1. Rhodomycin A, a novel Src-targeted compound, can suppress lung cancer cell progression via modulating Src-related pathways
Yi-Hua Lai, Min-Hsuan Chen, Sih-Yin Lin, Sheng-Yi Lin, Yung-Hao Wong, Sung-Liang Yu, Huei-Wen Chen, Chih-Hsin Yang, Gee-Chen Chang, Jeremy J W Chen Oncotarget. 2015 Sep 22;6(28):26252-65. doi: 10.18632/oncotarget.4761.
Src activation is involved in cancer progression and the interplay with EGFR. Inhibition of Src activity also represses the signalling pathways regulated by EGFR. Therefore, Src has been considered a target molecule for drug development. This study aimed to identify the compounds that target Src to suppress lung cancer tumourigenesis and metastasis and investigate their underlying molecular mechanisms. Using a molecular docking approach and the National Cancer Institute (NCI) compound dataset, eight candidate compounds were selected, and we evaluated their efficacy. Among them, rhodomycin A was the most efficient at reducing the activity and expression of Src in a dose-dependent manner, which was also the case for Src-associated proteins, including EGFR, STAT3, and FAK. Furthermore, rhodomycin A significantly suppressed cancer cell proliferation, migration, invasion, and clonogenicity in vitro and tumour growth in vivo. In addition, rhodomycin A rendered gefitinib-resistant lung adenocarcinoma cells more sensitive to gefitinib treatment, implying a synergistic effect of the combination therapy. Our data also reveal that the inhibitory effect of rhodomycin A on lung cancer progression may act through suppressing the Src-related multiple signalling pathways, including PI3K, JNK, Paxillin, and p130cas. These findings will assist the development of anti-tumour drugs to treat lung cancer.
2. Development of a Streptomyces venezuelae-based combinatorial biosynthetic system for the production of glycosylated derivatives of doxorubicin and its biosynthetic intermediates
Ah Reum Han, Je Won Park, Mi Kyeong Lee, Yeon Hee Ban, Young Ji Yoo, Eun Ji Kim, Eunji Kim, Byung-Gee Kim, Jae Kyung Sohng, Yeo Joon Yoon Appl Environ Microbiol. 2011 Jul;77(14):4912-23. doi: 10.1128/AEM.02527-10. Epub 2011 May 20.
Doxorubicin, one of the most widely used anticancer drugs, is composed of a tetracyclic polyketide aglycone and l-daunosamine as a deoxysugar moiety, which acts as an important determinant of its biological activity. This is exemplified by the fewer side effects of semisynthetic epirubicin (4'-epi-doxorubicin). An efficient combinatorial biosynthetic system that can convert the exogenous aglycone ε-rhodomycinone into diverse glycosylated derivatives of doxorubicin or its biosynthetic intermediates, rhodomycin D and daunorubicin, was developed through the use of Streptomyces venezuelae mutants carrying plasmids that direct the biosynthesis of different nucleotide deoxysugars and their transfer onto aglycone, as well as the postglycosylation modifications. This system improved epirubicin production from ε-rhodomycinone by selecting a substrate flexible glycosyltransferase, AknS, which was able to transfer the unnatural sugar donors and a TDP-4-ketohexose reductase, AvrE, which efficiently supported the biosynthesis of TDP-4-epi-l-daunosamine. Furthermore, a range of doxorubicin analogs containing diverse deoxysugar moieties, seven of which are novel rhodomycin D derivatives, were generated. This provides new insights into the functions of deoxysugar biosynthetic enzymes and demonstrates the potential of the S. venezuelae-based combinatorial biosynthetic system as a simple biological tool for modifying structurally complex sugar moieties attached to anthracyclines as an alternative to chemical syntheses for improving anticancer agents.
3. Rhodomycin analogues from Streptomyces purpurascens: isolation, characterization and biological activities
Sunita Holkar, Deovrat Begde, Nandita Nashikkar, Tukaram Kadam, Avinash Upadhyay Springerplus. 2013 Mar 9;2(1):93. doi: 10.1186/2193-1801-2-93. Print 2013 Dec.
During a screening program for bioactive natural products, a potential Streptomyces sp was isolated from soil. On the basis of biochemical, cultural, physiological and 16S rRNA gene analysis, it was identified as Streptomyces purpurascens. The isolate was grown in liquid medium and the crude antibiotic complex was obtained by ethyl acetate extraction. Seven purified fractions were obtained by preparative Thin Layer Chromatography (TLC). Acid hydrolysis of each fraction and subsequent TLC led to the identification of aglycones and sugars indicating these compounds to be Rhodomycin and its analogues. The identity of these compounds was established on the basis of UV-visible and FT-IR spectra and comparison with published data. The compounds were active against Gram-positive bacteria. Compound E, identified as Rhodomycin B, was found to be the most potent compound with an MIC of 2 μg/ml against Bacillus subtilis. Compounds A and F identified as α2-Rhodomycin II and Obelmycin respectively, and Compound E exhibited an IC50 of 8.8 μg/ml against HeLa cell line but no cytotoxicity was found against L929.