BACKGROUND & AIMS: Tumor-suppressor proteins are inactivated by many different mechanisms, including nuclear exclusion by chromosome region maintenance (CRM)-1. Increased tumor levels of CRM-1 have been correlated with poor prognosis of patients with pancreatic cancer, making it a therapeutic target. Selective inhibitors of nuclear export (SINEs) bind to CRM-1 to irreversibly inhibit its ability to export proteins; we investigated a new class of SINEs in pancreatic cancer cells. METHODS: We studied the effects of SINE analogs in a panel of pancreatic cancer cell lines and nontransformed human pancreatic ductal epithelial cells using proliferation, apoptosis, immunoblot, co-immunoprecipitation, small inhibitor RNA, and fluorescence microscopy analyses. The effects of the SINEs also were investigated in mice with subcutaneous and orthotopic tumors. RESULTS: SINEs (KPT-185, KPT-127, KPT-205, and KPT-227) inhibited proliferation and promoted apoptosis of pancreatic cancer cells, but did not affect human pancreatic ductal epithelial cells. The nuclei of cells incubated with KPT-185 accumulated tumor-suppressor proteins (p27, FOXO, p73, and prostate apoptosis response-4 [PAR-4]) and inhibited interactions between CRM-1 and these proteins. Mutations in the region of CRM-1 that bind to SINEs (Cys-528), or small inhibitor RNA knockdown of PAR-4, prevented the ability of KPT-185 to block proliferation and induce apoptosis of pancreatic cancer cells. Oral administration of KPT-330 to mice reduced growth of subcutaneous and orthotopic xenograft tumors without major toxicity. Analysis of tumor remnants showed that KPT-330 disrupted the interaction between CRM-1 and PAR-4, activated PAR-4 signaling, and reduced proliferation of tumor cells. CONCLUSIONS: We identified SINEs that inhibit CRM-1 and promote nuclear accumulation of tumor-suppressor proteins in pancreatic cancer cells. Oral administration of the drug to mice reduces growth of xenograft tumors.
BACKGROUND & AIMS:Tumor-suppressor proteins are inactivated by many different mechanisms, including nuclear exclusion by chromosome region maintenance (CRM)-1. Increased tumor levels of CRM-1 have been correlated with poor prognosis of patients with pancreatic cancer, making it a therapeutic target. Selective inhibitors of nuclear export (SINEs) bind to CRM-1 to irreversibly inhibit its ability to export proteins; we investigated a new class of SINEs in pancreatic cancer cells. METHODS: We studied the effects of SINE analogs in a panel of pancreatic cancer cell lines and nontransformed humanpancreatic ductal epithelial cells using proliferation, apoptosis, immunoblot, co-immunoprecipitation, small inhibitor RNA, and fluorescence microscopy analyses. The effects of the SINEs also were investigated in mice with subcutaneous and orthotopic tumors. RESULTS:SINEs (KPT-185, KPT-127, KPT-205, and KPT-227) inhibited proliferation and promoted apoptosis of pancreatic cancer cells, but did not affect humanpancreatic ductal epithelial cells. The nuclei of cells incubated with KPT-185 accumulated tumor-suppressor proteins (p27, FOXO, p73, and prostate apoptosis response-4 [PAR-4]) and inhibited interactions between CRM-1 and these proteins. Mutations in the region of CRM-1 that bind to SINEs (Cys-528), or small inhibitor RNA knockdown of PAR-4, prevented the ability of KPT-185 to block proliferation and induce apoptosis of pancreatic cancer cells. Oral administration of KPT-330 to mice reduced growth of subcutaneous and orthotopic xenograft tumors without major toxicity. Analysis of tumor remnants showed that KPT-330 disrupted the interaction between CRM-1 and PAR-4, activated PAR-4 signaling, and reduced proliferation of tumor cells. CONCLUSIONS: We identified SINEs that inhibit CRM-1 and promote nuclear accumulation of tumor-suppressor proteins in pancreatic cancer cells. Oral administration of the drug to mice reduces growth of xenograft tumors.
Authors: Asfar S Azmi; Philip A Philip; Syed F Zafar; Fazlul H Sarkar; Ramzi M Mohammad Journal: Expert Opin Ther Targets Date: 2010-06 Impact factor: 6.902
Authors: A S Azmi; P A Philip; F W J Beck; Z Wang; S Banerjee; S Wang; D Yang; F H Sarkar; R M Mohammad Journal: Oncogene Date: 2010-09-06 Impact factor: 9.867
Authors: D Kögel; C Reimertz; P Mech; M Poppe; M C Frühwald; H Engemann; K H Scheidtmann; J H Prehn Journal: Br J Cancer Date: 2001-11-30 Impact factor: 7.640
Authors: Takahito Miyake; Sunila Pradeep; Sherry Y Wu; Rajesha Rupaimoole; Behrouz Zand; Yunfei Wen; Kshipra M Gharpure; Archana S Nagaraja; Wei Hu; Min Soon Cho; Heather J Dalton; Rebecca A Previs; Morgan L Taylor; Takeshi Hisamatsu; Yu Kang; Tao Liu; Sharon Shacham; Dilara McCauley; David H Hawke; John E Wiktorowicz; Robert L Coleman; Anil K Sood Journal: Clin Cancer Res Date: 2015-04-15 Impact factor: 12.531
Authors: Dongqing Yan; Anthony D Pomicter; Srinivas Tantravahi; Clinton C Mason; Anna V Senina; Jonathan M Ahmann; Qiang Wang; Hein Than; Ami B Patel; William L Heaton; Anna M Eiring; Phillip M Clair; Kevin C Gantz; Hannah M Redwine; Sabina I Swierczek; Brayden J Halverson; Erkan Baloglu; Sharon Shacham; Jamshid S Khorashad; Todd W Kelley; Mohamed E Salama; Rodney R Miles; Kenneth M Boucher; Josef T Prchal; Thomas O'Hare; Michael W Deininger Journal: Clin Cancer Res Date: 2018-12-18 Impact factor: 12.531
Authors: Takahito M Miyake; Sunila Pradeep; Emine Bayraktar; Elaine Stur; Katelyn F Handley; Sherry Y Wu; Cristian Rodriguez-Aguayo; Ju-Seog Lee; Gabriel Lopez-Berestein; Robert L Coleman; Anil K Sood Journal: Mol Cancer Ther Date: 2020-06-04 Impact factor: 6.261
Authors: Yan Cheng; Michael P Holloway; Kevin Nguyen; Dilara McCauley; Yosef Landesman; Michael G Kauffman; Sharon Shacham; Rachel A Altura Journal: Mol Cancer Ther Date: 2014-01-15 Impact factor: 6.261