Adenosine (A)2A receptor modulation of nicotine-induced locomotor sensitization: a pharmacological and transgenic approach

Preclinical evidence indicates an important role of adenosine (A)2A receptors in drug addiction while their therapeutic relevance is still a matter of debate. We examined the influence of the A2A receptor agonist CGS 21680 and the antagonist KW 6002 on nicotine sensitization and conditioned locomotor activity in adult (8-week old) male Sprague-Dawley rats (WT). Moreover, behavioral responses to nicotine were studied in rats overexpressing A2A receptors under the control of the neuronal specific enolase (NSE) promotor. Changes in the levels of dopamine, glutamate and γ-aminobutyric acid in wild type (WT) and NSEA2A rats were determined with using LC-MS. KW 6002 significantly enhanced expression of nicotine sensitization and conditioned locomotion, while CGS 21680 reduced all these effects in WT rats. A reduction of the expression of nicotine-evoked conditioned locomotor activity was also observed in the NSEA2A animals. The transgenic rats displayed a reduced basal tissue level of glutamate in the prefrontal cortex and hippocampus while dopamine basal levels in the nucleus accumbens were raised. Chronic nicotine treatment caused a significant reduction in the glutamate tissue level in the dorsal and ventral striatum, prefrontal cortex and cerebellum in wild type rats. In NSEA2A animals the same drug treatment instead produced a rise of glutamate levels in the hippocampus and dorsal striatum. Taken together, A2A receptor signaling in the rat brain can counteract locomotor sensitization and conditioned locomotion to nicotine which are related to nicotine reward-learning. It is suggested that treatment with A2A receptor agonists can help counteract the abuse actions of nicotine

Curcumin enhances the cytogenotoxic effect of etoposide in leukemia cells through induction of reactive oxygen species

Monika A Papież,1 Wirginia Krzyściak,2 Krzysztof Szade,3 Karolina Bukowska-Straková,3,4 Magdalena Kozakowska,3 Karolina Hajduk,3 Beata Bystrowska,5 Jozef Dulak,3,6 Alicja Jozkowicz31Department of Cytobiology, 2Department of Medical Diagnostic, Faculty of Pharmacy, Jagiellonian University Medical College, 3Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, 4Department of Clinical Immunology, Institute of Pediatrics, 5Department of Toxicology, Faculty of Pharmacy, Jagiellonian University Medical College, 6Malopolska Centre of Biotechnology, Jagiellonian University, Krakow, PolandAbstract: Curcumin may exert a more selective cytotoxic effect in tumor cells with elevated levels of free radicals. Here, we investigated whether curcumin can modulate etoposide action in myeloid leukemia cells and in normal cells of hematopoietic origin. HL-60 cell line, normal myeloid progenitor cluster of differentiation (CD)-34+ cells, and granulocytes were incubated for 4 or 24 hours at different concentrations of curcumin and/or etoposide. Brown Norway rats with acute myeloid leukemia (BNML) were used to prove the influence of curcumin on etoposide action in vivo. Rats were treated with curcumin for 23 days and etoposide was administered for the final 3 days of the experiment. Curcumin synergistically potentiated the cytotoxic effect of etoposide, and it intensified apoptosis and phosphorylation of the histone H2AX induced by this cytostatic drug in leukemic HL-60 cells. In contrast, curcumin did not significantly modify etoposide-induced cytotoxicity and H2AX phosphorylation in normal CD34+ cells and granulocytes. Curcumin modified the cytotoxic action of etoposide in HL-60 cells through intensification of free radical production because preincubation with N-acetyl-l-cysteine (NAC) significantly reduced the cytotoxic effect of curcumin itself and a combination of two compounds. In contrast, NAC did not decrease the cytotoxic effect of etoposide. Thus, oxidative stress plays a greater role in the cytotoxic effect of curcumin than that of etoposide in HL-60 cells. In vitro results were confirmed in a BNML model. Pretreatment with curcumin enhanced the antileukemic activity of etoposide in BNML rats (1.57-fold tumor reduction versus etoposide alone; P<0.05) and induced apoptosis of BNML cells more efficiently than etoposide alone (1.54-fold change versus etoposide alone; P<0.05), but this treatment protected nonleukemic B-cells from apoptosis. Thus, curcumin can increase the antileukemic effect of etoposide through reactive oxygen species in sensitive myeloid leukemia cells, and it is harmless to normal human cells.Keywords: acute myeloid leukemia, curcumin, etoposide, ROS, γ-H2AX, apoptosi