatment. Although treatment with the patellazoles resulted in an increased amount of p53, the p53 null cells were still strongly affected by treatment.; The inhibition of translation by patellazole treatment is linked to the inhibition of the mTOR/p70 pathway. Like the mTOR inhibitor rapamycin, the patellazoles inhibit translation through the 4EBP1 and S6 Kinase pathways. However, the cytotoxicity and inhibition profile of rapamycin and the patellazoles differ greatly in HCT 116 cells. The cellular target of the patellazoles is still unknown; the patellazole-induced inhibition of this pathway occurs either downstream or parallel to AKT.; Lissoclinolide has been described to possess antimicrobial activity but its effect upon mammalian cells was previously unknown. This small, non-nitrogenous L. patella metabolite is cytotoxic towards a range of tumor cell lines. Treatment with lissoclinolide results in G2/M arrest. However, neither p53 nor p21 are involved in the cellular response and apoptosis is not induced. COMPARE analysis in the NCI 60 tumor cell line panel revealed broad toxicity with some specificity towards colon tumor cell lines. |
