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Inhibition of the Pentose-phosphate Pathway Selectively Sensitizes Leukemia Lymphocytes to Chemotherapeutics by ROS-independent Mechanism

The aim of the present study was to investigate: (i) the possibility of sensitizing leukemia lymphocytes to anticancer drugs by inhibiting pentose-phosphate pathway using 6-aminonicotinamide (6-ANA); (ii) to find combinations with synergistic cytotoxic effect on leukemia lymphocytes and to investigate their cytotoxicity towards normal lymphocytes; (iii) and to clarify the role of reactive oxygen species (ROS) in the induction of apoptosis by those combinations. The study covers 15 anticancer drugs - conventional and new-generation. The experiments were performed on Jurkat leukemia cell line and normal lymphocytes, isolated from clinically healthy blood donors. Four parameters were analyzed simultaneously in both cell suspensions treated by drug or 6-ANA (separately, and in combination): cell viability, induction of apoptosis, level of ROS, and level of protein-carbonyl products. Most combinations of drug plus 6-ANA were characterized by synergistic cytotoxic effects on Jurkat cells. The synergism increased with increasing incubation time. Upon combination of 6-ANA with conventional chemotherapeutic (e.g. doxorubicin), synergistic cytotoxic effects were also detected in normal lymphocytes. In both cell types, the cytotoxicity of the combination of doxorubicin plus 6-ANA was accompanied by increased induction of apoptosis, but by a slight reduction of ROS and protein-carbonyl products compared to cells treated with doxorubicin only. Upon combination of 6-ANA with new-generation anticancer drugs (e.g. everolimus or barasertib), the synergistic cytotoxic effect on leukemia lymphocytes was also accompanied by very strong induction of apoptosis through ROS-independent mechanism(s). Neither of these combinations exhibited any cytotoxicity towards normal lymphocytes. The data suggest that 6-ANA could be used as a supplementary component in anticancer chemotherapy, and would allows therapeutic doses of anticancer drugs to be reduced, thereby minimizing their side-effects.

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Proteasome