Ukr.Biochem.J. 2016; Том 88, спецвипуск, c. 87-98

Modulation of temozolomide action towards rat and human glioblastoma cells in vitro by its combination with doxorubicin and immobilization with nanoscale polymeric carrier

19.07.2016   Без категорії   No comments

N. S. Finiuk1, J. V. Senkiv1, A. O. Riabtseva2,
N. Y. Mitina2, N. I. Molochii1, M. O. Kitsera1,
S. S. Avdieiev3, O. S. Zaichenko2, R. S. Stoika1

1Institute of Cell Biology, National Academy of Science of Ukraine, Lviv;
2Lviv National Polytechnic University, Ukraine;
3Institute of Molecular Biology and Genetics, National Academy
of Science of Ukraine, Ukraine;
е-mail: stoika@cellbiol.lviv.ua

Malignant gliomas (glioblastoma multiforme and anaplastic astrocytoma) occur more frequently than other types of primary central nervous system tumors, having a combined incidence of 5–8/100,000 population. Even with aggressive treatment using surgery, radiation, and chemotherapy, median reported survival is less than one year. Alkylating agents, such as temozolomide (TMZ), are among the most effective cytotoxic agents used for malignant gliomas, however, the responses still remain poor. Here, we present data about an enhancement of TMZ treatment effect towards rat and human glioma cells in vitro by immobilizing this drug with a new nanoscale polymeric-phospholipidic delivery system. It is a water-soluble comb-like poly(PM-co-GMA)-graft-PEG polymer consisting of a backbone that is a copolymer of 5-tert-butyl-peroxy-5-methyl-l-hexene-3-yne (PM) and glycidyl methacrylate (GMA) and polyethylene glycol (PEG) side chains. The molecular weight of the carrier was 94,000 g/mol. Conjugation of TMZ with a novel polymeric carrier functionalized with phosphatidylcholine resulted in approximately 2 times enhancement of anticancer activity of TMZ. Combining of TMZ with doxorubicin (50 nM) resulted in further enhancement by 23% of the anti-proliferative effect of TMZ. TMZ caused apoptosis in glioma cells via activation of MAPK signaling pathway, inhibition of STAT3, and affected a transition through G2/M phase of cell cycle. These features make the novel nano-formulation of TMZ a perspective strategy for further development of this drug.

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