A Marine Alkaloid, Ascomylactam A, Suppresses Lung Tumorigenesis via Inducing Cell Cycle G1/S Arrest through ROS/Akt/Rb Pathway

Abstract

Ascomylactam A was reported for the first time as a new 13-membered-ring macrocyclic alkaloid in 2019 from the mangrove endophytic fungus Didymella sp. CYSK-4 from the South China Sea. The aim of our study was to delineate the effects of ascomylactam A (AsA) on lung cancer cells and explore the antitumor molecular mechanisms underlying of AsA. In vitro, AsA markedly inhibited the cell proliferation with half-maximal inhibitory concentration (IC50) values from 4 to 8 μM on six lung cancer cell lines, respectively. In vivo, AsA suppressed the tumor growth of A549, NCI-H460 and NCI-H1975 xenografts significantly in mice. Furthermore, by analyses of the soft agar colony formation, 5-ethynyl-20-deoxyuridine (EdU) assay, reactive oxygen species (ROS) imaging, flow cytometry and Western blotting, AsA demonstrated the ability to induce cell cycle arrest in G1 and G1/S phases by increasing ROS generation and decreasing of Akt activity. Conversely, ROS inhibitors and overexpression of Akt could decrease cell growth inhibition and cell cycle arrest induced by AsA. Therefore, we believe that AsA blocks the cell cycle via an ROS-dependent Akt/Cyclin D1/Rb signaling pathway, which consequently leads to the observed antitumor effect both in vitro and in vivo. Our results suggest a novel leading compound for antitumor drug development.

Didymorenloids A and B, two polycyclic cyclopenta[b]fluorene-type alkaloids with anti-hepatoma activity from the mangrove endophytic fungus Didymella sp. CYSK-4

“…Crystal data for didymorenloid A (1): C 42 H 51 NO 9 , M r = 752.87, monoclinic, a = 11.0538 (3) Å, b = 12.9279 (3) Å, c = 14.5732 (4) Å, α = 90.00°, β = 110.0380° (10), γ = 90.00°, V = 1956.48 (9) Å 3 , T = 149.99 K, space group P2 1 , Z = 2, μ (CuKα) = 0.091 mm −1 , 28157 reflections collected, 9629 independent reflections (R int = 0.0617, R sigma = 0.0794). The final R 1 values were 0.0552 (I > 2σ(I)).…”

“…These compounds have also attracted attention from many biological and chemical scholars to study their activity mechanism, biosynthesis and chemical synthesis owing to the novel structure and significant activity of the decahydrofluorene class. [7][8][9][10] To date, more than sixty decahydrofluorene-class alkaloids with diverse structures have been reported. However, the number of cyclopenta[b]fluorene-type alkaloids is only fourteen.…”

“…1) of compounds with the mass ions of m/z 714 [M + H] + and 698 [M + H] + was traced for subsequent isolation. Guided by this approach, didymorenloid A (1), which features an unprecedented 6,13,16-trioxa-21-azole- tricyclo-[10.7.2.2 7,10 .0 12,19 .0 14,18 ]tricosane core, and didymorenloid B (2) (Fig. 2) were identified from Didymella sp.…”

Anti-Tumor Secondary Metabolites Originating from Fungi in the South China Sea’s Mangrove Ecosystem

“…CYSK-4 with a special structure of 12- or 13-membered-ring macrocyclic, displaying moderate anti-proliferative activity against MDA-MB-435, MDA-MB-231, SNB19 (glioma), HCT116, NCI-H460 (lung cancer), and PC-3 cells, with IC 50 values ranging from 4.2 to 7.8 μM [ 49 ]. Further research for ascomylactams A ( 71 ) showed that it suppressed the growth of A549, NCI-H460, and NCI-H1975 mice tumor xenografts in vivo and arrested the cell cycle through the ROS/Akt/Cyclin D1/Rb pathway both in vivo and in vitro [ 48 ]. Fusarisetins E-F ( 73 – 74 ) were two novel 3-decalinoyltetramic acid derivatives with the structure of a peroxide bridge derived from Fusarium sp.…”

Marine Alkaloids: Compounds with In Vivo Activity and Chemical Synthesis

“…According to the authors, the treatment with this alkaloid improved the efficiency of radiation therapy wherein the proposed mechanism involved an increase in the stress in the endoplasmic reticulum (increased levels of activating transcription factor 4) and eventual apoptosis during the radiotherapy treatment. In another experiment with mice, Wang et al [ 11 ] explored the effect of ascomylactam A ( 2 ) against human lung cancer (A549, NCI-H460, and NCI-H1975). The main effects of the treatment with this alkaloid were the significant reduction in the volume and weight of NCI-H460 tumor and the reduction in the volume of A549 tumors in mice treated with 6 mg/kg/day.…”