Simvastatin and downstream inhibitors circumvent constitutive and stromal cell-induced resistance to doxorubicin in IGHV unmutated CLL cells.
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.
Division of Hematology, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, University of Torino, Torino, Italy.|Center for Experimental Research and Medical Studies, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, Torino, Italy.
Micol
M
Rigoni
Department of Oncology, University of Torino, Torino, Italy.
Chiara
C
Riganti
Division of Hematology, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, University of Torino, Torino, Italy.|Center for Experimental Research and Medical Studies, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, Torino, Italy.
Candida
C
Vitale
Division of Hematology, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, University of Torino, Torino, Italy.|Center for Experimental Research and Medical Studies, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, Torino, Italy.
Valentina
V
Griggio
Department of Oncology, University of Torino, Torino, Italy.
Ivana
I
Campia
Division of Hematology, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, University of Torino, Torino, Italy.
Marta
M
Robino
Division of Hematology, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, University of Torino, Torino, Italy.|Center for Experimental Research and Medical Studies, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, Torino, Italy.
Myriam
M
Foglietta
Center for Experimental Research and Medical Studies, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, Torino, Italy.
Barbara
B
Castella
Division of Hematology, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, University of Torino, Torino, Italy.|Center for Experimental Research and Medical Studies, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, Torino, Italy.
Patrizia
P
Sciancalepore
Department of Oncology, University of Torino, Torino, Italy.
Ilaria
I
Buondonno
Division of Hematology, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, University of Torino, Torino, Italy.
Daniela
D
Drandi
Division of Hematology, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, University of Torino, Torino, Italy.
Marco
M
Ladetto
Division of Hematology, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, University of Torino, Torino, Italy.
Mario
M
Boccadoro
Center for Experimental Research and Medical Studies, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, Torino, Italy.|S.C. Ematologia e Terapie Cellulari, Azienda Ospedaliera Ordine Mauriziano di Torino, Torino, Italy.
Massimo
M
Massaia
Division of Hematology, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, University of Torino, Torino, Italy.|Center for Experimental Research and Medical Studies, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, Torino, Italy.
Marta
M
Coscia
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D015153:Blotting, Western; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D018920:Coculture Techniques; D004317:Doxorubicin / Q000494:pharmacology*; D018432:Drug Resistance, Multiple / Q000187:drug effects* / Q000235:genetics; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D007135:Immunoglobulin Variable Region / Q000235:genetics; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000097:blood / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D015398:Signal Transduction / Q000187:drug effects; D019821:Simvastatin / Q000494:pharmacology*; D017154:Stromal Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D014407:Tumor Cells, Cultured
D018435:ATP Binding Cassette Transporter, Subfamily B; D000903:Antibiotics, Antineoplastic; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region; D004317:Doxorubicin; D019821:Simvastatin
chronic lymphocytic leukemia; mevalonate pathway; multidrug resistance; statins