Selective Nuclear Export Inhibitor KPT-330 Enhances the Antitumor Activity of Gemcitabine in Human Pancreatic Cancer

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 pancreas of athymic nude mice, which were treated with 1) vehicle (PBS 1 mL/kg IP, 2/week and povidone/pluronic F68 1 mL/kg PO, 3/week), 2) KPT-330 (20 mg/kg PO, 3/week), 3) gemcitabine (100 mg/kg IP, 2/week), or 4) 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 to 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 anti-apoptotic proteins, and induction of apoptosis.

First-in-Class, First-in-Human Phase I Study of Selinexor, a Selective Inhibitor of Nuclear Export, in Patients With Advanced Solid Tumors

“…Preclinical evaluation of selinexor in combination therapies, with platins, taxanes, irinotecan, temozolomide, gemcitabine, vemurafenib, and ABT737, demonstrated enhanced efficacy in mouse xenograft models. [29][30][31][32][33][34] In addition, selinexor acted synergistically with radiation therapy in non-small-cell lung cancer to enhance cell death, at least in part through the inhibition of DNA damage repair enzymes. 35 Together, these data highlight the potential for selinexor in combination with commonly used therapeutic regimens and warrant further investigation of selinexor in clinical trials, some of which are currently ongoing.…”

TNPO2 operates downstream of DYNC1I1 and promotes gastric cancer cell proliferation and inhibits apoptosis

“…According to the recent research, karyopherin-β family is regarded as a potential target for cancer therapy. 3,[7][8][9][10] The TNPO2-mediated transport of the material into the nuclear process is similar to the above described system. But TNPO2 only transports limited nuclear-destined cargoes, and participates only in the nuclear process, without participating in the cargo export process.…”

“…Importins are bound by Ran‐GTP, releasing the cargo proteins in the nucleus and recycling them in the cytoplasm. According to the recent research, karyopherin‐β family is regarded as a potential target for cancer therapy . The TNPO2‐mediated transport of the material into the nuclear process is similar to the above described system.…”

Development and potential applications of CRISPR-Cas9 genome editing technology in sarcoma

“…In recent years, over expression of XPO1 has been observed in osteosarcoma and has been correlated with poor prognosis and resistance to therapy [83]. Selinexor (KPT-330), an inhibitor of XPO1, is currently undergoing phase 2 clinical trials and has demonstrated high response rates as a therapeutic agent in phase 1 trials for heavily pretreated, relapsed, and refractory hematological and solid tumor malignancies in humans [16, 36, 53]. Selinexor could inhibit the function and formation of XPO1, possibly through binding to the cysteine 528 residue of XPO1, which leads to an accumulation of tumor suppressor proteins in the nucleus of treated cells, and thus cell cycle arrest and apoptosis [16, 36, 53].…”