Bisacodyl and its cytotoxic activity on human glioblastoma stem-like cells. Implication of inositol 1,4,5-triphosphate receptor dependent calcium signaling

Abstract

Glioblastoma is the most common malignant brain tumor. The heterogeneity at the cellular level, metabolic specificities and plasticity of the cancer cells are a challenge for glioblastoma treatment. Identification of cancer cells endowed with stem properties and able to propagate the tumor in animal xenografts has opened a new paradigm in cancer therapy. Thus, to increase efficacy and avoid tumor recurrence, therapies need to target not only the differentiated cells of the tumor mass, but also the cancer stem-like cells. These therapies need to be effective on cells present in the hypoxic, slightly acidic microenvironment found within tumors. Such a microenvironment is known to favor more aggressive undifferentiated phenotypes and a slow-growing "quiescent state" that preserves the cells from chemotherapeutic agents, which mostly target proliferating cells. Based on these considerations, we performed a differential screening of the Prestwick Chemical Library of approved drugs on both proliferating and quiescent glioblastoma stem-like cells and identified bisacodyl as a cytotoxic agent with selectivity for quiescent glioblastoma stem-like cells. In the present study we further characterize bisacodyl activity and show its efficacy in vitro on clonal macro-tumorospheres, as well as in vivo in glioblastoma mouse models. Our work further suggests that bisacodyl acts through inhibition of Ca release from the InsP3 receptors.

Research progress on therapeutic targeting of quiescent cancer cells

“…In particular, microenvironment acidification of cultured GSCs induces cell cycle arrest and sensitization to DDPM [66,67]. Further reports have shown that bisacodyl/ DDPM triggers necrosis in quiescent GSCs by inhibiting InsP3-induced Ca 2þ release [66]. Moreover, DDPM endows cytotoxic effects by suppressing the activity of a kinase cascade composed of WNK1 and its upstream regulators, AKT and SGK1, triggering a subsequent increase in NBC family Na þ /HCO3cotransporter activity [67].…”

“…The laxative bisacodyl/DDPM is the first small molecule identified displaying cytotoxicity to slow-growing cancer cells [3]. Accumulating evidence indicates that DDPM, the active metabolite of bisacodyl, induces necrosis of quiescent human glioblastoma stem-like cells (GSCs) in vivo and in vitro without exerting deleterious effects on non-cancer neural cells [5,66]. In particular, microenvironment acidification of cultured GSCs induces cell cycle arrest and sensitization to DDPM [66,67].…”

“…Accumulating evidence indicates that DDPM, the active metabolite of bisacodyl, induces necrosis of quiescent human glioblastoma stem-like cells (GSCs) in vivo and in vitro without exerting deleterious effects on non-cancer neural cells [5,66]. In particular, microenvironment acidification of cultured GSCs induces cell cycle arrest and sensitization to DDPM [66,67]. Further reports have shown that bisacodyl/ DDPM triggers necrosis in quiescent GSCs by inhibiting InsP3-induced Ca 2þ release [66].…”

WNK1 kinase and its partners Akt, SGK1 and NBC-family Na+/HCO3− cotransporters are potential therapeutic targets for glioblastoma stem-like cells linked to Bisacodyl signaling

“…Using in vitro experimental models of TMZ-resistant proliferating and quiescent GSC derived from GBM patients, we recently identified DDPM (4,4’-dihydroxydiphenyl-2-pyridyl-methane), as a cytotoxic compound inducing necrosis of GSC in a quiescent state whereas sparing proliferating GSC [ 19 , 20 ]. DDPM is a hydrolysis derivative of the commonly used laxative drug Bisacodyl (4,4’-diacetoxydiphenyl-2-pyridyl-methane), and is responsible for all pharmacological actions of this compound.…”

“…These 3D clonal macro-spheres, also called “organoids” [ 21 ], recapitulate many histological aspects of GBM tumors in vivo , including development of necrotic areas. Finally, an in vivo antitumoral activity of Bisacodyl was demonstrated in orthotopic xenograft mouse models of GBM [ 19 ].…”