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

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.

• Authors: Yoshihiro Shirai, Nobuhiro Saito, Tadashi Uwagawa, Hiroaki Shiba, Takashi Horiuchi, Ryota Iwase, Koichiro Haruki, Toya Ohashi, Katsuhiko Yanaga
• Journal: Oncotarget (Oncotarget) Vol. 9 Issue 20 Pg. 15292-15301 (Mar 16 2018) ISSN: 1949-2553 [Electronic] United States
• PMID: 29632644 (Publication Type: Journal Article)