Induction of Ca-dependent autophagy and concurrent lysosomal alkalinization underlies the cytotoxic effects of NNC-55-0396 on glioblastoma cells.

Diverse agents targeting (macro)autophagy, a critical metabolic stress response in cancer cells, have been proposed for cancer therapy. In previous studies, we showed that NNC-55-0396 (NNC) induces glioblastoma cell death by activating the Unfolded Protein Response (UPR) of ER stress and increasing cytosolic Ca levels. Here, we report that NNC affects both ends of the autophagy process, causing extensive cytoplasmic vacuolation.

Tetralol derivative NNC-55-0396 targets hypoxic cells in the glioblastoma microenvironment: an organ-on-chip approach.

Glioblastoma (GBM) is a highly malignant brain tumour characterised by limited treatment options and poor prognosis. The tumour microenvironment, particularly the central hypoxic region of the tumour, is known to play a pivotal role in GBM progression. Cells within this region adapt to hypoxia by stabilising transcription factor HIF1-α, which promotes cell proliferation, dedifferentiation and chemoresistance.

T-type channels in cancer cells: Driving in reverse.

In the strongly polarized membranes of excitable cells, activation of T-type Ca channels (TTCCs) by weak depolarizing stimuli allows the influx of Ca which further amplifies membrane depolarization, thus "recruiting" higher threshold voltage-gated channels to promote action potential firing. Nonetheless, TTCCs perform other functions in the plasma membrane of both excitable and non-excitable cells, in which they regulate a number of biochemical pathways relevant for cell cycle and cell fate. Furthermore, data obtained in the last 20 years have shown the involvement of TTCCs in tumor biology, designating them as promising chemotherapeutic targets.

Tetralol derivative NNC-55-0396 induces glioblastoma cell death by activating IRE1α, JNK1 and calcium signaling.

Mibefradil and NNC-55-0396, tetralol derivatives with a proven -ability to block T-type calcium channels in excitable cells, reduce cancer cell viability in vitro, causing cell death. Furthermore, they reduce tumor growth in preclinical models of Glioblastoma multiforme (GBM), a brain tumor of poor prognosis. Here we found that GBM cells treated with cytotoxic concentrations of NNC-55-0396 paradoxically increased cytosolic calcium levels through the activation of inositol triphosphate receptors (IPR) and ER stress.

Targeting T-type channels in cancer: What is on and what is off?

Over the past 20 years, various studies have demonstrated a pivotal role of T-type calcium channels (TTCCs) in tumor progression. Cytotoxic effects of TTCC pharmacological blockers have been reported in vitro and in preclinical models. However, their roles in cancer physiology are only beginning to be understood.

FAK Inhibition Induces Glioblastoma Cell Senescence-Like State through p62 and p27.

Focal adhesion kinase (FAK) is a central component of focal adhesions that regulate cancer cell proliferation and migration. Here, we studied the effects of FAK inhibition in glioblastoma (GBM), a fast growing brain tumor that has a poor prognosis. Treating GBM cells with the FAK inhibitor PF-573228 induced a proliferative arrest and increased cell size.

The rise of T-type channels in melanoma progression and chemotherapeutic resistance.

Hyperactivation of the Mitogen Activated Protein Kinase (MAPK) pathway is prevalent in melanoma, principally due to mutations in the BRAF and NRAS genes. MAPK inhibitors are effective only short-term, and recurrence occurs due to functional redundancies or intertwined pathways. The remodeling of Ca signaling is also common in melanoma cells, partly through the increased expression of T-type channels (TTCCs).

The Hard-To-Close Window of T-Type Calcium Channels.

T-Type calcium channels (TTCCs) are key regulators of membrane excitability, which is the reason why TTCC pharmacology is subject to intensive research in the neurological and cardiovascular fields. TTCCs also play a role in cancer physiology, and pharmacological blockers such as tetralols and dihydroquinazolines (DHQs) reduce the viability of cancer cells in vitro and slow tumor growth in murine xenografts. However, the available compounds are better suited to blocking TTCCs in excitable membranes rather than TTCCs contributing window currents at steady potentials.

T-Type Ca3.1 Channels Mediate Progression and Chemotherapeutic Resistance in Glioblastoma.

T-type Ca channels (TTCC) have been identified as key regulators of cancer cell cycle and survival. studies in glioblastoma (GBM) murine xenografts have shown that drugs able to block TTCC (such as tetralol derivatives mibefradil/NNC-55-096, or different 3,4-dihydroquinazolines) slow tumor progression. However, currently available TTCC pharmacologic blockers have limited selectivity for TTCC and are unable to distinguish between TTCC isoforms.