Selective nuclear export inhibitor KPT-330 enhances the antitumor activity of gemcitabine in human pancreatic cancer

Sabiha Kazim, Mokenge P. Malafa, Domenico Coppola, Kazim Husain, Sherma Zibadi, Trinayan Kashyap, Marsha Crochiere, Yosef Landesman, Tami Rashal, Daniel M. Sullivan, Amit Mahipal

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

Pancreatic cancer is an aggressive and deadly malignancy responsible for the death of over 37,000 Americans each year. Gemcitabine-based therapy is the standard treatment for pancreatic cancer but has limited efficacy due to chemoresistance. In this study, we evaluated the in vitro and in vivo effects of gemcitabine combined with the selective nuclear export (CRM1) inhibitor KPT-330 on pancreatic cancer growth. Human pancreatic cancer MiaPaCa-2 and metastatic pancreatic cancer L3.6pl cell lines were treated with different concentrations of KPT-330 and gemcitabine alone or in combination, and anchorage-dependent/independent growth was recorded. In addition, L3.6pl cells with luciferase were injected orthotopically into the pancreas of athymic nude mice, which were treated with (i) vehicle (PBS 1 mL/kg i.p., 2/week and povidone/pluronic F68 1 mL/kg p.o., 3/week), (ii) KPT-330 (20 mg/kg p.o., 3/week), (iii) gemcitabine (100 mg/kg i.p., 2/week), or (iv) KPT-330 (10 mg/kg) + gemcitabine (50 mg/kg) for 4 weeks. KPT-330 and gemcitabine alone dose-dependently inhibited anchorage-dependent growth in vitro and tumor volume in vivo compared with vehicle treatment. However, the combination inhibited growth synergistically. In combination, KPT-330 and gemcitabine acted synergistically to enhance pancreatic cancer cell death greater than each single-agent therapy. Mechanistically, KPT-330 and gemcitabine promoted apoptosis, induced p27, depleted survivin, and inhibited accumulation of DNA repair proteins. Together, our data suggest that KPT-330 potentiates the antitumor activity of gemcitabine in human pancreatic cancer through inhibition of tumor growth, depletion of the antiapoptotic proteins, and induction of apoptosis.

Original languageEnglish (US)
Pages (from-to)1570-1581
Number of pages12
JournalMolecular Cancer Therapeutics
Volume14
Issue number7
DOIs
StatePublished - Jul 1 2015
Externally publishedYes

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gemcitabine
Cell Nucleus Active Transport
Pancreatic Neoplasms
Growth
Nude Mice
Apoptosis
KPT-330
Poloxamer
Povidone
Tumor Burden
Luciferases
DNA Repair

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Selective nuclear export inhibitor KPT-330 enhances the antitumor activity of gemcitabine in human pancreatic cancer. / Kazim, Sabiha; Malafa, Mokenge P.; Coppola, Domenico; Husain, Kazim; Zibadi, Sherma; Kashyap, Trinayan; Crochiere, Marsha; Landesman, Yosef; Rashal, Tami; Sullivan, Daniel M.; Mahipal, Amit.

In: Molecular Cancer Therapeutics, Vol. 14, No. 7, 01.07.2015, p. 1570-1581.

Research output: Contribution to journalArticle

Kazim, S, Malafa, MP, Coppola, D, Husain, K, Zibadi, S, Kashyap, T, Crochiere, M, Landesman, Y, Rashal, T, Sullivan, DM & Mahipal, A 2015, 'Selective nuclear export inhibitor KPT-330 enhances the antitumor activity of gemcitabine in human pancreatic cancer', Molecular Cancer Therapeutics, vol. 14, no. 7, pp. 1570-1581. https://doi.org/10.1158/1535-7163.MCT-15-0104
Kazim, Sabiha ; Malafa, Mokenge P. ; Coppola, Domenico ; Husain, Kazim ; Zibadi, Sherma ; Kashyap, Trinayan ; Crochiere, Marsha ; Landesman, Yosef ; Rashal, Tami ; Sullivan, Daniel M. ; Mahipal, Amit. / Selective nuclear export inhibitor KPT-330 enhances the antitumor activity of gemcitabine in human pancreatic cancer. In: Molecular Cancer Therapeutics. 2015 ; Vol. 14, No. 7. pp. 1570-1581.
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AU - Kashyap, Trinayan

AU - Crochiere, Marsha

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AU - Rashal, Tami

AU - Sullivan, Daniel M.

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