イマイ　ヨウイチ   IMAI YOICHI   今井　陽一    所属   医学部 医学科（東京女子医科大学病院）    職種   非常勤講師
論文種別	原著
言語種別	英語
査読の有無	査読なし
表題	Histone deacetylase inhibitor panobinostat induces calcineurin degradation in multiple myeloma.
掲載誌名	正式名：JCI insight 略　 称：JCI Insight ISSNコード：2379-3708(Linking)
巻・号・頁	1(5),pp.e85061
著者・共著者	IMAI Yoichi†, OHTA Eri, TAKEDA Shu, SUNAMURA Satoko, ISHIBASHI Mariko, TAMURA Hideto, WANG Yan-Hua, DEGUCHI Atsuko, TANAKA Junji, MARU Yoshiro, MOTOJI Toshiko
担当区分	筆頭著者
発行年月	2016/04
概要	Multiple myeloma (MM) is a relapsed and refractory disease, one that highlights the need for developing new molecular therapies for overcoming of drug resistance. Addition of panobinostat, a histone deacetylase (HDAC) inhibitor, to bortezomib and dexamethasone improved progression-free survival (PFS) in relapsed and refractory MM patients. Here, we demonstrate how calcineurin, when inhibited by immunosuppressive drugs like FK506, is involved in myeloma cell growth and targeted by panobinostat. mRNA expression of PPP3CA, a catalytic subunit of calcineurin, was high in advanced patients. Panobinostat degraded PPP3CA, a degradation that should have been induced by inhibition of the chaperone function of heat shock protein 90 (HSP90). Cotreatment with HDAC inhibitors and FK506 led to an enhanced antimyeloma effect with a greater PPP3CA reduction compared with HDAC inhibitors alone both in vitro and in vivo. In addition, this combination treatment efficiently blocked osteoclast formation, which results in osteolytic lesions. The poor response and short PFS duration observed in the bortezomib-containing therapies of patients with high PPP3CA suggested its relevance to bortezomib resistance. Moreover, bortezomib and HDAC inhibitors synergistically suppressed MM cell viability through PPP3CA inhibition. Our findings underscore the usefulness of calcineurin-targeted therapy in MM patients, including patients who are resistant to bortezomib.
DOI	10.1172/jci.insight.85061
PMID	27699258