Oncotarget

Research Papers:

Pomalidomide promotes chemosensitization of pancreatic cancer by inhibition of NF-κB

Yoshihiro Shirai _, Nobuhiro Saito, Tadashi Uwagawa, Hiroaki Shiba, Takashi Horiuchi, Ryota Iwase, Koichiro Haruki, Toya Ohashi and Katsuhiko Yanaga

PDF  |  HTML  |  How to cite  |  Order a Reprint

Oncotarget. 2018; 9:15292-15301. https://doi.org/10.18632/oncotarget.24577

Metrics: PDF 956 views  |   HTML 1529 views  |   ?  


Abstract

Yoshihiro Shirai1,2, Nobuhiro Saito1,2,*, Tadashi Uwagawa1,3, Hiroaki Shiba1, Takashi Horiuchi1,2, Ryota Iwase1, Koichiro Haruki1, Toya Ohashi2 and Katsuhiko Yanaga1

1Department of Surgery, The Jikei University School of Medicine, Tokyo, Japan

2Division of Gene Therapy, Research Center for Medical Sciences, The Jikei University School of Medicine, Tokyo, Japan

3Division of Clinical Oncology and Hematology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan

*This author contributed equally to this work

Correspondence to:

Yoshihiro Shirai, email: shirai@jikei.ac.jp

Toya Ohashi, email: tohashi@jikei.ac.jp

Katsuhiko Yanaga, email: kyanaga@jikei.ac.jp

Keywords: pancreatic cancer; pomalidomide; NF-κB; gemcitabine; S1

Received: September 05, 2017     Accepted: February 21, 2018     Epub: February 26, 2018     Published: March 16, 2018

ABSTRACT

Introduction: Nuclear factor κB (NF-κB) plays an important role in cancer progression and causes therapeutic resistance to chemotherapy. Pomalidomide, a third-generation immunomodulating drug derived from thalidomide, has been approved for uncontrolled multiple myeloma. We hypothesized that pomalidomide may inhibit the anticancer agent-induced NF-κB activity and enhance chemosensitization of combination chemotherapy with gemcitabine and S1 (Gem/S1) in pancreatic cancer.

Methods: In vitro, we assessed NF-κB activity, induction of caspase cascade, cell apoptosis and cell proliferation using human pancreatic cancer cell lines (MIA PaCa-2 and PANC-1). In vivo, we established an orthotopic xenograft mouse model for human pancreatic cancer by injection of PANC-1 cells. At 5 weeks after injection, the animals were randomly divided into four groups and treated with Gem (100 mg/kg) /S1 (10 mg/kg), with oral administration of pomalidomide (0.5 mg/kg), with combination of gemcitabine, S1, and pomalidomide or vehicle only.

Results: Although chemotherapeutic agents induced NF-κB activation in pancreatic cancer cells, pomalidomide inhibited anticancer agent-induced NF-κB activation (p < 0.01). Of the four groups tested for the apoptosis-related caspase signals and apoptosis under both in vitro and in vivo conditions, Gem/S1/Pomalidomide group demonstrated the strongest activation of the caspase signals and proapoptotic effect. In Gem/S1/Pomalidomide group, cell proliferation and tumor growth were slower than those in other groups both in vitro and in vivo (p < 0.01). There were no obvious adverse effects except for thrombocytosis by using pomalidomide.

Conclusions: Pomalidomide promotes chemosensitization of pancreatic cancer by inhibiting chemotherapeutic agents-induced NF-κB activation.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
PII: 24577