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Wortmannin as a new potential anticancer drug

Wortmannin as a new potential anticancer drug

Publish date: 2015-02-04

Wortmannin sensitize the tumour cells for standard treatment with ethoposid and cisplatin, makes the treatment more effectiveness. What it means for the glioma patient? That there is potential new drug, which is effective in laboratory and kills glioma cells.

Tags: cancer , glioblastoma , glioma , oncology , brain cancer

NHEJ is a process that directly ligate the break within the DNA without a strand as a template. In this process many proteins play an important role. The most important are DNA-PKcs, DNA Ligase IV, Ku70/80, ATM and ATR. The subject of the study was wortmanin, the drug that inhibits the kinase activity specifically of DNA-dependent protein kinase (DNA-PKcs from PI3-K family) and its catalythic subunit. By inhibition of DNA-PKcs, wortmanin inhibits the whole mechanism process. Therefore, this potential drug would probably increase the effectiveness of the therapy with the use of cytostatins.

Study was performed on human glioblastoma cell lines – MO59. Scientists used two types of those, K and J, which differs from each other in content of the DNA-PKcs. High level of this substance is observed in MO59K, low in MO59. Scientists assess the effectiveness of this therapy using XTT assay.

Wortmannin occurred to be effective in both types of cells, thus despite the fact, that it inhibits DNA-PKcs, it has to also inhibits other enzymes activities probably from the PI3-K family. Wortmannin also caused cell cycle arrest at G2/M checkpoint and S – phase (because of accumulation unrepaired DSBs). Substance of interest was actually DNA-PKcs (that was presented within MO59K) but surprisingly, better efficacy was observed within MO59J cells – with lower content of this kinase. This suggests, that wortmannin may also inhibits other enzymes from PI3-K family – ATM or ATR. Wortmannins molecular activity is assesed to cause DSBs and mainly inhibition of NHEJ.

So far the best effective treatment for glioma patients seems to be the combination therapy of ethoposid and cisplatin – the cytostatins. The efficacy of this therapy lies in the ability of generation the most fatal damages – double strand breaks (DSBs)within DNA strand. Unfortunately as in all healthy cells, also in cancer ones, there are mechanisms that repair the DNA breakage, for example non homologous end joining (NHEJ), microhomology-mediated end joining (MMEJ) and homologous recombination (HR). Within glioma cells (and in general in mammals) the most often occurs NHEJ mechanism. To increase the efficiency of the treatment using standard combination scientists are looking for substance that would disturb or block the DNA repairing process.

Hanna Banasiak

Sources:

Pastwa E, Poplawski T, Lewandowska U, Somiari SB, Blasiak J, Somiari RI. Wortmannin potentiates the combined effect of etoposide and cisplatin in human glioma cells. Int J Biochem Cell Biol. 2014 Aug;53:423–31.

Pastwa E, Malinowski M. Non-homologous DNA end joining in anticancer therapy. Curr Cancer Drug Targets. 2007 May;7(3):243–50.

Poplawski T, Pastwa E, Blasiak J. Non-homologous DNA end joining in normal and cancer cells and its dependence on break structures. Genet Mol Biol. 2010 Apr;33(2):368–73. 

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