Molecular Pathways: Anticancer Activity by Inhibition of Nucleocytoplasmic Shuttling.
A dynamic distribution between nucleus and cytoplasm (nucleocytoplasmic shuttling) is one of the control mechanisms adapted by normal cells to regulate the activity of a variety of molecules. Growing evidence suggests that dysregulation of the nucleocytoplasmic shuttling is involved in promoting abnormal cell survival, tumor progression, and drug resistance, and is associated with poor cancer prognosis. Aberrant nucleocytoplasmic shuttling in cancer cells may result from a hyperactive status of diverse signal-transduction pathways, such as the PI3K-AKT and MAPK pathways, or from alterations in the general nuclear import/export machinery. Among the large number of molecules involved in the shuttling process, exportin XPO1, also known as chromosome region maintenance 1, appears to play a particularly prominent role in pathogenesis of both hematological malignancies and solid tumors. Given the importance of nucleocytoplasmic shuttling in cancer pathogenesis and the rapidly expanding knowledge in this field, attempts have been made to develop compounds able to revert the aberrant nucleocytoplasmic shuttling. A promising new drug, KPT-330 (Selinexor), which belongs to the class of XPO1 inhibitors called selective inhibitors of nuclear export, is now being tested in phase I/II clinical trials.
Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia.
Fabio
F
Conforti
Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia. National Cancer Institute, Bethesda, Maryland.
Yisong
Y
Wang
Department of Genetics, Physical Anthropology and Animal Physiology, University of the Basque Country (UPV/EHU), Leioa, Spain.
Jose A
JA
Rodriguez
Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia.
Anna Teresa
AT
Alberobello
Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia.
Yu-Wen
YW
Zhang
Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia. gg496@georgetown.edu.
Giuseppe
G
Giaccone
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002467:Cell Nucleus / Q000187:drug effects* / Q000378:metabolism; D003593:Cytoplasm / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
D000970:Antineoplastic Agents; D019869:Phosphatidylinositol 3-Kinases