2 research outputs found
Rhizochalinin Exhibits Anticancer Activity and Synergizes with EGFR Inhibitors in Glioblastoma In Vitro Models
Rhizochalinin (Rhiz) is a recently
discovered cytotoxic
sphingolipid
synthesized from the marine natural compound rhizochalin. Previously,
Rhiz demonstrated high in vitro and in vivo efficacy in various cancer
models. Here, we report Rhiz to be highly active in human glioblastoma
cell lines as well as in patient-derived glioma-stem like neurosphere
models. Rhiz counteracted glioblastoma cell proliferation by inducing
apoptosis, G2/M-phase cell cycle arrest, and inhibition of autophagy.
Proteomic profiling followed by bioinformatic analysis suggested suppression
of the Akt pathway as one of the major biological effects of Rhiz.
Suppression of Akt as well as IGF-1R and MEK1/2 kinase was confirmed
in Rhiz-treated GBM cells. In addition, Rhiz pretreatment resulted
in a more pronounced inhibitory effect of γ-irradiation on the
growth of patient-derived glioma-spheres, an effect to which the Akt
inhibition may also contribute decisively. In contrast, EGFR upregulation,
observed in all GBM neurospheres under Rhiz treatment, was postulated
to be a possible sign of incipient resistance. In line with this,
combinational therapy with EGFR-targeted tyrosine kinase inhibitors
synergistically increased the efficacy of Rhiz resulting in dramatic
inhibition of GBM cell viability as well as a significant reduction
of neurosphere size in the case of combination with lapatinib. Preliminary
in vitro data generated using a parallel artificial membrane permeability
(PAMPA) assay suggested that Rhiz cannot cross the blood brain barrier
and therefore alternative drug delivery methods should be used in
the further in vivo studies. In conclusion, Rhiz is a promising new
candidate for the treatment of human glioblastoma, which should be
further developed in combination with EGFR inhibitors
Rhizochalinin Exhibits Anticancer Activity and Synergizes with EGFR Inhibitors in Glioblastoma In Vitro Models
Rhizochalinin (Rhiz) is a recently
discovered cytotoxic
sphingolipid
synthesized from the marine natural compound rhizochalin. Previously,
Rhiz demonstrated high in vitro and in vivo efficacy in various cancer
models. Here, we report Rhiz to be highly active in human glioblastoma
cell lines as well as in patient-derived glioma-stem like neurosphere
models. Rhiz counteracted glioblastoma cell proliferation by inducing
apoptosis, G2/M-phase cell cycle arrest, and inhibition of autophagy.
Proteomic profiling followed by bioinformatic analysis suggested suppression
of the Akt pathway as one of the major biological effects of Rhiz.
Suppression of Akt as well as IGF-1R and MEK1/2 kinase was confirmed
in Rhiz-treated GBM cells. In addition, Rhiz pretreatment resulted
in a more pronounced inhibitory effect of γ-irradiation on the
growth of patient-derived glioma-spheres, an effect to which the Akt
inhibition may also contribute decisively. In contrast, EGFR upregulation,
observed in all GBM neurospheres under Rhiz treatment, was postulated
to be a possible sign of incipient resistance. In line with this,
combinational therapy with EGFR-targeted tyrosine kinase inhibitors
synergistically increased the efficacy of Rhiz resulting in dramatic
inhibition of GBM cell viability as well as a significant reduction
of neurosphere size in the case of combination with lapatinib. Preliminary
in vitro data generated using a parallel artificial membrane permeability
(PAMPA) assay suggested that Rhiz cannot cross the blood brain barrier
and therefore alternative drug delivery methods should be used in
the further in vivo studies. In conclusion, Rhiz is a promising new
candidate for the treatment of human glioblastoma, which should be
further developed in combination with EGFR inhibitors