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Synthesis of a hemin-containing copolymer as a novel immunostimulator that induces IFN-gamma production.

ABSTRACT: Hemozoin, a chemical analog of a malarial pigment, is a crystal composed of heme dimers that can act as a potent Th1-type adjuvant, which strongly induces antibody production. However, the clinical applications of malarial hemozoin have limitations due to biosafety concerns and difficulties in the manufacturing process. Based on the premise that an analog of the heme polymer might display immunostimulatory effects, a hemin-containing polymer was developed as a novel immunostimulator.To synthesize the copolymer containing hemin and N-isopropylacrylamide (NIPAM), this study employed a conventional radical polymerization method using 2,2'-azodiisobutyronitrile as the radical initiator; the synthesized copolymer was designated as NIPAM-hemin.NIPAM-hemin was soluble and showed no cytotoxicity in vitro. The NIPAM-hemin copolymer induced the production of interferon (IFN)-? and interleukin (IL)-6 from peripheral blood mononuclear cells, although hemin and the NIPAM monomer individually did not induce the production of any cytokines. The production of IFN-? induced by NIPAM-hemin was independent of toll-like receptor 9 and the NLRP3 inflammasome pathway.Given that NIPAM-hemin induced IL-6 and IFN-? production in immune cells without any cytotoxic effects, NIPAM-hemin has potential therapeutic applications as a Th1-type adjuvant.

SUBMITTER: Hoshi K

PROVIDER: S-EPMC6080671 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Synthesis of a hemin-containing copolymer as a novel immunostimulator that induces IFN-gamma production.

Hoshi Kazuaki K Yamazaki Tomohiko T Yoshikawa Chiaki C Tsugawa Wakako W Ikebukuro Kazunori K Sode Koji K

International journal of nanomedicine 20180802

<h4>Background</h4>Hemozoin, a chemical analog of a malarial pigment, is a crystal composed of heme dimers that can act as a potent Th1-type adjuvant, which strongly induces antibody production. However, the clinical applications of malarial hemozoin have limitations due to biosafety concerns and difficulties in the manufacturing process. Based on the premise that an analog of the heme polymer might display immunostimulatory effects, a hemin-containing polymer was developed as a novel immunostim ...[more]

PMID: 30122920

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Project description:Pancreatic ductal adenocarcinoma (PDAC) is the most prevalent and aggressive form of pancreatic cancer. Gemcitabine (GEM), the first‑line treatment for PDAC, which alleviates symptoms and enhances the quality of life of patients. However, it is prone to lead to the development of drug resistance during treatment. Interferon (IFN)‑γ exhibits antitumor and immunomodulatory properties. The present study aimed to explore the impact of IFN‑γ on the viability, migration and apoptosis of GEM‑resistant pancreatic cancer cells. Firstly, a GEM‑resistant pancreatic cancer cell line, named PANC‑1/GEM, was constructed. Hematoxylin and eosin staining analyzed the cell morphology, whereas reverse transcription‑quantitative PCR (RT‑qPCR) assessed the expression levels of the drug‑resistance genes multidrug resistance‑associated protein (MRP) and breast cancer resistance protein (BCRP). The MTT assay and cell counting techniques were used to determine the appropriate concentration of IFN‑y and its effects on cell viability. The IFN‑γ‑induced apoptosis of PANC‑1/GEM cells was assessed using an Apoptosis Detection Kit, whereas the impact of IFN‑γ on the migration of these cells was evaluated using a wound‑healing assay. The MTT assay revealed a resistance index of 22.4 in the PANC‑1/GEM cell line. RT‑qPCR indicated that, compared with in wild‑type cells, the PANC‑1/GEM resistant strain exhibited lower MRP and higher BCRP mRNA expression levels. The optimal concentration of IFN‑γ for affecting PANC‑1/GEM cells was determined to be 0.3 µg/ml. At this concentration, IFN‑γ induced PANC‑1/GEM cell apoptosis, along with a notable reduction in migration. Following treatment of PANC‑1/GEM cells with IFN‑γ, MRP expression increased whereas BCRP mRNA expression decreased, indicating a reversal in their drug‑resistance gene expression. In conclusion, IFN‑γ exhibited antitumor immune properties by upregulating MRP and downregulating BCRP expression, reversing drug‑resistance gene expression, and reducing cell viability and migration, while promoting apoptosis in PANC‑1/GEM cells. IFN‑γ could potentially serve as a treatment option for patients with GEM‑resistant pancreatic cancer.

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Synthesis of a hemin-containing copolymer as a novel immunostimulator that induces IFN-gamma production.

Publications

Synthesis of a hemin-containing copolymer as a novel immunostimulator that induces IFN-gamma production.

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