Bortezomib (BZ) induces unfolded protein response (UPR) and endoplasmic reticulum (ER) stress, as well as exhibits clinical activity in patients with relapsed and refractory Mantle Cell Lymphoma (MCL). Here, we determined the molecular basis of the improved in vitro and in vivo activity of the combination of pan-histone deacetylase (HDAC) inhibitor (HDI) panobinostat (PS) and BZ against human, cultured and primary MCL cells.
Immunoblot analyses, RT-PCR and immunofluorescent and electron microscopy were utilized to determine the effects of PS on BZ-induced aggresome formation and ER stress in MCL cells.
Treatment with PS treatment induced heat shock protein (hsp) 90 acetylation, depleted the levels of hsp90 client proteins, CDK4, c-RAF and AKT, as well as abrogated BZ-induced aggresome formation in MCL cells. PS also induced lethal UPR, associated with induction of CHOP. Conversely, knockdown of CHOP attenuated PS-induced cell death of MCL cells. Compared to each agent alone, co-treatment with PS increased BZ-induced CHOP and NOXA expressions, as well as increased BZ-induced UPR and apoptosis of cultured and primary MCL cells. Co-treatment with PS also increased BZ-mediated in vivo tumor growth inhibition and improved survival of mice bearing human Z138C MCL cell xenograft.
These findings suggest that increased UPR and induction of CHOP are involved in enhanced anti-MCL activity of the combination of PS and BZ.