Demeclocycline Reduces the Growth of Human Brain Tumor-Initiating Cells: Direct Activity and Through Monocytes

Abstract

Myeloid cells that infiltrate into brain tumors are deactivated or exploited by the tumor cells. We previously demonstrated that compromised microglia, monocytes, and macrophages in malignant gliomas could be reactivated by amphotericin-B to contain the growth of brain tumorinitiating cells (BTICs). We identified meclocycline as another activator of microglia, so we sought to test whether its better-tolerated derivative, demeclocycline, also stimulates monocytes to restrict BTIC growth. Monocytes were selected for study as they would be exposed to demeclocycline in the circulation prior to entry into brain tumors to become macrophages. We found that demeclocycline increased the activity of monocytes in culture, as determined by tumor necrosis factor-α production and chemotactic capacity. The conditioned medium of demeclocycline-stimulated monocytes attenuated the growth of BTICs generated from human glioblastoma resections, as evaluated using neurosphere and alamarBlue assays, and cell counts. Demeclocycline also had direct effects in reducing BTIC growth. A global gene expression screen identified several genes, such as DNA damage inducible transcript 4, frizzled class receptor 5 and reactive oxygen species modulator 1, as potential regulators of demeclocycline-mediated BTIC growth reduction. Amongst several tetracycline derivatives, only demeclocycline directly reduced BTIC growth. In summary, we have identified demeclocycline as a novel inhibitor of the growth of BTICs, through direct effect and through indirect stimulation of monocytes. Demeclocycline is a candidate to reactivate compromised immune cells to improve the prognosis of patients with gliomas.

A microglia-CD4+ T cell partnership generates protective anti-tumor immunity to glioblastoma

“…Furthermore, patients whose tumors had a higher ratio of microglia-specific transcripts (P2RY12) to tumor associated macrophage (TAM)-specific transcripts (CD163) displayed longer overall survival (Figure 4J), suggestive of microglial anti-tumor activities. This is in line with recent studies that analyzed distinctive microglia markers and suggested that microglia are protective against glioblastoma (Chicoine et al, 2007;Hwang et al, 2009;Sarkar et al, 2014;Sarkar et al, 2020;Woolf et al, 2021).…”

Neuroprotective Effects of a Novel Demeclocycline Derivative Lacking Antibiotic Activity: From a Hit to a Promising Lead Compound

“…DMC is clinically used to treat susceptible bacterial infections and can be systemically administrated due to its low toxicity in human cells, even neurons [ 28 ]. In order to uncover if this was also the case for DDMC, we first evaluated its impact on cell viability by measuring MTT turnover [ 17 ] in SH-SY5Y cell cultures, using similar concentrations as those used by Braun et al for DMC [ 13 ].…”

High-Throughput Identification of Antibacterials Against Pseudomonas aeruginosa

“…It is used as a broad-spectrum antibiotic, but may be more often used to treat chronic syndrome of inappropriate secretion of antidiuretic hormone (SIADH) ( Miell et al, 2015 ). According to reports, DMCT is expected to be used as a contrast agent for intraoperative detection of brain tumors ( Sarkar et al, 2020 ). In our study, we collected 6 MDR clinical isolate strains of P. aeruginosa for combination therapy.…”