Tag Archives: doxorubicin

Impact of N-acetylcysteine on antitumor activity of doxorubicin and landomycin A in NK/Ly lymphoma-bearing mice

Yu. S. Kozak1, R. R. Panchuk2, N. R. Skorokhyd2, L. V. Lehka2, R. S. Stoika1,2

 1Ivan Franko National University of Lviv, Ukraine;
2Іnstitute of Cell Biology, National Academy of Sciences of Ukraine, Lviv;
e-mail: stoika@cellbiol.lviv.ua

N-acetylcysteine (NAC) is a dietary supplement demonstrating antioxidant and liver protecting effects that is widely used in clinics. NAC is considered to possess potential therapeutic activity for health disorders characterized by generation of free oxygen radicals, as well as potential for decreasing negative side effects of various drugs. However, the mechanisms of such tissue-protective actions of NAC remain poorly understood. The main aim of this work was to study therapeutic effects of NAC applied together with the “gold standard” of chemotherapy doxorubicin (Dx) or the novel experimental drug landomycin A (LA) to mice bearing NK/Ly lymphoma. It was revealed that NAC significantly decreased the nephrotoxicity of Dx (measured as creatinine level), possessed moderate immunomodulating activity (as revealed by an increase in number of cytotoxic T-lymphocytes), and partially increased survival of NK/Ly lymphoma-bearing animals treated with Dx. On the contrary, there was little tissue-protective effect of NAC towards LA due to the weak side effects of this anticancer drug, however, the combined use of NAC and LA significantly increased survival (60+ days) of LA-treated animals with NK/Ly lymphoma. Summarizing, NAC possesses a moderate tissue-protective activity towards Dx action but lacks a major therapeutic effect. However, in the case of LA action, NAC significantly increases its anticancer activity with no impact on its negative side effects. Further studies of the molecular mechanisms underlying that activity of NAC towards the action of LA are in progress.

Evaluation of antiproliferative activity of pyrazolothiazolopyrimidine derivatives

N. S. Finiuk1,2, Yu. V. Ostapiuk2, V. P. Hreniukh2, Ya. R. Shalai2,
V. S. Matiychuk2, M. D. Obushak2, R.S. Stoika1*, A. M. Babsky2**

1Institute of Cell Biology, National Academy of Sciences of Ukraine, Lviv;
2Ivan Franko National University of Lviv, Ukraine;
*e-mail: stoika@cellbiol.lviv.ua; **e-mail: andriy.babsky@lnu.edu.ua

The research aim was to test cytotoxic effects in vitro of seven novel pyrazolothiazolopyrimidine derivatives in targeting several lines of tumor and pseudo-normal mammalian cells. We demonstrated that cytotoxic effects of these derivatives depended on the tissue origin of targeted cells. Leukemia cells were found to be the most sensitive to the action of compounds 2 and 7. Compound 2 demonstrated approximately two times higher toxicity towards the multidrug-resistant sub-line of HL-60/ADR cells compared to the Doxorubicin effect. Antiproliferative action of compounds 2 and 7 dropped in the order: leukemia > melanoma > hepatocarcinoma > glioblastoma > colon carcinoma > breast and ovarian carcinoma cells. These compounds were less toxic than Doxorubicin towards the non-tumor cells. The novel pyrazolothiazolopyrimidine, compound 2, demonstrated high toxicity towards human leukemia and, of special importance, towards multidrug-resistant leukemia cells, and low toxicity towards pseudo-normal cells.

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

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.