Temporally designed treatment of melanoma cells by ATRA and polyI

Abstract

In the last three decades, the incidence of melanoma has increased worldwide and no effective treatment modalities have been developed yet. All-trans retinoic acid (ATRA) and polyinosinic:polycytidylic acid (polyI:C) are strong inducers of toll-like receptor 3 (TLR3) and MDA5 expression, and polyI:C-induced TLR3 and MDA5 signaling specifically causes cell death in melanoma cells in vitro. We addressed the question of whether ATRA pretreatment could enhance the efficacy of polyI:C and, if so, would ATRA have any additional effects on this process. We found that the combined treatment of human melanoma cells with ATRA and polyI:C strongly increased the expression of TLR3 and MDA5 in both WM35 and WM983A cells associated with significantly higher mRNA and secreted levels of interferon β (IFNβ), CXCL1, CXCL8/IL-8, CXCL9, and CXCL10 than cells treated with either ATRA or polyI:C. Silencing of MDA5 by siRNA moderately affected IFNβ secretion, whereas TLR3 knockdown interfered with both CXCL chemokine and IFNβ production. Furthermore, the supernatants of ATRA+polyI:C-activated cultures increased the migration of both human monocyte-derived macrophages and CD1a dendritic cells significantly as compared with the supernatants of cells treated with either ATRA or polyI:C, and this effect occurred in a TLR3-dependent manner. In conclusion, consecutive treatment with ATRA and polyI:C results in strong, TLR3/MDA5-mediated chemokine and IFN responses in cultured human melanoma cells, which triggers a functional migratory response in professional antigen-presenting cells. This novel mode of concomitant activation may represent a more efficient treatment option for future melanoma therapy.

MDA5 complements TLR3 in suppression of neuroblastoma

“…Importantly, in consistence with the in vitro studies, MDA5 and TLR3 expression in tumor tissues also showed a synergistic effect on NB patient survival. The complementary roles of TLR3 and MDA5 have also been demonstrated in other studies with melanoma and NK cells [ 16 , 17 ]. These lines of evidence strongly support the potential role of targeting innate immune system in the treatment of NB.…”

CXCL9, CXCL10, CXCL11/CXCR3 axis for immune activation – A target for novel cancer therapy

“…Other existing treatments, such as lapatinib with doxorubicin,[88] all-trans retinoic acid (ATRA), [89] and existing chemotherapies[90, 91] have been reported to exert therapeutic effects through the CXCL9, -10, -11/CXCR3 axis, suggesting that activation of CXCL9, -10, -11/CXCR3 axis may increase efficacies of cytotoxic and targeted therapies. (Table 2)…”

Neuropharmacology of N,N-dimethyltryptamine

“…In vitro DMT administration has shown an increase of secreted interferons (beta and gamma) in vitro in NK cell and dendritic cell cultures. Interferons are potent anticancer factors (Caraglia et al, 2009; Gonzalez-Navajas et al, 2012; Szabo et al, 2012; Windbichler et al, 2000). If DMT does increase interferon secretion, it may be beneficial in contributing to or aid in better elimination of malignant and/or infected cells.…”