Inhibition of PIM1 blocks the autophagic flux to sensitize glioblastoma cells to ABT-737-induced apoptosis

Remy, Janina; Linder, Benedikt; Weirauch, Ulrike; Konovalova, Julia; Marschalek, Rolf; Aigner, Achim; Kögel, Donat

doi:10.1016/j.bbamcr.2018.10.017

Cited by 17 publications

(26 citation statements)

References 51 publications

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“…This, in turn, would imply that calcitriol-treated cells are more sensitive towards conventional chemotherapy, such as TMZ. To test this hypothesis, we first generated GFP-expressing NCH644 (NCH644 GFP + ) and NCH421k (NCH421k GFP + ) cells and applied them in an ex vivo tumor growth assay using organotypic tissue culture (OTC), as described recently [ 29 , 41 ]. For this purpose, the OTCs were prepared and, one day after tumor transplantation (termed d0), they were treated three times per week using solvent (DMSO for TMZ; EtOH for calcitriol), TMZ, calcitriol or a combination of both.…”

Section: Resultsmentioning

confidence: 99%

Calcitriol Promotes Differentiation of Glioma Stem-Like Cells and Increases Their Susceptibility to Temozolomide

Gerstmeier

Possmayer

Bozkurt

et al. 2021

Cancers

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Glioblastoma (GBM) is the most common and most aggressive primary brain tumor, with a very high rate of recurrence and a median survival of 15 months after diagnosis. Abundant evidence suggests that a certain sub-population of cancer cells harbors a stem-like phenotype and is likely responsible for disease recurrence, treatment resistance and potentially even for the infiltrative growth of GBM. GBM incidence has been negatively correlated with the serum levels of 25-hydroxy-vitamin D3, while the low pH within tumors has been shown to promote the expression of the vitamin D3-degrading enzyme 24-hydroxylase, encoded by the CYP24A1 gene. Therefore, we hypothesized that calcitriol can specifically target stem-like glioblastoma cells and induce their differentiation. Here, we show, using in vitro limiting dilution assays, quantitative real-time PCR, quantitative proteomics and ex vivo adult organotypic brain slice transplantation cultures, that therapeutic doses of calcitriol, the hormonally active form of vitamin D3, reduce stemness to varying extents in a panel of investigated GSC lines, and that it effectively hinders tumor growth of responding GSCs ex vivo. We further show that calcitriol synergizes with Temozolomide ex vivo to completely eliminate some GSC tumors. These findings indicate that calcitriol carries potential as an adjuvant therapy for a subgroup of GBM patients and should be analyzed in more detail in follow-up studies.

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Section: Resultsmentioning

confidence: 99%

Calcitriol Promotes Differentiation of Glioma Stem-Like Cells and Increases Their Susceptibility to Temozolomide

Gerstmeier

Possmayer

Bozkurt

et al. 2021

Cancers

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show abstract

“…Adult, organotypic brain slices (OTC) from 8–12 week old C56BL/6JOlaHsd mice were prepared as recently described [77]. Briefly, the brains were embedded in 2% low-melting agarose (Carl Roth) and cut on a Vibratome VT1000 (Leica, Wetzlar, Germany) in 250 µm thick transverse sections and cultured on Millicell cell culture inserts (PICMORG50, Merck) in 6-well plates containing OTC-specific, FCS-free medium (DMEM/F12, 1× B27, 1× N2-supplement, 1% P/S; all from Gibco).…”

Section: Methodsmentioning

confidence: 99%

Arsenic Trioxide and (−)-Gossypol Synergistically Target Glioma Stem-Like Cells via Inhibition of Hedgehog and Notch Signaling

Linder

Wehle

Hehlgans

et al. 2019

Cancers

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Glioblastoma is one of the deadliest malignancies and is virtually incurable. Accumulating evidence indicates that a small population of cells with a stem-like phenotype is the major culprit of tumor recurrence. Enhanced DNA repair capacity and expression of stemness marker genes are the main characteristics of these cells. Elimination of this population might delay or prevent tumor recurrence following radiochemotherapy. The aim of this study was to analyze whether interference with the Hedgehog signaling (Hh) pathway or combined Hh/Notch blockade using small-molecule inhibitors can efficiently target these cancer stem cells and sensitize them to therapy. Using tumor sphere lines and primary patient-derived glioma cultures we demonstrate that the Hh pathway inhibitor GANT61 (GANT) and the arsenic trioxide (ATO)-mediated Hh/Notch inhibition are capable to synergistically induce cell death in combination with the natural anticancer agent (−)-Gossypol (Gos). Only ATO in combination with Gos also strongly decreased stemness marker expression and prevented sphere formation and recovery. These synergistic effects were associated with distinct proteomic changes indicating diminished DNA repair and markedly reduced stemness. Finally, using an organotypic brain slice transplantation model, we show that combined ATO/Gos treatment elicits strong growth inhibition or even complete elimination of tumors. Collectively, our data show for the first time that ATO and Gos, two drugs that can be used in the clinic, represent a promising targeted therapy approach for the synergistic elimination of glioma stem-like cells.

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“…This in turn would imply that calcitriol-treated cells are more sensitive towards conventional chemotherapy such as TMZ. To test this hypothesis, we first generated GFP-expressing NCH644 (NCH644 GFP + ) and NCH421k (NCH421k GFP + ) cells and applied them in an ex vivo tumor growth assay using organotypic tissue culture (OTC) as described recently [29,41]. For this purpose, the OTCs were prepared and one day after tumor transplantation (termed d0) they were treated 3 times per week using solvent (DMSO for TMZ; EtOH for calcitriol), TMZ, calcitriol or a combination of both.…”

Section: Calcitriol Reduces Tumor Growth Ex Vivo and Synergizes With Tmzmentioning

confidence: 99%

“…Adult organotypic slice culture (OTC) was carried out based on the method described previously [29,41]. Mouse brains were dissected and dura mater was removed.…”

Section: Adult Organotypic Slice Cultures and Ex Vivo Tumor Growth Assaymentioning

confidence: 99%

Calcitriol Promotes Differentiation of Glioma Stem-Like Cells and Increases their Susceptibility to Temozolomide

Gerstmeier¹,

Possmayer²,

Bozkurt³

et al. 2021

Preprint

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: Glioblastoma (GBM) is the most common and most aggressive primary brain tumor with a very high rate of recurrence and a median survival of 15 months after diagnosis. Abundant evi-dence suggests that a certain sub-population of cancer cells harbors a stem-like phenotype and is likely responsible for disease recurrence, treatment resistance and potentially even for the infil-trative growth of GBM. GBM incidence has been negatively correlated with the serum levels of 25-hydroxy-vitamin D3, while the low pH within tumors has been shown to promote the ex-pression of the vitamin D3-degrading enzyme 24-hydroxylase, encoded by the CYP24A1 gene. Therefore, we hypothesized that calcitriol can specifically target stem-like glioblastoma cells and induce their differentiation. Here, we show using in vitro limiting dilution assays, quantita-tive real-time PCR and ex vivo adult organotypic brain slice transplantation cultures that thera-peutic doses of calcitriol, the hormonally active form of vitamin D3, reduces stemness to varying extent in a panel of investigated GSC lines and effectively hinders tumor growth of responding GSCs ex vivo. We further show that calcitriol synergizes with Temozolomide ex vivo to com-pletely eliminate some GSC tumors. These findings indicate that calcitriol carries potential as an adjuvant therapy for a subgroup of GBM patients and should be analyzed in more detail in fol-low-up studies.

show abstract

Inhibition of PIM1 blocks the autophagic flux to sensitize glioblastoma cells to ABT-737-induced apoptosis

Cited by 17 publications

References 51 publications

Calcitriol Promotes Differentiation of Glioma Stem-Like Cells and Increases Their Susceptibility to Temozolomide

Calcitriol Promotes Differentiation of Glioma Stem-Like Cells and Increases Their Susceptibility to Temozolomide

Arsenic Trioxide and (−)-Gossypol Synergistically Target Glioma Stem-Like Cells via Inhibition of Hedgehog and Notch Signaling

Calcitriol Promotes Differentiation of Glioma Stem-Like Cells and Increases their Susceptibility to Temozolomide

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