Anticancer Properties of Lamellarins

Abstract

In 1985 the first lamellarins were isolated from a small oceanic sea snail. Today, more than 50 lamellarins have been inventoried and numerous derivatives synthesized and tested as antiviral or anticancer agents. The lead compound in the family is lamellarin D, characterized as a potent inhibitor of both nuclear and mitochondrial topoisomerase I but also capable of directly interfering with mitochondria to trigger cancer cell death. The pharmacology and chemistry of lamellarins are discussed here and the mechanistic portrait of lamellarin D is detailed. Lamellarins frequently serve as a starting point in the design of anticancer compounds. Extensive efforts have been devoted to create novel structures as well as to improve synthetic methods, leading to lamellarins and related pyrrole-derived marine alkaloids.

Marine Natural Products as Models to Circumvent Multidrug Resistance

“…Compound 38 was 16 folds more sensitive than verapamil in doxorubicin-resistant Lo Vo/Dx cell line, and it increased the cytotoxicity of doxorubin, vinblastine, and daunorubicine in MDR cells because it directly inhibited P-gp pump function and increased drug accumulation in the cells [102]. Lamellarin O (41) is relevant as a multiple P-gp, BCRP, and MRP1 inhibitor [96], but synthetic analogs of 41, designed by QSAR studies and incorporating the methoxyacetophenone moiety unit, did not show BCRP inhibitory activity [103]. This study also allowed to establish some SAR features: bromo or mono-/dimethyl substituents on the indole moiety (Aryl-R 2 ) in lamellarin O (41) lead to a decrease in the BCRP inhibitory activity [103] ( Figure 8).…”

“…More than 50 lamellarins have been described and mainly differ in the number and position of hydroxyl and methoxy groups on the common chromenoindoles I scaffold (Figure 8) [96]. Some lamellarins possess interesting biological activities e.g., lamellarin L (36) which exhibits cytotoxicity against P388 and A549 cancer cell lines [97], lamellarin D (37) which is also an inhibitor of topoisomerase I-targeted antitumor agents and an antiproliferative agent [96,98] and the immunomodulating lamellarin α-20 sulfate which inhibits also HIV [99]. Lamellarin I (38) was the most potent polycyclic pyrrole-containing alkaloid described as a MDR modulator.…”

Marine Pharmaceuticals: A New Wave of Anti-angiogenic Drugs

“…It exerts potent cytotoxicity by apoptosis against multiple cancer cell lines [46]. Lamellarin D interferes with the activity of multiple kinases involved in cancer including CDKs and Glycogen Synthase Kinase-3 (GSK-3) [47]. CDKs play important role in endothelial cell cycle and migration, therefore they directly affect angiogenesis.…”

Marine Mollusk‐Derived Agents with Antiproliferative Activity as Promising Anticancer Agents to Overcome Chemotherapy Resistance

“…Since the first report, more than 50 lamellarins have been found mainly in Didemnum spp. ascidians as well as in various sponges . Of all the lamellarins identified up to date, lamellarin D ( 76 ; Fig.…”

“…Of all the lamellarins identified up to date, lamellarin D ( 76 ; Fig. ; Table ) displays the highest growth inhibitory effects on cancer cells, with GI 50 values ranging between 10 and 20 nM in a large panel of cancer cell lines . In addition to the nuclear targeting involving topoisomerase I inhibition with the modulation of several apoptotic mediators, lamellarin D accumulates rapidly inside the mitochondria, directly poisoning the mitochondrial topoisomerase I (Top1mt), and thus leading to the dysfunctional mitochondrial respiration in cells .…”