Dataset Information

Chloroquine-Containing HPMA Copolymers as Polymeric Inhibitors of Cancer Cell Migration Mediated by the CXCR4/SDF-1 Chemokine Axis.

ABSTRACT: Chloroquine-containing HPMA copolymers (pCQs) were synthesized for the first time by copolymerization of methacryloylated hydroxychloroquine and HPMA. The copolymers showed lower cytotoxicity when compared with hydroxychloroquine. Treatment of cancer cells with pCQ resulted in decreased surface expression of chemokine receptor CXCR4. The pCQ copolymers showed effective inhibition of CXCR4/SDF1-mediated cancer cell migration that was fully comparable with a commercial small-molecule CXCR4 antagonist AMD3100. The reported pCQ represent unique and simple polymeric drugs with potential use as part of a combination antimetastatic therapies.

SUBMITTER: Yu F

PROVIDER: S-EPMC5084841 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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Chloroquine-Containing HPMA Copolymers as Polymeric Inhibitors of Cancer Cell Migration Mediated by the CXCR4/SDF-1 Chemokine Axis.

Yu Fei F Xie Ying Y Wang Yan Y Peng Zheng-Hong ZH Li Jing J Oupický David D

ACS macro letters 20160217 3

Chloroquine-containing HPMA copolymers (pCQs) were synthesized for the first time by copolymerization of methacryloylated hydroxychloroquine and HPMA. The copolymers showed lower cytotoxicity when compared with hydroxychloroquine. Treatment of cancer cells with pCQ resulted in decreased surface expression of chemokine receptor CXCR4. The pCQ copolymers showed effective inhibition of CXCR4/SDF1-mediated cancer cell migration that was fully comparable with a commercial small-molecule CXCR4 antagon ...[more]

PMID: 27795873

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Project description:BackgroundThe stromal cell derived factor (SDF)-1/chemokine receptor (CXCR)-4 signaling pathway plays a key role in lung cancer metastasis and is molecular target for therapy. In the present study we investigated whether interleukin (IL)-24 can inhibit the SDF-1/CXCR4 axis and suppress lung cancer cell migration and invasion in vitro. Further, the efficacy of IL-24 in combination with CXCR4 antagonists was investigated.MethodsHuman H1299, A549, H460 and HCC827 lung cancer cell lines were used in the present study. The H1299 lung cancer cell line was stably transfected with doxycycline-inducible plasmid expression vector carrying the human IL-24 cDNA and used in the present study to determine the inhibitory effects of IL-24 on SDF-1/CXCR4 axis. H1299 and A549 cell lines were used in transient transfection studies. The inhibitory effects of IL-24 on SDF1/CXCR4 and its downstream targets were analyzed by quantitative RT-PCR, western blot, luciferase reporter assay, flow cytometry and immunocytochemistry. Functional studies included cell migration and invasion assays.Principal findingsEndogenous CXCR4 protein expression levels varied among the four human lung cancer cell lines. Doxycycline-induced IL-24 expression in the H1299-IL24 cell line resulted in reduced CXCR4 mRNA and protein expression. IL-24 post-transcriptionally regulated CXCR4 mRNA expression by decreasing the half-life of CXCR4 mRNA (>40%). Functional studies showed IL-24 inhibited tumor cell migration and invasion concomitant with reduction in CXCR4 and its downstream targets (pAKTS473, pmTORS2448, pPRAS40T246 and HIF-1α). Additionally, IL-24 inhibited tumor cell migration both in the presence and absence of the CXCR4 agonist, SDF-1. Finally, IL-24 when combined with CXCR4 inhibitors (AMD3100, SJA5) or with CXCR4 siRNA demonstrated enhanced inhibitory activity on tumor cell migration.ConclusionsIL-24 disrupts the SDF-1/CXCR4 signaling pathway and inhibits lung tumor cell migration and invasion. Additionally, IL-24, when combined with CXCR4 inhibitors exhibited enhanced anti-metastatic activity and is an attractive therapeutic strategy for lung metastasis.

Dataset Information

Chloroquine-Containing HPMA Copolymers as Polymeric Inhibitors of Cancer Cell Migration Mediated by the CXCR4/SDF-1 Chemokine Axis.

Publications

Chloroquine-Containing HPMA Copolymers as Polymeric Inhibitors of Cancer Cell Migration Mediated by the CXCR4/SDF-1 Chemokine Axis.

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