Bcl-2<i>high</i>mantle cell lymphoma cells are sensitized to acadesine with ABT-199

Abstract

// Arnau Montraveta 1 , S&iacute;lvia Xargay-Torrent 1 , Laia Rosich 1 , M&ograve;nica L&oacute;pez-Guerra 1,2 , Jocabed Rold&aacute;n 1 , Vanina Rodr&iacute;guez 1 , Eriong Lee-Verg&eacute;s 1 , Merc&egrave; de Fr&iacute;as 3 , Clara Camp&agrave;s 3 , Elias Campo 2 , Ga&euml;l Rou&eacute; 1 and Dolors Colomer 1,2 1 Experimental Therapeutics in Lymphoid Malignancies Group, Institut d&rsquo;Investigacions Biom&egrave;diques August Pi i Sunyer (IDIBAPS), Barcelona, Spain 2 Unitat d&rsquo;Hematopatologia, Hospital Clinic, IDIBAPS, Barcelona, Spain 3 Advancell-Advanced In Vitro Cell Technologies S.A., Barcelona, Spain Correspondence to: Dolors Colomer, email: // Keywords : acadesine (AICAR), mantle cell lymphoma, Mcl-1, ABT-199, Bcl-2 Received : March 23, 2015 Accepted : May 13, 2015 Published : May 22, 2015 Abstract Acadesine is a nucleoside analogue with known activity against B-cell malignancies. Herein, we showed that in mantle cell lymphoma (MCL) cells acadesine induced caspase-dependent apoptosis through turning on the mitochondrial apoptotic machinery. At the molecular level, the compound triggered the activation of the AMPK pathway, consequently modulating known downstream targets, such as mTOR and the cell motility-related vasodilator-stimulated phosphoprotein (VASP). VASP phosphorylation by acadesine was concomitant with a blockade of CXCL12-induced migration. The inhibition of the mTOR cascade by acadesine, committed MCL cells to enter in apoptosis by a translational downregulation of the antiapoptotic Mcl-1 protein. In contrast, Bcl-2 protein levels were unaffected by acadesine and MCL samples expressing high levels of Bcl-2 tended to have a reduced response to the drug. Targeting Bcl-2 with the selective BH3-mimetic agent ABT-199 sensitized Bcl-2 high MCL cells to acadesine. This effect was validated in vivo , where the combination of both agents displayed a more marked inhibition of tumor outgrowth than each drug alone. These findings support the notions that antiapoptotic proteins of the Bcl-2 family regulate MCL cell sensitivity to acadesine and that the combination of this agent with Bcl-2 inhibitors might be an interesting therapeutic option to treat MCL patients.