6-Br-5methylindirubin-3′oxime (5-Me-6-BIO) targeting the leishmanial glycogen synthase kinase-3 (GSK-3) short form affects cell-cycle progression and induces apoptosis-like death: Exploitation of GSK-3 for treating leishmaniasis

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6-Br-5methylindirubin-3′oxime (5-Me-6-BIO) targeting the leishmanial glycogen synthase kinase-3 (GSK-3) short form affects cell-cycle progression and induces apoptosis-like death: Exploitation of GSK-3 for treating leishmaniasis. / Xingi, Evangelia; Smirlis, Despina; Myrianthopoulos, Vassilios et al.
In: International Journal for Parasitology, Vol. 39, No. 12, 10.2009, p. 1289-1303.

Research output: Contribution to Journal/Magazine › Journal article › peer-review

Harvard

Xingi, E, Smirlis, D, Myrianthopoulos, V, Prokopios, M, Grant, K, Meijer, L, Mikros, E, Skaltsounis, A-L & Soteriadou, K 2009, '6-Br-5methylindirubin-3′oxime (5-Me-6-BIO) targeting the leishmanial glycogen synthase kinase-3 (GSK-3) short form affects cell-cycle progression and induces apoptosis-like death: Exploitation of GSK-3 for treating leishmaniasis', International Journal for Parasitology, vol. 39, no. 12, pp. 1289-1303. https://doi.org/10.1016/j.ijpara.2009.04.005

APA

Xingi, E., Smirlis, D., Myrianthopoulos, V., Prokopios, M., Grant, K., Meijer, L., Mikros, E., Skaltsounis, A-L., & Soteriadou, K. (2009). 6-Br-5methylindirubin-3′oxime (5-Me-6-BIO) targeting the leishmanial glycogen synthase kinase-3 (GSK-3) short form affects cell-cycle progression and induces apoptosis-like death: Exploitation of GSK-3 for treating leishmaniasis. International Journal for Parasitology, 39(12), 1289-1303. https://doi.org/10.1016/j.ijpara.2009.04.005

Vancouver

Xingi E, Smirlis D, Myrianthopoulos V, Prokopios M, Grant K, Meijer L et al. 6-Br-5methylindirubin-3′oxime (5-Me-6-BIO) targeting the leishmanial glycogen synthase kinase-3 (GSK-3) short form affects cell-cycle progression and induces apoptosis-like death: Exploitation of GSK-3 for treating leishmaniasis. International Journal for Parasitology. 2009 Oct;39(12):1289-1303. doi: 10.1016/j.ijpara.2009.04.005

Author

Xingi, Evangelia ; Smirlis, Despina ; Myrianthopoulos, Vassilios et al. / 6-Br-5methylindirubin-3′oxime (5-Me-6-BIO) targeting the leishmanial glycogen synthase kinase-3 (GSK-3) short form affects cell-cycle progression and induces apoptosis-like death: Exploitation of GSK-3 for treating leishmaniasis. In: International Journal for Parasitology. 2009 ; Vol. 39, No. 12. pp. 1289-1303.

Bibtex

@article{ec31ba4cfc0e48bdb3294bdecddca847,

title = "6-Br-5methylindirubin-3′oxime (5-Me-6-BIO) targeting the leishmanial glycogen synthase kinase-3 (GSK-3) short form affects cell-cycle progression and induces apoptosis-like death: Exploitation of GSK-3 for treating leishmaniasis",

abstract = "Indirubins known to target mammalian cyclin-dependent kinases (CDKs) and glycogen synthase kinase (GSK-3) were tested for their antileishmanial activity. 6-Br-indirubin-3'-oxime (6-BIO), 6-Br-indirubin-3'acetoxime and 6-Br-5methylindirubin-3'oxime (5-Me-6-BIO) were the most potent inhibitors of L. donovani promastigote and amastigote growth (IC50 values ≤ 1.2 μM). Since the 6-Br substitution on the indirubin backbone greatly enhances the selectivity for mammalian GSK-3 over CDKs, we identified the leishmanial GSK-3 homologues, a short (LdGSK-3s) and a long one, focusing on LdGSK-3s which is closer to human GSK-3β for further studies. Kinase assays showed that 5-Me-6-BIO inhibited LdGSK-3s more potently than CRK3 (the CDK1 homologue in Leishmania), while 6-BIO was more selective for CRK3. Promastigotes treated with 5-Me-6-BIO accumulated in the S and G2/M cell-cycle phases and underwent apoptosis-like death. Interestingly, these phenotypes were completely reversed in parasites over-expressing LdGSK-3s. This finding strongly supports that LdGSK-3s is a) the intracellular target of 5-Me-6-BIO and b) involved in cell-cycle control and in pathways leading to apoptosis-like death. 6-BIO treatment induced a G2/M arrest, consistent with inhibition of CRK3, and apoptosis-like death. These effects were partially reversed in parasites over-expressing LdGSK-3s suggesting that in vivo 6-BIO may also target LdGSK-3s. Molecular docking of 5-Me-6-BIO in CRK3 and 6-BIO in human GSK-3β and LdGSK-3s active sites predict the existence of functional/structural differences that are sufficient to explain the observed difference in their affinity. In conclusion, LdGSK-3s is validated as a potential drug target in Leishmania and could be exploited for the development of selective indirubin-based leishmanicidals.",

keywords = "L. donovani glycogen synthase kinase-3 short, 5-Me-6-BIO, 6-BIO, indirubins, apoptosis-like death, drug target",

author = "Evangelia Xingi and Despina Smirlis and Vassilios Myrianthopoulos and Magiatis Prokopios and Karen Grant and Laurent Meijer and Emmanuel Mikros and Alexios-Leandros Skaltsounis and Ketty Soteriadou",

year = "2009",

month = oct,

doi = "10.1016/j.ijpara.2009.04.005",

language = "English",

volume = "39",

pages = "1289--1303",

journal = "International Journal for Parasitology",

issn = "0020-7519",

publisher = "Elsevier Limited",

number = "12",

}

RIS

TY - JOUR

T1 - 6-Br-5methylindirubin-3′oxime (5-Me-6-BIO) targeting the leishmanial glycogen synthase kinase-3 (GSK-3) short form affects cell-cycle progression and induces apoptosis-like death: Exploitation of GSK-3 for treating leishmaniasis

AU - Xingi, Evangelia

AU - Smirlis, Despina

AU - Myrianthopoulos, Vassilios

AU - Prokopios, Magiatis

AU - Grant, Karen

AU - Meijer, Laurent

AU - Mikros, Emmanuel

AU - Skaltsounis, Alexios-Leandros

AU - Soteriadou, Ketty

PY - 2009/10

Y1 - 2009/10

N2 - Indirubins known to target mammalian cyclin-dependent kinases (CDKs) and glycogen synthase kinase (GSK-3) were tested for their antileishmanial activity. 6-Br-indirubin-3'-oxime (6-BIO), 6-Br-indirubin-3'acetoxime and 6-Br-5methylindirubin-3'oxime (5-Me-6-BIO) were the most potent inhibitors of L. donovani promastigote and amastigote growth (IC50 values ≤ 1.2 μM). Since the 6-Br substitution on the indirubin backbone greatly enhances the selectivity for mammalian GSK-3 over CDKs, we identified the leishmanial GSK-3 homologues, a short (LdGSK-3s) and a long one, focusing on LdGSK-3s which is closer to human GSK-3β for further studies. Kinase assays showed that 5-Me-6-BIO inhibited LdGSK-3s more potently than CRK3 (the CDK1 homologue in Leishmania), while 6-BIO was more selective for CRK3. Promastigotes treated with 5-Me-6-BIO accumulated in the S and G2/M cell-cycle phases and underwent apoptosis-like death. Interestingly, these phenotypes were completely reversed in parasites over-expressing LdGSK-3s. This finding strongly supports that LdGSK-3s is a) the intracellular target of 5-Me-6-BIO and b) involved in cell-cycle control and in pathways leading to apoptosis-like death. 6-BIO treatment induced a G2/M arrest, consistent with inhibition of CRK3, and apoptosis-like death. These effects were partially reversed in parasites over-expressing LdGSK-3s suggesting that in vivo 6-BIO may also target LdGSK-3s. Molecular docking of 5-Me-6-BIO in CRK3 and 6-BIO in human GSK-3β and LdGSK-3s active sites predict the existence of functional/structural differences that are sufficient to explain the observed difference in their affinity. In conclusion, LdGSK-3s is validated as a potential drug target in Leishmania and could be exploited for the development of selective indirubin-based leishmanicidals.

AB - Indirubins known to target mammalian cyclin-dependent kinases (CDKs) and glycogen synthase kinase (GSK-3) were tested for their antileishmanial activity. 6-Br-indirubin-3'-oxime (6-BIO), 6-Br-indirubin-3'acetoxime and 6-Br-5methylindirubin-3'oxime (5-Me-6-BIO) were the most potent inhibitors of L. donovani promastigote and amastigote growth (IC50 values ≤ 1.2 μM). Since the 6-Br substitution on the indirubin backbone greatly enhances the selectivity for mammalian GSK-3 over CDKs, we identified the leishmanial GSK-3 homologues, a short (LdGSK-3s) and a long one, focusing on LdGSK-3s which is closer to human GSK-3β for further studies. Kinase assays showed that 5-Me-6-BIO inhibited LdGSK-3s more potently than CRK3 (the CDK1 homologue in Leishmania), while 6-BIO was more selective for CRK3. Promastigotes treated with 5-Me-6-BIO accumulated in the S and G2/M cell-cycle phases and underwent apoptosis-like death. Interestingly, these phenotypes were completely reversed in parasites over-expressing LdGSK-3s. This finding strongly supports that LdGSK-3s is a) the intracellular target of 5-Me-6-BIO and b) involved in cell-cycle control and in pathways leading to apoptosis-like death. 6-BIO treatment induced a G2/M arrest, consistent with inhibition of CRK3, and apoptosis-like death. These effects were partially reversed in parasites over-expressing LdGSK-3s suggesting that in vivo 6-BIO may also target LdGSK-3s. Molecular docking of 5-Me-6-BIO in CRK3 and 6-BIO in human GSK-3β and LdGSK-3s active sites predict the existence of functional/structural differences that are sufficient to explain the observed difference in their affinity. In conclusion, LdGSK-3s is validated as a potential drug target in Leishmania and could be exploited for the development of selective indirubin-based leishmanicidals.

KW - L. donovani glycogen synthase kinase-3 short

KW - 5-Me-6-BIO

KW - 6-BIO

KW - indirubins

KW - apoptosis-like death

KW - drug target

UR - http://www.scopus.com/inward/record.url?scp=68249107643&partnerID=8YFLogxK

U2 - 10.1016/j.ijpara.2009.04.005

DO - 10.1016/j.ijpara.2009.04.005

M3 - Journal article

VL - 39

SP - 1289

EP - 1303

JO - International Journal for Parasitology

JF - International Journal for Parasitology

SN - 0020-7519

IS - 12

ER -

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