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Production of Life-Saving Drugs from Marine Sources
Published in Prasenjit Mondal, Ajay K. Dalai, Sustainable Utilization of Natural Resources, 2017
Actin is an essential component of the cell’s cytoskeleton which participates in the regulation of many motor functions in the cell, such as cell migration, cell division, and muscle contraction. Notable number of highly potent cytotoxic agents that interact with actin have been produced by marine organisms (Figure 10.4). Latrunculins were the first actin-binding substances isolated from a marine source. Ichthyotoxicity principle isolated from sponge Latrunculia magnifica, Latrunculin A (33), was later shown to be cytotoxic (Kashman et al. 1980). Latrunculin A (33), a well-known actin-binding macrolide, arrests polylysine-induced nucleation at the level of an antiparallel dimer (Bubb et al. 2002). Antitumor macrolide aplyronine A (34) inhibits the polymerization of globular actin to fibrous actin by forming 1:1 complex with globular actin. Aplyronine A (34) binds to actin molecule by intercalating its aliphatic tail into a hydrophobic cleft of the actin molecule (Hirata et al. 2006). Spisulosine (35; ES-285), isolated from the sea mollusc Spisula polynyma, is a novel antiproliferative (antitumoral) compound of marine origin. It inhibits cell proliferation by preventing assembly of actin stress fibers (Cuadros et al. 2000). Marine sponge Mycale sp. derived NP mycalolide B (36) and a related kabiramide D (37) are actin-depolymerizing cytotoxic compounds (Wada et al. 1998). A polyketide bistramide-A (38), isolated from the marine ascidian Lissoclinum bistratum, disruptes actin cytoskeleton both by depolymerizing F-actin and binding directly to monomeric actin in vitro (Rizvi et al. 2006; Statsuk et al. 2005). Dimeric macrolides, bistheonellide-A or misakinolide-A (39), isolated from an Okinawan Theonella sp. sponge (Terry et al. 1997) and swinholide A (40) isolated from Symploca and Geitlerinema species of cyanobacteria (Andrianasolo et al. 2005) bind with two molecules of actin per molecule of these cytotoxic agents. Jasplakinolide (41), a cyclodepsipeptide isolated from marine sponge, Jaspis johnstoni, showed 50% growth inhibition of prostate carcinoma cell lines PC-3, LNCaP, and TSU-Pr1 at 65 nM, 41 nM, and 170 nM, respectively, on 48 h exposure (Senderowicz et al. 1995). Microcarpalide (42), isolated from culture broth of an endophytic fungus hosted by a Ficus microcarpa L. (Ratnayake et al. 2001), cause complete disruption of actin microfilament of NIH/3T3 fibroblasts incubated with microcarpalide (42; Furstner et al. 2007). Cytochalasin D (43) showed cytotoxicity at 100 nM against T cells (Suria et al. 1999).
Astral microtubules determine the final division axis of cells confined on anisotropic surface topography
Published in Journal of Experimental Nanoscience, 2020
Kyunghee Lee, Yen Ling Koon, Jaewon Kim, Keng-Hwee Chiam, Sungsu Park
Cortical cues have been shown to dictate spindle orientation of cells cultured on 2D FN coated surfaces [12]. To further investigate whether cortical cues can also affect spindle orientation of cells grown on microgratings, CD was treated to cells to perturb focal adhesion contacts and abolish cortical cues. Low concentrations of CD (0.2 μM) have been found to be sufficient to prevent membrane ruffling and disrupt treadmilling [28]. We immunostained RPE-1 and HeLa cells with vinculin both in the absence and presence of 1 µM CD. Vinculin is a membrane-cytoskeleton protein that is a constituent of focal adhesion plaques, and is involved in the linkage to actin. For control cells grown on 1 µm grating, vinculin accumulated along the ridges of the grating, with a preference for the ridge edge (Figure 2(A) top row). With the addition of CD, fluorescence intensities of both actin and vinculin decreased suggesting that focal adhesion cues were inhibited at these CD concentrations (Figure 2(A) bottom row). When cells are treated with 1 μM CD, aspect ratios for RPE-1 and HeLa increased by approximately 50% and 30%, respectively (Figure 2(B,C), top row and Table 4). In accordance to Hertwig’s rule, spindle angles of both cell lines decreased after CD treatment (Figure 2(B,C) bottom row and Table 4). To ensure consistency in our results, we also treated RPE-1 cells with another actin polymerisation inhibitor, Latrunculin A (Lat A). Lat A at low concentrations is known to induce the loss of stress fibers in fibroblasts [29,30]. Fluorescence intensities of both actin and vinculin disappeared in RPE-1 cells on the 1 μm grating when cells are treated with 100 nM Lat A for 12 h (Supplementary Figure 1(A)). In agreement with the CD results, aspect ratios of RPE-1 cells increased while spindle angles decreased in the presence of Lat A (Supplementary Figure 1(B,C)).