A curcumin derivative hydrazinobenzoylcurcumin suppresses stem‐like features of glioblastoma cells by targeting Ca²⁺/calmodulin‐dependent protein kinase II

Abstract

Glioblastoma multiforme (GBM) is the most aggressive and common type of human primary brain tumor. Glioblastoma stem‐like cells (GSCs) have been proposed to contribute to tumor initiation, progression, recurrence, and therapeutic resistance of GBM. Therefore, targeting GSCs could be a promising strategy to treat this refractory cancer. Calmodulin (CaM), a major regulator of Ca2+‐dependent signaling, controls various cellular functions via interaction with multiple target proteins. Here, we investigated the anticancer effect of hydrazinobenzoylcurcumin (HBC), a Ca 2+/CaM antagonist, against GSCs derived from U87MG and U373MG cells. HBC significantly inhibited not only the self‐renewal capacity, such as cell growth and neurosphere formation but also the metastasis‐promoting ability, such as migration and invasion of GSCs. HBC induced apoptosis of GSCs in a caspase‐dependent manner. Notably, HBC repressed the phosphorylation of Ca 2+/CaM‐dependent protein kinase II (CaMKII), c‐Met, and its downstream signal transduction mediators, thereby reducing the expression levels of GSC markers, such as CD133, Nanog, Sox2, and Oct4. In addition, the knockdown of CaMKIIγ remarkably decreased the cancer stem cell‐like phenotypes as well as the expression of stemness markers by blocking c‐Met signaling pathway in U87MG GSCs. These results suggest that HBC suppresses the stem‐like features of GBM cells via downregulation of CaM/CaMKII/c‐Met axis and therefore CaMKII may be a novel therapeutic target to eliminate GSCs.

Curcumin Loaded in Niosomal Nanoparticles Improved the Anti-tumor Effects of Free Curcumin on Glioblastoma Stem-like Cells: an In Vitro Study

“…GSCs are suggested to be responsible for tumor occurrence and progression as well as chemo-and radiation-therapy resistance [2]. In line with our data, several studies have shown that different curcuminoids, such as free curcumin [55], hydrazinobenzoylcurcumin [56], and demethoxycurcumin [20], exert cytotoxic effects on GSCs. In addition, application of liposomal or phytosomal curcumin inhibits the growth of GSCs [57,58] [61].…”

The Multi-Faceted Effect of Curcumin in Glioblastoma from Rescuing Cell Clearance to Autophagy-Independent Effects

“…In line with this, curcumin derivatives exert beneficial effects on GBM due to their potential to suppress the tumorigenic features of GSCs [ 63 , 65 , 93 , 94 ]. Increasing evidence demonstrates that these synthetic compounds decrease cancer stem cell-like phenotype as well as invasive potential by targeting upstream regulators of the mTOR signaling in GSCs.…”

“…It is noteworthy that curcumin recently emerges as a promising adjunct therapy against GBM owing to its potential to target GSCs [ 50 , 51 , 52 , 61 , 62 , 63 , 64 , 65 , 66 ]. This represents a sub-population of cancer cells endowed with stem-like features, such as increased self-renewal, pluripotency, and clonogenic potential [ 22 , 39 ].…”

“…Increasing evidence demonstrates that these synthetic compounds decrease cancer stem cell-like phenotype as well as invasive potential by targeting upstream regulators of the mTOR signaling in GSCs. For instance, hydrazinobenzoylcurcumin (HBC) suppresses self-renewal ability, cell migration, and invasion by down-regulating the Ca 2+ /CaM-dependent protein kinase II (CaMKII)/c-Met axis, which, in turn, modulates the expression of stemness markers through the activation of Akt/mTOR signaling [ 65 ].…”

The Role of Calmodulin in Tumor Cell Migration, Invasiveness, and Metastasis

“…CaMK-IIγ has been implicated in the signaling pathways responsible for the stemness of glioblastoma cells involving the activation of a series of transcription factors including Nanog, Sox2 and Oct4. The CaM inhibitor hydrazinobenzoylcurcumin has anti-tumor effects by inhibiting, among other processes, the migratory and the invasive capacity of glioblastoma stem cells as a result of targeting the CaMK-II/c-Ret pathway [239]. c-Ret is a tyrosine kinase receptor activated by glial-derived neurotrophic factor (reviewed in [240]).…”