XPO1 inhibition by selinexor induces potent cytotoxicity against high grade bladder malignancies

Han Bit Baek, Alan P. Lombard, Stephen J. Libertini, Aleida Fernandez-Rubio, Ruth Louise Vinall, Regina F Gandour-Edwards, Rachel Nakagawa, Kathleen Vidallo, Kristine Nishida, Salma Siddiqui, Hiromi Wettersten, Yosef Landesman, Robert H Weiss, Paramita M Ghosh, Maria Mudryj

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Treatment options for high grade urothelial cancers are limited and have remained largely unchanged for several decades. Selinexor (KPT-330), a first in class small molecule that inhibits the nuclear export protein XPO1, has shown efficacy as a single agent treatment for numerous different malignancies, but its efficacy in limiting bladder malignancies has not been tested. In this study we assessed selinexor-dependent cytotoxicity in several bladder tumor cells and report that selinexor effectively reduced XPO1 expression and limited cell viability in a dose dependent manner. The decrease in cell viability was due to an induction of apoptosis and cell cycle arrest. These results were recapitulated in in vivo studies where selinexor decreased tumor growth. Tumors treated with selinexor expressed lower levels of XPO1, cyclin A, cyclin B, and CDK2 and increased levels of RB and CDK inhibitor p27, a result that is consistent with growth arrest. Cells expressing wildtype RB, a potent tumor suppressor that promotes growth arrest and apoptosis, were most susceptible to selinexor. Cell fractionation and immunofluorescence studies showed that selinexor treatment increased nuclear RB levels and mechanistic studies revealed that RB ablation curtailed the response to the drug. Conversely, limiting CDK4/6 dependent RB phosphorylation by palbociclib was additive with selinexor in reducing bladder tumor cell viability, confirming that RB activity has a role in the response to XPO1 inhibition. These results provide a rationale for XPO1 inhibition as a novel strategy for the treatment of bladder malignancies.

Original languageEnglish (US)
Pages (from-to)34567-34581
Number of pages15
JournalOncotarget
Volume9
Issue number77
DOIs
StatePublished - Oct 1 2018

Fingerprint

Urinary Bladder
Neoplasms
Cell Survival
Urinary Bladder Neoplasms
Growth
Cyclin-Dependent Kinase Inhibitor p27
Apoptosis
Cyclin B
Cell Fractionation
KPT-330
Cyclin A
Cell Nucleus Active Transport
Therapeutics
Nuclear Proteins
Cell Cycle Checkpoints
Fluorescent Antibody Technique
Phosphorylation
Pharmaceutical Preparations

Keywords

  • Bladder cancer
  • Cell cycle
  • Retinoblastoma
  • Selinexor
  • XPO1

ASJC Scopus subject areas

  • Oncology

Cite this

XPO1 inhibition by selinexor induces potent cytotoxicity against high grade bladder malignancies. / Baek, Han Bit; Lombard, Alan P.; Libertini, Stephen J.; Fernandez-Rubio, Aleida; Vinall, Ruth Louise; Gandour-Edwards, Regina F; Nakagawa, Rachel; Vidallo, Kathleen; Nishida, Kristine; Siddiqui, Salma; Wettersten, Hiromi; Landesman, Yosef; Weiss, Robert H; Ghosh, Paramita M; Mudryj, Maria.

In: Oncotarget, Vol. 9, No. 77, 01.10.2018, p. 34567-34581.

Research output: Contribution to journalArticle

Baek, HB, Lombard, AP, Libertini, SJ, Fernandez-Rubio, A, Vinall, RL, Gandour-Edwards, RF, Nakagawa, R, Vidallo, K, Nishida, K, Siddiqui, S, Wettersten, H, Landesman, Y, Weiss, RH, Ghosh, PM & Mudryj, M 2018, 'XPO1 inhibition by selinexor induces potent cytotoxicity against high grade bladder malignancies', Oncotarget, vol. 9, no. 77, pp. 34567-34581. https://doi.org/10.18632/oncotarget.26179
Baek, Han Bit ; Lombard, Alan P. ; Libertini, Stephen J. ; Fernandez-Rubio, Aleida ; Vinall, Ruth Louise ; Gandour-Edwards, Regina F ; Nakagawa, Rachel ; Vidallo, Kathleen ; Nishida, Kristine ; Siddiqui, Salma ; Wettersten, Hiromi ; Landesman, Yosef ; Weiss, Robert H ; Ghosh, Paramita M ; Mudryj, Maria. / XPO1 inhibition by selinexor induces potent cytotoxicity against high grade bladder malignancies. In: Oncotarget. 2018 ; Vol. 9, No. 77. pp. 34567-34581.
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AU - Siddiqui, Salma

AU - Wettersten, Hiromi

AU - Landesman, Yosef

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AU - Ghosh, Paramita M

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