Resistomycin Inhibits Wnt/ß-Catenin Signaling to Induce the Apoptotic Death of Human Colorectal Cancer Cells.

Resistomycin is a natural antibiotic related to quinone that has been shown to exhibit robust antitumor activity. To further characterize the mechanistic basis for such activity, human colorectal cancer (CRC) cells were selected as a model to explore the role of Wnt/ß-catenin signaling in the ability of resistomycin to induce apoptotic cell death. These analyses revealed that resistomycin was able to suppress ß-catenin, TCF4, and GSK-3ß expression, together with that of the downstream targets c-Myc and survivin. This coincided with elevated cleaved caspase-3 and Bax protein levels and a decline in Bcl-2 content. When ß-catenin was silenced, this further enhanced the ability of resistomycin to induce apoptotic CRC cell death, whereas this apoptotic process was partially ablated when cells were treated using lithium chloride to activate Wnt/ß-catenin signaling. Overall, these results support a model wherein resistomycin inhibits Wnt/ß-catenin signaling within CRC cells, thereby inducing apoptotic death. Further research may be warranted to better clarify the potential utility of this compound as a candidate drug for use in the treatment of patients suffering from this form of cancer.

Polyguluronic acid alleviates doxorubicin-induced cardiotoxicity by suppressing Peli1-NLRP3 inflammasome-mediated pyroptosis.

Polyguluronic acid (PG), a polysaccharide from alginate, possesses excellent bioactivities. We prepared high-purity PG with 10.41 kDa molecular weight (Mw) and a 59 average degree of polymerization (DP) by acid hydrolysis, three pH grades, Q-Sepharose column elution, and Sephadex G-25 column desalination. Then, we evaluated the PG protective effects on doxorubicin-induced cardiotoxicity (DIC) in vitro and in vivo. The nontoxic PG enhanced cellular viability, reduced cell pyroptosis morphology, diminished the LDH and IL-1ß release, and downregulated expressions of ASC oligomerization, NLRP3, cl-CASP1, and GSDMD, by which PG protected the cardiomyocytes from NLRP3 inflammasome-mediated pyroptosis in doxorubicin-stimulated HL-1 cells and C57BL/6J mice. The probable underlying mechanism may be that PG downregulated doxorubicin -induced Peli1, the deficiency of which could inhibit doxorubicin-induced NLRP3 inflammasome-mediated pyroptosis. These results suggested that polysaccharide PG from alginate could prevent DIC and may be a potential therapeutic agent or bioactive material for preventing DIC.

Saquayamycin B1 Suppresses Proliferation, Invasion, and Migration by Inhibiting PI3K/AKT Signaling Pathway in Human Colorectal Cancer Cells.

Moromycin B (Mor B), saquayamycin B1 (Saq B1), saquayamycin B (Saq B), and landomycin N (Lan N), four angucyclines produced by the marine-derived actinomycete Streptomyces sp., are a class of polyketone compounds containing benzanthracene. Here, the structure-activity relationship of these four compounds was analyzed in human colorectal cancer (CRC) cells. Saq B1, which showed the strongest cytotoxicity with an IC50 of 0.18-0.84 µM for CRC cells in MTT assays, was employed to test underlying mechanisms of action in SW480 and SW620 cells (two invasive CRC cell lines). Our results showed that Saq B1 inhibited CRC cell proliferation in a dose- and time-dependent manner. Notably, lower cytotoxicity was measured in normal human hepatocyte cells (QSG-7701). Furthermore, we observed proapoptosis, antimigration, and anti-invasion activities of Saq B1 in CRC cells. At the same time, the protein and mRNA expression of important markers related to the epithelial-mesenchymal transition (EMT) and apoptosis changed, including N-cadherin, E-cadherin, and Bcl-2, in Saq B1-treated CRC cells. Surprisingly, the PI3K/AKT signaling pathway was shown to be involved in Saq B1-induced apoptosis, and in inhibiting invasion and migration. Computer docking models also suggested that Saq B1 might bind to PI3Kα. Collectively, these results indicate that Saq B1 effectively inhibited growth and decreased the motor ability of CRC cells by regulating the PI3K/AKT signaling pathway, which provides more possibilities for the development of drugs in the treatment of CRC.