JLK1486, a Bis 8-Hydroxyquinoline-Substituted Benzylamine, Displays Cytostatic Effects in Experimental Gliomas through MyT1 and STAT1 Activation and, to a Lesser Extent, PPARγ Activation

Abstract

Gliomas account for 5% to 7% of all solid cancers in adults and up to 30% of solid cancers in children; glioblastomas are the most malignant type of glioma and often have dismal prognoses. The alkylating agent temozolomide provides the greatest chemotherapeutic benefits currently available; however, glioblastoma patients cannot be cured. Novel drugs that efficiently combat glioblastomas are therefore of great interest. We report here that JLK1486, an 8-hydroxyquinoline-substituted benzylamine, could represent a novel chemical scaffold to reach this goal. Indeed, JLK1486 mediated anticancer activity in vivo (through intravenous as well as oral routes of administrations) in an orthotopic xenograft model and displayed efficiency similar to that of temozolomide. The therapeutic benefits of JLK1486 seem to relate to its ability to activate various transcription factors (including Myt1, STAT1, and peroxisome proliferator-activated receptor γ) in glioma cells. These transcription factors are implicated in the control of glioma cell proliferation, and the resultant global effect of their activation by JLK1486 was cytostatic, not cytotoxic. Thus, the current study opens the door for the development of novel compounds to combat glioblastoma using 8-hydroxyquinoline benzylamine analogs.

A study on the correlation between STAT‑1 and mutant p53 expression in glioma

“…STAT-1, which was the first member of the STAT family to be discovered, is able to inhibit cell proliferation and promote apoptosis (3). STAT-1 has been identified as a tumor-inhibiting factor, and reduced STAT-1 expression is associated with the occurrence and progression of malignant tumors (4). In addition, it has been demonstrated that the activation of STAT-1 expression in tumor cells by exogenous or endogenous stimuli can improve the sensitivity of these cells to chemotherapy (5).…”

JLK1486, a N,N‐[(8‐hydroxyquinoline)methyl]‐substituted benzylamine analogue, inhibits melanoma proliferation and induces autophagy

“…Bruyère et al . also reported absence of any significant changes in cell cycle profile when glioblastoma cells were treated with 100 n m JLK1486 despite significant growth inhibition at this concentration (IC 50 values for anti‐proliferative activity ranged between ∼80 and 290 n m for glioblastoma cells investigated) .…”

“…This cell-specific difference together with approximately 3-fold difference in IC 50 between MTT proliferation assay and cell cycle analysis indicates that the anti-proliferatory mechanism of JLK1486 is not exclusively dependent on cell cycle arrest and suggests that G 0 /G 1 arrest observed in the melanoma cells is a secondary effect, in response to JLK1486 treatment, possibly ER stress as has been reported for U87 glioblastoma cells (4). Bruy ere et al also reported absence of any significant changes in cell cycle profile when glioblastoma cells were treated with 100 nM JLK1486 despite significant growth inhibition at this concentration (IC 50 values for anti-proliferative activity ranged between $80 and 290 nM for glioblastoma cells investigated) (13).…”

Transcription Factors with Targeting Potential in Gliomas

“…The benefits of JLK1486-treatment derive from its ability to activate various transcription factors, such as Myt1, STAT1, and peroxisome proliferator-activated receptor γ, in glioma cells. The activation of these TFs by JLK1486 had a cytostatic rather than a cytotoxic outcome of glioma cells [ 147 ].…”