Simvastatin and downstream inhibitors circumvent constitutive and stromal cell-induced resistance to doxorubicin in IGHV unmutated CLL cells
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Micol Rigoni1,2,*, Chiara Riganti3,*, Candida Vitale1,2, Valentina Griggio1,2, Ivana Campia3, Marta Robino1, Myriam Foglietta1,2, Barbara Castella2, Patrizia Sciancalepore1,2, Ilaria Buondonno3, Daniela Drandi1, Marco Ladetto1, Mario Boccadoro1, Massimo Massaia2,4,*, Marta Coscia1,2,*
1Division of Hematology, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, University of Torino, Torino, Italy
2Center for Experimental Research and Medical Studies, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, Torino, Italy
3Department of Oncology, University of Torino, Torino, Italy
4S.C. Ematologia e Terapie Cellulari, Azienda Ospedaliera Ordine Mauriziano di Torino, Torino, Italy
*These authors have contributed equally to this work
Marta Coscia, e-mail: firstname.lastname@example.org
Keywords: chronic lymphocytic leukemia, multidrug resistance, mevalonate pathway, statins
Received: August 28, 2014 Accepted: May 15, 2015 Published: May 27, 2015
The immunoglobulin heavy-chain variable region (IGHV) mutational status is a strong determinant of remission duration in chronic lymphocytic leukemia (CLL). The aim of this work was to compare the multidrug resistance (MDR) signature of IGHV mutated and unmutated CLL cells, identifying biochemical and molecular targets potentially amenable to therapeutic intervention.
We found that the mevalonate pathway-dependent Ras/ERK1–2 and RhoA/RhoA kinase signaling cascades, and the downstream HIF-1α/P-glycoprotein axis were more active in IGHV unmutated than in mutated cells, leading to a constitutive protection from doxorubicin-induced cytotoxicity. The constitutive MDR phenotype of IGHV unmutated cells was partially dependent on B cell receptor signaling, as shown by the inhibitory effect exerted by ibrutinib. Stromal cells further protected IGHV unmutated cells from doxorubicin by upregulating Ras/ERK1–2, RhoA/RhoA kinase, Akt, HIF-1α and P-glycoprotein activities. Mevalonate pathway inhibition with simvastatin abrogated these signaling pathways and reversed the resistance of IGHV unmutated cells to doxorubicin, also counteracting the protective effect exerted by stromal cells. Similar results were obtained via the targeted inhibition of the downstream molecules ERK1–2, RhoA kinase and HIF-1α.
Therefore, targeting the mevalonate pathway and its downstream signaling cascades is a promising strategy to circumvent the MDR signature of IGHV unmutated CLL cells.
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