Pleiotropic Anti-Angiogenic and Anti-Oncogenic Activities of the Novel Mithralog Demycarosyl-3D-ß-D-Digitoxosyl-Mithramycin SK (EC-8042).
Demycarosyl-3D-ß-D-digitoxosyl-mithramycin SK (DIG-MSK) is a recently isolated analogue of mithramycin A (MTA) that showed differences with MTA in the DNA binding strength and selectivity. These differences correlated with a better therapeutic index and less toxicity in animal studies. Herein, we show that DIG-MSK displays a potent anti-tumor activity against different types of cancer cell lines, ovarian tumor cells being particularly sensitive to this drug. Of relevance, DIG-MSK exerts low toxicity on fibroblasts and peripheral blood mononuclear cells, this toxicity being significantly lower than that of MTA. In correlation with its antitumor activity, DIG-MSK strongly inhibited Sp1-mediated transcription and endogenous Sp1 mRNA expression, which correlated with the inhibition of the expression of key Sp1-regulated genes involved in tumorigenesis, including VEGFA, BCL2L1 (Bcl-XL), hTERT, BRCA2, MYC and SRC in several ovarian cells. Significantly, DIG-MSK was a stronger inhibitor of VEGFA expression than MTA. Accordingly, DIG-MSK also exhibited potent anti-angiogenic activity on microvascular endothelial cells. Likewise, it significantly inhibited the gene expression of VEGFR1, VEGFR2, FGFR, PDGFB and PDGFRA and, additionally, it induced the expression of the anti-angiogenic factors angiostatin and tunstatin. These effects correlated with a pro-apoptotic effect on proliferating microvascular endothelial cells and the inhibition of the formation of endothelial capillary structures. Overall, the pleiotropic activity of DIG-MSK in inhibiting key oncogenic and angiogenic pathways, together with its low toxicity profile, highlight the therapeutic potential of this new drug..
Medienart: |
E-Artikel |
---|
Erscheinungsjahr: |
2015 |
---|---|
Erschienen: |
2015 |
Enthalten in: |
Zur Gesamtaufnahme - volume:10 |
---|---|
Enthalten in: |
PLoS ONE - 10(2015), 11, p e0140786 |
Sprache: |
Englisch |
---|
Beteiligte Personen: |
Azahara Fernández-Guizán [VerfasserIn] |
---|
Links: |
doi.org [kostenfrei] |
---|
Themen: |
---|
doi: |
10.1371/journal.pone.0140786 |
---|
funding: |
|
---|---|
Förderinstitution / Projekttitel: |
|
PPN (Katalog-ID): |
DOAJ005983037 |
---|
LEADER | 01000caa a22002652 4500 | ||
---|---|---|---|
001 | DOAJ005983037 | ||
003 | DE-627 | ||
005 | 20230309195143.0 | ||
007 | cr uuu---uuuuu | ||
008 | 230225s2015 xx |||||o 00| ||eng c | ||
024 | 7 | |a 10.1371/journal.pone.0140786 |2 doi | |
035 | |a (DE-627)DOAJ005983037 | ||
035 | |a (DE-599)DOAJ83710cf680c6406cb141edd759977f02 | ||
040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
041 | |a eng | ||
100 | 0 | |a Azahara Fernández-Guizán |e verfasserin |4 aut | |
245 | 1 | 0 | |a Pleiotropic Anti-Angiogenic and Anti-Oncogenic Activities of the Novel Mithralog Demycarosyl-3D-ß-D-Digitoxosyl-Mithramycin SK (EC-8042). |
264 | 1 | |c 2015 | |
336 | |a Text |b txt |2 rdacontent | ||
337 | |a Computermedien |b c |2 rdamedia | ||
338 | |a Online-Ressource |b cr |2 rdacarrier | ||
520 | |a Demycarosyl-3D-ß-D-digitoxosyl-mithramycin SK (DIG-MSK) is a recently isolated analogue of mithramycin A (MTA) that showed differences with MTA in the DNA binding strength and selectivity. These differences correlated with a better therapeutic index and less toxicity in animal studies. Herein, we show that DIG-MSK displays a potent anti-tumor activity against different types of cancer cell lines, ovarian tumor cells being particularly sensitive to this drug. Of relevance, DIG-MSK exerts low toxicity on fibroblasts and peripheral blood mononuclear cells, this toxicity being significantly lower than that of MTA. In correlation with its antitumor activity, DIG-MSK strongly inhibited Sp1-mediated transcription and endogenous Sp1 mRNA expression, which correlated with the inhibition of the expression of key Sp1-regulated genes involved in tumorigenesis, including VEGFA, BCL2L1 (Bcl-XL), hTERT, BRCA2, MYC and SRC in several ovarian cells. Significantly, DIG-MSK was a stronger inhibitor of VEGFA expression than MTA. Accordingly, DIG-MSK also exhibited potent anti-angiogenic activity on microvascular endothelial cells. Likewise, it significantly inhibited the gene expression of VEGFR1, VEGFR2, FGFR, PDGFB and PDGFRA and, additionally, it induced the expression of the anti-angiogenic factors angiostatin and tunstatin. These effects correlated with a pro-apoptotic effect on proliferating microvascular endothelial cells and the inhibition of the formation of endothelial capillary structures. Overall, the pleiotropic activity of DIG-MSK in inhibiting key oncogenic and angiogenic pathways, together with its low toxicity profile, highlight the therapeutic potential of this new drug. | ||
653 | 0 | |a Medicine | |
653 | 0 | |a R | |
653 | 0 | |a Science | |
653 | 0 | |a Q | |
700 | 0 | |a Alejandro López-Soto |e verfasserin |4 aut | |
700 | 0 | |a Andrea Acebes-Huerta |e verfasserin |4 aut | |
700 | 0 | |a Leticia Huergo-Zapico |e verfasserin |4 aut | |
700 | 0 | |a Mónica Villa-Álvarez |e verfasserin |4 aut | |
700 | 0 | |a Luz-Elena Núñez |e verfasserin |4 aut | |
700 | 0 | |a Francisco Morís |e verfasserin |4 aut | |
700 | 0 | |a Segundo Gonzalez |e verfasserin |4 aut | |
773 | 0 | 8 | |i In |t PLoS ONE |d Public Library of Science (PLoS), 2007 |g 10(2015), 11, p e0140786 |w (DE-627)DOAJ000113018 |x 19326203 |7 nnns |
773 | 1 | 8 | |g volume:10 |g year:2015 |g number:11, p e0140786 |
856 | 4 | 0 | |u https://doi.org/10.1371/journal.pone.0140786 |z kostenfrei |
856 | 4 | 0 | |u https://doaj.org/article/83710cf680c6406cb141edd759977f02 |z kostenfrei |
856 | 4 | 0 | |u https://doi.org/10.1371/journal.pone.0140786 |z kostenfrei |
856 | 4 | 2 | |u https://doaj.org/toc/1932-6203 |y Journal toc |z kostenfrei |
912 | |a GBV_USEFLAG_A | ||
912 | |a GBV_DOAJ | ||
951 | |a AR | ||
952 | |d 10 |j 2015 |e 11, p e0140786 |