Microarray-Based Transcriptional Profiling of Renieramycin M and Jorunnamycin C, Isolated from Thai Marine Organisms

Renieramycin M and jorunnamycin C, two isoquinolinequinone compounds differing only at the C-22 ester side chain, were evaluated for their cytotoxic effects on human colon (HCT116) and breast (MDA-MB-435) cancer cell lines. These two compounds displayed potent cancer cell growth inhibition, their IC50 values reaching nanomolar order. To examine their effects on transcription, we carried out oligonucleotide microarray analysis with focus on the similarities and differences between the two compounds in terms of transcriptional profiles. We found that the down-regulation of PTPRK (protein tyrosine phosphatase receptor type K) can be considered as a biomarker responsive to the cytotoxic effects of this class of antitumor marine natural products

Molecular network profiling of U373MG human glioblastoma cells following induction of apoptosis by novel marine-derived anti-cancer 1,2,3,4-tetrahydroisoquinoline alkaloids

<p>Abstract</p> <p>Background</p> <p>Glioblastoma is the most aggressive form of brain tumors showing resistance to treatment with various chemotherapeutic agents. The most effective way to eradicate glioblastoma requires the concurrent inhibition of multiple signaling pathways and target molecules involved in the progression of glioblastoma. Recently, we obtained a series of 1,2,3,4-tetrahydroisoquinoline alkaloids with potent anti-cancer activities, including ecteinascidin-770 (ET-770; the compound 1a) and renieramycin M (RM; the compound 2a) from Thai marine invertebrates, together with a 2’<it>-N</it>-4”-pyridinecarbonyl derivative of ET-770 (the compound 3). We attempted to characterize the molecular pathways responsible for cytotoxic effects of these compounds on a human glioblastoma cell line U373MG.</p> <p>Methods</p> <p>We studied the genome-wide gene expression profile on microarrays and molecular networks by using pathway analysis tools of bioinformatics.</p> <p>Results</p> <p>All of these compounds induced apoptosis of U373MG cells at nanomolar concentrations. The compound 3 reduced the expression of 417 genes and elevated the levels of 84 genes, while ET-770 downregulated 426 genes and upregulated 45 genes. RM decreased the expression of 274 genes and increased the expression of 9 genes. The set of 196 downregulated genes and 6 upregulated genes showed an overlap among all the compounds, suggesting an existence of the common pathways involved in induction of apoptosis. We identified the ErbB (EGFR) signaling pathway as one of the common pathways enriched in the set of downregulated genes, composed of PTK2, AKT3, and GSK3B serving as key molecules that regulate cell movement and the nervous system development. Furthermore, a GSK3B-specific inhibitor induced apoptosis of U373MG cells, supporting an anti-apoptotic role of GSK3B.</p> <p>Conclusion</p> <p>Molecular network analysis is a useful approach not only to characterize the glioma-relevant pathways but also to identify the network-based effective drug targets.</p

Chemistry of Renieramycins. 15. Synthesis of 22‑<i>O</i>‑Ester Derivatives of Jorunnamycin A and Their Cytotoxicity against Non-Small-Cell Lung Cancer Cells

Eighteen 22-<i>O</i>-ester derivatives of jorunnamycin A (<b>2</b>) were prepared via <b>2</b>, and their cytotoxicity against human non-small-cell lung cancer (NSCLC) cells was evaluated. Preliminary study of the structure–cytotoxicity relationship revealed that the ester part containing a nitrogen-heterocyclic ring elevated the cytotoxicity of the 22-<i>O</i>-ester derivatives. Among them, 22-<i>O</i>-(4-pyridinecarbonyl) ester <b>6a</b> is the most potent compound (IC₅₀ 1.1 and 1.6 nM), exhibiting 21-fold and 5-fold increases in cytotoxicity against the H292 and H460 NSCLC cell lines, respectively, relative to renieramycin M (<b>1</b>), the major cytotoxic bistetrahydro­isoquinolinequinone alkaloid of the Thai blue sponge <i>Xestospongia</i> sp