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Open Access 01-12-2014 | Review

Nucleo-cytoplasmic transport as a therapeutic target of cancer

Authors: Giovanni Luca Gravina, William Senapedis, Dilara McCauley, Erkan Baloglu, Sharon Shacham, Claudio Festuccia

Published in: Journal of Hematology & Oncology | Issue 1/2014

Abstract

Shuttling of specific proteins out of the nucleus is essential for the regulation of the cell cycle and proliferation of both normal and malignant tissues. Dysregulation of this fundamental process may affect many other important cellular processes such as tumor growth, inflammatory response, cell cycle, and apoptosis. It is known that XPO1 (Exportin-1/Chromosome Region Maintenance 1/CRM1) is the main mediator of nuclear export in many cell types. Nuclear proteins exported to the cytoplasm by XPO1 include the drug targets topoisomerase IIα (topo IIα) and BCR-ABL and tumor suppressor proteins such as Rb, APC, p53, p21, and p27. XPO1 can mediate cell proliferation through several pathways: (i) the sub-cellular localization of NES-containing oncogenes and tumor suppressor proteins, (ii) the control of the mitotic apparatus and chromosome segregation, and (iii) the maintenance of nuclear and chromosomal structures. The XPO1 protein is elevated in ovarian carcinoma, glioma, osteosarcoma, pancreatic and cervical cancer. There is a growing body of research indicating that XPO1 may have an important role as a prognostic marker in solid tumors. Because of this, nuclear export inhibition through XPO1 is a potential target for therapeutic intervention in many cancers. The best understood XPO1 inhibitors are the small molecule nuclear export inhibitors (NEIs; Leptomycin B and derivatives, ratjadones, PKF050-638, valtrate, ACA, CBS9106, selinexor/KPT-330, and verdinexor/KPT-335). Selinexor and verdinexor are orally bioavailable, highly potent, small molecules that are classified as Selective Inhibitors of Nuclear Export (SINE). KPT-330 is the only NEI currently in Phase I/II human clinical trials in hematological and solid cancers. Of all the potential targets in nuclear cytoplasmic transport, the nuclear export receptor XPO1 remains the best understood and most advanced therapeutic target for the treatment of cancer.

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Tai YT, Landesman Y, Acharya C, Calle Y, Zhong MY, Cea M, Tannenbaum D, Cagnetta A, Reagan M, Munshi AA, Senapedis W, Saint-Martin JR, Kashyap T, Shacham S, Kauffman M, Gu Y, Wu L, Ghobrial I, Zhan F, Kung AL, Schey SA, Richardson P, Munshi NC, Anderson KC: CRM1 inhibition induces tumor cell cytotoxicity and impairs osteoclastogenesis in multiple myeloma: molecular mechanisms and therapeutic implications.Leukemia 2013.,

93.

Etchin J, Sanda T, Mansour MR, Kentsis A, Montero J, Le BT, Christie AL, McCauley D, Rodig SJ, Kauffman M, Shacham S, Stone R, Letai A, Kung AL, Look AT: KPT-330 inhibitor of CRM1 (XPO1)-mediated nuclear export has selective anti-leukaemic activity in preclinical models of T-cell acute lymphoblastic leukaemia and acute myeloid leukaemia. Br J Haematol. 2013, 161: 117-127.PubMedCentralPubMed

94.

Walker CJ, Oaks JJ, Santhanam R, Neviani P, Harb JG, Ferenchak G, Ellis JJ, Landesman Y, Eisfeld AK, Gabrail NY, Smith CL, Caligiuri MA, Hokland P, Roy DC, Reid A, Milojkovic D, Goldman JM, Apperley J, Garzon R, Marcucci G, Shacham S, Kauffman MG, Perrotti D: Preclinical and clinical efficacy of XPO1/CRM1 inhibition by the karyopherin inhibitor KPT-330 in Ph+ leukemias. Blood. 2013, 122: 3034-3044.PubMedCentralPubMed

95.

Ranganathan P, Yu X, Na C, Santhanam R, Shacham S, Kauffman M, Walker A, Klisovic R, Blum W, Caligiuri M, Croce CM, Marcucci G, Garzon R: Preclinical activity of a novel CRM1 inhibitor in acute myeloid leukemia. Blood. 2012, 120: 1765-1773.PubMedCentralPubMed

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Azmi AS, Al-Katib A, Aboukameel A, McCauley D, Kauffman M, Shacham S, Mohammad RM: Selective inhibitors of nuclear export for the treatment of non-Hodgkin's lymphomas. Haematologica. 2013, 98: 1098-1106.PubMedCentralPubMed

97.

Inoue H, Kauffman M, Shacham S, Landesman Y, Yang J, Evans CP, Weiss RH: CRM1 blockade by selective inhibitors of nuclear export attenuates kidney cancer growth. J Urol. 2013, 189: 2317-2326.PubMedCentralPubMed

98.

Azmi AS, Aboukameel A, Bao B, Sarkar FH, Philip PA, Kauffman M, Shacham S, Mohammad RM: Selective inhibitors of nuclear export block pancreatic cancer cell proliferation and reduce tumor growth in mice. Gastroenterology. 2013, 144: 447-456.PubMedCentralPubMed

99.

Cheng Y, Holloway MP, Nguyen K, McCauley D, Landesman Y, Kauffman MG, Shacham S, Altura RA: XPO1 (CRM1) inhibition represses STAT3 activation to drive a survivin-dependent oncogenic switch in triple negative breast cancer. Mol Cancer Ther. 2014, 13 (3): 675-686.PubMedCentralPubMed

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Salas Fragomeni RA, Chung HW, Landesman Y, Senapedis W, Saint-Martin JR, Tsao H, Flaherty KT, Shacham S, Kauffman M, Cusack JC: CRM1 and BRAF inhibition synergize and induce tumor regression in braf-mutant melanoma. Mol Cancer Ther. 2013, 12: 1171-1179.PubMed

102.

Yang J, Bill MA, Young GS, La Perle K, Landesman Y, Shacham S, Kauffman M, Senapedis W, Kashyap T, Saint-Martin JR, Kendra K, Lesinski GB: Novel small molecule XPO1/CRM1 inhibitors induce nuclear accumulation of TP53, phosphorylated MAPK and apoptosis in human melanoma cells. PLoS One. 2014, 9: e102983-PubMedCentralPubMed

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Miyake TM, Pradeep S, Zand B, Dalton HJ, Wen Y, Armaitz Pena GN, Kauffman M, McCauley D, Shacham S, Wiktorowicz JE, Sood AK: Abstract 5541: therapeutic targeting of CRM1 in ovarian cancer. Cancer Res. 2013, 73: 5541-

104.

Attiyeh EF, McKeon-Fish A, Trillo R, Landesman Y, Senapedis W, McCauley D, Kashyap T, Shacham S, Kauffman M, Maris JM: Abstract B36: inhibition of exportin 1 (XPO1) potently suppresses growth of human neuroblastoma cell lines. Cancer Res. 2014, 74: B36-

105.

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106.

Yu X, Ranganathan P, Bhatnagar B, Hofstetter J, Shacham S, Kauffman M, Blum W, Garzon R: XPO1 inhibition using selinexor restores topoisomerase IIA (TOPO IIΑ) localization to the nucleus and sensitize primary refractory and relapsed acute myeloid leukemia (AML) blasts to chemotherapy. Haematologica. 2014, 99: 292-293.

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London CA, Bernabe LF, Barnard S, Kisseberth W, Borgatti A, Henson M, Wilson-Robles H, Jensen K, Ito D, Modiano J, Bear M, Pennell M, Saint-Martin J-R, McCauley D, Kauffman M, Shacham S: Abstract 3809: evaluation of the novel, orally bioavailable selective inhibitor of nuclear export (SINE) KPT-335 (verdinexor) in spontaneous canine cancer: results of phase I and phase II clinical trials. Cancer Res. 2014, 74: 3809-

Title: Nucleo-cytoplasmic transport as a therapeutic target of cancer
Authors: Giovanni Luca Gravina
William Senapedis
Dilara McCauley
Erkan Baloglu
Sharon Shacham
Claudio Festuccia
Publication date: 01-12-2014
Publisher: BioMed Central
Published in: Journal of Hematology & Oncology / Issue 1/2014
Electronic ISSN: 1756-8722
DOI: https://doi.org/10.1186/s13045-014-0085-1

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