Sensitization of U937 leukemia cells to doxorubicin by the MG132 proteasome inhibitor induces an increase in apoptosis by suppressing NF-kappa B and mitochondrial membrane potential loss

<jats:title>Abstract</jats:title> <jats:sec> <jats:title>Background</jats:title> <jats:p>The resistance of cancerous cells to chemotherapy remains the main limitation for cancer treatment at present. Doxorubicin (DOX) is a potent antitumor drug that activates the ubiquitin-proteasome system, but unfortunately it also activates the Nuclear factor kappa B (NF-кB) pathway leading to the promotion of tumor cell survival. MG132 is a drug that inhibits I kappa B degradation by the proteasome-avoiding activation of NF-кB. In this work, we studied the sensitizing effect of the MG132 proteasome inhibitor on the antitumor activity of DOX.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods</jats:title> <jats:p>U937 human leukemia cells were treated with MG132, DOX, or both drugs. We evaluated proliferation, viability, apoptosis, caspase-3, -8, and −9 activity and cleavage, cytochrome <jats:italic>c</jats:italic> release, mitochondrial membrane potential, the Bcl-2 and Bcl-XL antiapoptotic proteins, senescence, <jats:italic>p65</jats:italic> phosphorylation, and pro- and antiapoptotic genes.</jats:p> </jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p>The greatest apoptosis percentage in U937 cells was obtained with a combination of MG132 + DOX. Likewise, employing both drugs, we observed a decrease in tumor cell proliferation and important caspase-3 activation, as well as mitochondrial membrane potential loss. Therefore, MG132 decreases senescence, <jats:italic>p65</jats:italic> phosphorylation, and the DOX-induced Bcl-2 antiapoptotic protein. The MG132 + DOX treatment induced upregulation of proapoptotic genes <jats:italic>BAX</jats:italic>, <jats:italic>DIABLO</jats:italic>, <jats:italic>NOXA</jats:italic>, <jats:italic>DR4</jats:italic>, and <jats:italic>FAS</jats:italic>. It also induced downregulation of the antiapoptotic genes <jats:italic>BCL-XL</jats:italic> and <jats:italic>SURVIVIN.</jats:italic> </jats:p> </jats:sec> <jats:sec> <jats:title>Conclusion</jats:title> <jats:p>MG132 sensitizes U937 leukemia cells to DOX-induced apoptosis, increasing its anti-leukemic effectiveness.</jats:p> </jats:sec>