title: The STAT3 inhibitor WP1066 synergizes with vorinostat to induce apoptosis of mantle cell lymphoma cells.
abstract: Mantle cell lymphoma (MCL) is an aggressive B-cell non-Hodgkin lymphoma (NHL) characterized by the translocation t (11; 14) (q13; q32). Drug resistance remains a formidable obstacle to treatment and the median survival for MCL patients is between 3 and 5 years. Thus, there is an urgent need to discover novel approaches to MCL therapy. The signal transducer and activation of transcription 3 (STAT3) has been found to be constitutively activated in several subtypes of MCL cell lines and MCL tumors. WP1066, a small-molecule inhibitor of STAT3, exerted antitumor activity in hematological and solid malignancies by inhibiting key survival and growth signaling pathways. In the present study, we evaluated the antiproliferative and proapoptotic activity of WP1066 combined with pan-histone deacetylase (HDAC) inhibitor vorinostat (SAHA) in a panel of MCL cell lines. In addition, potential mechanisms involved were also explored. The outcome showed that combination of WP1066 with SAHA resulted in synergistic growth inhibition and apoptosis induction in MCL cell lines in vitro. Furthermore, combination of WP1066 with SAHA inhibited the constitutive STAT3 activation and modulated mRNA expressions of anti- and pro-apoptotic genes. Our findings suggest that agents targeting the STAT3 pathway such as WP1066 may be useful therapeutic drugs for MCL when combined with SAHA.
authors.affiliation: Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, PR China.
authors.forename: Kang
authors.initials: K
authors.lastname: Lu
authors.affiliation: Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, PR China.
authors.forename: Na
authors.initials: N
authors.lastname: Chen
authors.affiliation: Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, PR China.
authors.forename: Xiang-xiang
authors.initials: XX
authors.lastname: Zhou
authors.affiliation: Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, PR China.
authors.forename: Xue-ling
authors.initials: XL
authors.lastname: Ge
authors.affiliation: Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, PR China.
authors.forename: Li-li
authors.initials: LL
authors.lastname: Feng
authors.affiliation: Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, PR China.
authors.forename: Pei-pei
authors.initials: PP
authors.lastname: Li
authors.affiliation: Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, PR China.
authors.forename: Xin-yu
authors.initials: XY
authors.lastname: Li
authors.affiliation: Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, PR China.
authors.forename: Ling-yun
authors.initials: LY
authors.lastname: Geng
authors.affiliation: Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, PR China; Institute of Diagnostics, Shandong University School of Medicine, Jinan, Shandong 250021, PR China. Electronic address: xinw007@126.com.
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001402:B-Lymphocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic; D006655:Histone Deacetylases / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D020522:Lymphoma, Mantle-Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011725:Pyridines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D020032:Tyrphostins / Q000494:pharmacology*; D000077337:Vorinostat
chemical_list: D000970:Antineoplastic Agents; D006877:Hydroxamic Acids; D011725:Pyridines; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D020032:Tyrphostins; C519885:WP1066; D000077337:Vorinostat; D006655:Histone Deacetylases
keywords: Apoptosis; Histone deacetylase; Mantle cell lymphoma; Synergy