Immunomodulator polyinosinic-polycytidylic acid enhances the inhibitory effect of 13-cis-retinoic acid on neuroblastoma through a TLR3-related immunogenic-apoptotic response.

Abstract

High-risk neuroblastoma is associated with low long-term survival rates due to recurrence or metastasis. Retinoids, including 13-cis-retinoic acid (13cRA), are commonly used for the treatment of high-risk neuroblastoma after myeloablative therapy; however, there are significant side effects and resistance rates. In this study, we demonstrated that 13cRA has a better antiproliferative effect in MYCN-amplified neuroblastoma cells than in MYCN-nonamplified neuroblastoma cells. In MYCN-amplified SK-N-DZ cells, 13cRA induced significant upregulation of toll-like receptor 3 (TLR3) and mitochondrial antiviral-signaling protein (MAVS) expression in a time-dependent manner. Furthermore, poly (I:C), a synthetic agonist of TLR3, effectively synergized with 13cRA to enhance antiproliferative effects through upregulation of the innate immune signaling and the mitochondrial stress response, leading to augmentation of the apoptotic response in 13cRA-responsive cancer cells. In addition, the 13cRA/poly (I:C) combination induced neural differentiation through activation of retinoic acid receptors beta (RAR-β), restoring expression of α-thalassemia/mental retardation syndrome X-linked (ATRX) protein, and inhibiting vessel formation, leading to retarded tumor growth in a mouse xenograft model. These results suggest that the combination of poly (I:C) and RA may provide synergistic therapeutic benefits for treatment of patients with high-risk neuroblastoma.

• Authors: Hui-Ching Chuang, Hung-Yu Lin, Pei-Lin Liao, Chao-Cheng Huang, Li-Ling Lin, Wen-Ming Hsu, Jiin-Haur Chuang
• Journal: Laboratory investigation; a journal of technical methods and pathology (Lab Invest) Vol. 100 Issue 4 Pg. 606-618 (04 2020) ISSN: 1530-0307 [Electronic] United States
• PMID: 31857701 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Immunologic Factors
• Toll-Like Receptor 3
• Isotretinoin
• Poly I-C

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Cell Line
• Cell Proliferation (drug effects)
• Drug Synergism
• Immunologic Factors (pharmacology)
• Isotretinoin (pharmacology)
• Male
• Mice
• Mice, SCID
• Neuroblastoma (metabolism)
• Poly I-C (pharmacology)
• Signal Transduction (drug effects)
• Toll-Like Receptor 3 (metabolism)
• Xenograft Model Antitumor Assays