Cannabimimetic <i>N</i>-Stearoylethanolamine as “Double-Edged Sword” in Anticancer Chemotherapy: Proapoptotic Effect on Tumor Cells and Suppression of Tumor Growth versus Its Bio-Protective Actions in Complex with Polymeric Carrier on General Toxicity of Doxorubicin In Vivo
Rostyslav Panchuk,
Nadiya Skorokhyd,
Vira Chumak,
Lilya Lehka,
Halyna Kosiakova,
Tetyana Horid’ko,
Iehor Hudz,
Nadiya Hula,
Anna Riabtseva,
Nataliya Mitina,
Alexander Zaichenko,
Petra Heffeter,
Walter Berger,
Rostyslav Stoika
Affiliations
Rostyslav Panchuk
Institute of Cell Biology National Academy of Sciences of Ukraine, Drahomanov Str., 14/16, 79005 Lviv, Ukraine
Nadiya Skorokhyd
Institute of Cell Biology National Academy of Sciences of Ukraine, Drahomanov Str., 14/16, 79005 Lviv, Ukraine
Vira Chumak
Institute of Cell Biology National Academy of Sciences of Ukraine, Drahomanov Str., 14/16, 79005 Lviv, Ukraine
Lilya Lehka
Institute of Cell Biology National Academy of Sciences of Ukraine, Drahomanov Str., 14/16, 79005 Lviv, Ukraine
Halyna Kosiakova
Palladin Institute of Biochemistry National Academy of Sciences of Ukraine, Leontovycha Str. 9, 01030 Kyiv, Ukraine
Tetyana Horid’ko
Palladin Institute of Biochemistry National Academy of Sciences of Ukraine, Leontovycha Str. 9, 01030 Kyiv, Ukraine
Iehor Hudz
Palladin Institute of Biochemistry National Academy of Sciences of Ukraine, Leontovycha Str. 9, 01030 Kyiv, Ukraine
Nadiya Hula
Palladin Institute of Biochemistry National Academy of Sciences of Ukraine, Leontovycha Str. 9, 01030 Kyiv, Ukraine
Anna Riabtseva
Department of Organic Chemistry, Lviv Polytechnic National University, S. Bandera Str. 12, 79013 Lviv, Ukraine
Nataliya Mitina
Department of Organic Chemistry, Lviv Polytechnic National University, S. Bandera Str. 12, 79013 Lviv, Ukraine
Alexander Zaichenko
Department of Organic Chemistry, Lviv Polytechnic National University, S. Bandera Str. 12, 79013 Lviv, Ukraine
Petra Heffeter
Center for Cancer Research and Comprehensive Cancer Center, Medical University of Vienna, Borschkegasse 8a, 1090 Vienna, Austria
Walter Berger
Center for Cancer Research and Comprehensive Cancer Center, Medical University of Vienna, Borschkegasse 8a, 1090 Vienna, Austria
Rostyslav Stoika
Institute of Cell Biology National Academy of Sciences of Ukraine, Drahomanov Str., 14/16, 79005 Lviv, Ukraine
This study reports a dose-dependent pro-apoptotic action of synthetic cannabimimetic N-stearoylethanolamine (NSE) on diverse cancer cell lines, including multidrug-resistant models. No antioxidant or cytoprotective effects of NSE were found when it was applied together with doxorubicin. A complex of NSE with the polymeric carrier poly(5-(tert-butylperoxy)-5-methyl-1-hexen-3-yn-co-glycidyl methacrylate)-graft-PEG was synthesized. Co-immobilization of NSE and doxorubicin on this carrier led to a 2-10-fold enhancement of the anticancer activity, particularly, against drug-resistant cells overexpressing ABCC1 and ABCB1. This effect might be caused by accelerated nuclear accumulation of doxorubicin in cancer cells, which led to the activation of the caspase cascade, revealed by Western blot analysis. The NSE-containing polymeric carrier was also able to significantly enhance the therapeutic activity of doxorubicin in mice with implanted NK/Ly lymphoma or L1210 leukemia, leading to the complete eradication of these malignancies. Simultaneously, loading to the carrier prevented doxorubicin-induced elevation of AST and ALT as well as leukopenia in healthy Balb/c mice. Thus, a unique bi-functionality of the novel pharmaceutical formulation of NSE was revealed. It enhanced doxorubicin-induced apoptosis in cancer cells in vitro and promoted its anticancer activity against lymphoma and leukemia models in vivo. Simultaneously, it was very well tolerated preventing frequently observed doxorubicin-associated adverse effects.