Mithramycin SK, A Novel Antitumor Drug with Improved Therapeutic Index, Mithramycin SA, and Demycarosyl-mithramycin SK:  Three New Products Generated in the Mithramycin Producer Streptomyces argillaceus through Combinatorial Biosynthesis

Remsing, Lily L.; González, A.; Nur‐e‐Alam, Mohammad; Fernández-Lozano, M. José; Braña, Alfredo F.; Rix, Uwe; Oliveira, Marcos Antônio de; Méndez, Cármen; Salas, José A.; Rohr, Jürgen

doi:10.1021/ja034162h

Cited by 121 publications

(160 citation statements)

References 43 publications

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“…[9][10][11][12][13] In order to address these issues, extensive combinatorial biosynthesis has been performed on the MTM pathway and has resulted in several novel analogs. [14][15][16] The present authors have shown that the inactivation of the mtmW gene, which codes for the last enzyme in the MTM biosynthetic pathway, yields the most favorable of the new analogs, MTM SK (SK) and MTMSDK (SDK). 15,16 Both SK and SDK exhibited higher anticancer activity than the native MTM, 15,16 yet their short plasma retention time and low accumulation in tumors remained to be improved.…”

Section: Introductionmentioning

confidence: 91%

Nanoparticulate formulations of mithramycin analogs for enhanced cytotoxicity

Scott

Rohr

Bae

2011

IJN

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Mithramycin (MTM), a natural product of soil bacteria from the Streptomyces genus, displays potent anticancer activity but has been limited clinically by severe side effects and toxicities. Engineering of the MTM biosynthetic pathway has produced the 3-side-chain-modified analogs MTM SK (SK) and MTM SDK (SDK), which have exhibited increased anticancer activity and improved therapeutic index. However, these analogs still suffer from low bioavailability, short plasma retention time, and low tumor accumulation. In an effort to aid with these shortcomings, two nanoparticulate formulations, poly(ethylene glycol)-poly(aspartate hydrazide) self-assembled and cross-linked micelles, were investigated with regard to the ability to load and pH dependently release the drugs. Micelles were successfully formed with both nanoparticulate formulations of each drug analog, with an average size of 8.36 ± 3.21 and 12.19 ± 2.77 nm for the SK and SDK micelles and 29.56 ± 4.67 nm and 30.48 ± 7.00 nm for the SK and SDK cross-linked micelles respectively. All of the drug-loaded formulations showed a pH-dependent release of the drugs, which was accelerated as pH decreased from 7.4 to 5.0. The micelles retained biological activity of SK and SDK entrapped in the micelles, suppressing human A549 lung cancer cells effectively.

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Section: Introductionmentioning

confidence: 91%

Nanoparticulate formulations of mithramycin analogs for enhanced cytotoxicity

Scott

Rohr

Bae

2011

IJN

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“…Mithramycin A is an anti-tumour antibiotic which inhibits transcription from promoters containing GC-rich DNA sequences (Miller et al, 1987;Blume et al, 1991). Mithramycin A is licensed for clinical use, and therefore the elucidation of its mechanisms of action is of interest in that respect (Remsing et al, 2003;Ferrante et al, 2004). In this report, however, we have focussed on its application as a useful tool to probe the mechanisms whereby the expression of Hdm2 is regulated in cancer cells.…”

Section: Regulation Of Hdm2 By Mithramycin a A Phillips Et Almentioning

confidence: 99%

GC-selective DNA-binding antibiotic, Mithramycin A, reveals multiple points of control in the regulation of Hdm2 protein synthesis

2006

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The primary role of the Hdm2/Mdm2 oncoprotein is to regulate the levels and activity of the transcription factor p53. Hdm2 synthesis is itself tightly controlled and, as demonstrated by a recently described SNP (SNP309) in the hdm2-P2 promoter, minor variations in Hdm2 expression have phenotypic consequences on radiation sensitivity and cancer predisposition. To further define mechanisms regulating Hdm2 expression, we have investigated the effects of the GC-selective DNA-binding drug, Mithramycin A (MA) on hdm2 mRNA transcription, trafficking, and translation. Firstly we show that the constitutive hdm2-P1 promoter is inhibited by MA. We define, for the first time, the minimal sequence elements that are required for P1-promoter activity and identify those which confer MA sensitivity. Secondly, MA induces p53-dependent transcription from the hdm2-P2 promoter. Thirdly, and critically, MA also inhibits Hdm2 synthesis at the post-transcriptional level, with negative effects on hdm2 mRNA nuclear export and translation. This study highlights the complex interplay between the pathways that regulate Hdm2 protein synthesis in cancer cells, and furthermore emphasizes the export of hdm2 mRNA from the nucleus to the cytoplasm as a key point of control in this process.

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“…We next analysed the capabilities of siPa and siE1 to modulate sensitivity of MDA-MB-231 cells to the antitumor drug mithramycin A (Remsing et al, 2003) and UV light. Both PKCa and Ets1 have been reported to be involved in stress-induced responses.…”

Section: Sipa Interferes With Ets1 Protein Synthesis and Stabilitymentioning

confidence: 99%

Ets1 is an effector of protein kinase Cα in cancer cells

Vetter¹,

Blumenthal

Lindemann

et al. 2004

Oncogene

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PKCa and Ets1 are both associated with breast cancer progression. Our previous studies suggested that these proteins are likely to functionally interact with one another. Here, we show that attenuation of endogenous PKCa expression (siPa) by RNA interference leads to reduced Ets1 protein expression in a variety of cancer cells. Pulse-chase experiments and treatment with proteasome inhibitor MG-132 revealed that siPa interferes with both Ets1 protein synthesis and stability. The effect of siPa on Ets1 expression could be partially prevented by KN-93, suggesting that calcium/calmodulin-dependent kinase II (CaMKII), a modulator of Ets1 activity, may play a role in PKCa-dependent Ets1 regulation. In contrast, Ets1-regulating kinases ERK1/ 2 were not found to be involved in this process. To assess the importance of the PKCa/Ets1 interaction, we compared the biological responses of MDA-MB-231 cells to PKCa-and Ets1-specific siRNAs (siE1). While only siPa induced changes in cellular morphology and anchorage-independent growth, both siRNAs similarly affected cellular responses to the antitumor drug mithramycin A and to UV light. Microarray analyses further showed that the expression of a certain set of genes was equally affected by siPa and siE1. The data suggest that Ets1 serves as an effector for PKCa to fulfil certain functions in cancer cells.

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Mithramycin SK, A Novel Antitumor Drug with Improved Therapeutic Index, Mithramycin SA, and Demycarosyl-mithramycin SK: Three New Products Generated in the Mithramycin Producer Streptomyces argillaceus through Combinatorial Biosynthesis

Cited by 121 publications

References 43 publications

Nanoparticulate formulations of mithramycin analogs for enhanced cytotoxicity

Nanoparticulate formulations of mithramycin analogs for enhanced cytotoxicity

GC-selective DNA-binding antibiotic, Mithramycin A, reveals multiple points of control in the regulation of Hdm2 protein synthesis

Ets1 is an effector of protein kinase Cα in cancer cells

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