Enhanced growth inhibition of metastatic lung tumors by intravenous injection of ATRA-cationic liposome/IL-12 pDNA complexes in mice

Abstract

Interleukin 12 (IL-12) is a proinflammatory cytokine with antitumor activity. All-trans-retinoic acid (ATRA) exerts antitumor effects by regulating a variety of gene expressions, including tumor necrosis factor receptor 1 (TNFR1), increases the number of TNFR1 and potentiates TNF-a-induced apoptosis in cancer cells. In this study, ATRA-incorporated cationic liposome (ATRA-cationic liposome)/ IL-12 plasmid DNA (pDNA) complexes were prepared to improve therapeutic efficacy of cationic liposome/IL-12 pDNA complexes in a mouse model of metastatic lung tumor after intravenous injection. IL-12 production in lungs by ATRA-cationic liposome/IL-12 pDNA complexes was comparable with that by cationic liposome/IL-12 pDNA complexes. The number of metastatic tumor cells (colon26/Luc) was quantitatively evaluated by measuring luciferase activity. ATRA-cationic liposome/IL-12 pDNA complexes reduced the number of colon26/Luc cells and tumor nodules in lungs. ATRA-cationic liposome/IL-12 pDNA complexes significantly prolonged the survival time of mice, whereas cationic liposome/IL-12 pDNA only slightly prolonged it. ATRA-cationic liposome/IL-12 pDNA complexes increased the TNFR1 mRNA upregulation and the number of apoptotic cells in the lung. Moreover, reduced serum alanine transaminase (ALT) and aspartate transaminase (AST) activities were observed in mice treated with ATRA-cationic liposome/IL-12 pDNA complexes. These results suggest that intravenous injection of ATRA-cationic liposome/IL-12 pDNA complexes is an effective method for the treatment of lung metastasis in mice.

HDAC2 phosphorylation-dependent Klf5 deacetylation and RARα acetylation induced by RAR agonist switch the transcription regulatory programs of p21 in VSMCs

“…Generally, in the absence of ligands, RARs are associated with co-repressors to inhibit transcription, while liganded RARs recruit co-activators to activate transcription [32]. Clinical applications of AtRA have had some success in the treatment of human diseases such as cancer, psoriasis, leukemia, restenosis and plaque formation [31,33]. Nevertheless, the precise mechanism by which RARs function to control p21 and thus govern cell proliferation is still not well understood.…”

Retinoic Acid Receptor α Mediates All-trans-retinoic Acid-induced Klf4 Gene Expression by Regulating Klf4 Promoter Activity in Vascular Smooth Muscle Cells

“…RARs are now considered to be an attractive research target for treatment of VSMC proliferation disease (28,29). Clinical applications of ATRA have successfully been applied in human diseases such as leukemia, cancer, restenosis, and plaque formation (29,30). Despite these advances, the mechanisms by which ATRA functions to induce Klf4 transcription are still largely unknown.…”

All-trans retinoic acid-incorporated nanoparticles of deoxycholic acid-conjugated dextran for treatment of CT26 colorectal carcinoma cells

“…Antimetastatic effects of RA against mouse pulmonary metastatic model have been investigated by several researchers. 25,27 We also demonstrated the antimetastatic activity of RA-incorporated nanoparticles using mouse pulmonary metastatic model of CT26 cells, as shown in Figure 7. Suzuki et al reported that RA-encapsulated cationic liposome suppressed pulmonary metastasis of tumor cells.…”

“…25,26 CT26 cells were administered into the tail vein of BALb/C mice (1 × 10 5 cells/0.2 mL Hank's balanced salt solution). RA was dissolved in 5% HCO-60 (Nicco Chemicals, Tokyo, Japan) solution, and RAincorporated nanoparticles were administered via the tail vein (RA dose 5 mg/kg) at day 3 after tumor inoculation.…”