Chloroquine or Chloroquine-PI3K/Akt Pathway Inhibitor Combinations Strongly Promote γ-Irradiation-Induced Cell Death in Primary Stem-Like Glioma Cells

Abstract

We asked whether inhibitors of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway, which is highly active in cancer stem cells (CSCs) and upregulated in response to genotoxic treatments, promote γ-irradiationγIR)-induced cell death in highly radioresistant, patient-derived stem-like glioma cells (SLGCs). Surprisingly, in most cases the inhibitors did not promote γIR-induced cell death. In contrast, the strongly cytostatic Ly294002 and PI-103 even tended to reduce it. Since autophagy was induced we examined whether addition of the clinically applicable autophagy inhibitor chloroquine (CQ) would trigger cell death in SLGCs. Triple therapy with CQ at doses as low as 5 to 10 µM indeed caused strong apoptosis. At slightly higher doses, CQ alone strongly promoted γIR-induced apoptosis in all SLGC lines examined. The strong apoptosis in combinations with CQ was invariably associated with strong accumulation of the autophagosomal marker LC3-II, indicating inhibition of late autophagy. Thus, autophagy-promoting effects of PI3K/Akt pathway inhibitors apparently hinder cell death induction in γ-irradiated SLGCs. However, as we show here for the first time, the late autophagy inhibitor CQ strongly promotes γIR-induced cell death in highly radioresistant CSCs, and triple combinations of CQ, γIR and a PI3K/Akt pathway inhibitor permit reduction of the CQ dose required to trigger cell death.

Autophagy Inhibitors as a Potential Antiamoebic Treatment for Acanthamoeba Keratitis

“…Previous reports have suggested that autophagy-related protein plays an important role during the encystation of Acanthamoeba cells (19,23). In this study, we found that autophagy inhibitors 3MA and chloroquine significantly reduced the encystation ratio of Acanthamoeba cells.…”

“…Chloroquine is widely used as an antimalarial drug that interferes with hemozoin formation (27). Currently, the most widely used autophagy inhibitor is chloroquine (23,28). Chloroquine is a well-known antimalarial drug in clinical use (29).…”

Chloroquine inhibits the malignant phenotype of glioblastoma partially by suppressing TGF-beta

“…Indeed, we previously showed that radiotherapy triggers an inflammation response as well as TGF-β expression [38]. Therefore, exploiting the radiosensitizing property of CQ could improve responses obtained by radiation treatments, as was observed in other studies [46,47]. Moreover, acknowledging that GBM typically depict resistance to standard chemotherapeutics, one could argue that adding CQ might hinder this other malignant glioma characteristic.…”

Chloroquine Targets Pancreatic Cancer Stem Cells via Inhibition of CXCR4 and Hedgehog Signaling

“…Following a first observational study that reported an inhibitory effect of chloroquine on the pancreatic cancer cell line PaTu II (12), the effects of chloroquine on tumor growth were later confirmed in mouse models of PDAC and attributed to the inhibition of autophagy (13), which is responsible for recycling bioenergetic components to ensure cell survival in nutrient-deprived times or locations (13). For breast cancer and glioblastoma, chloroquine has been suggested to also have an impact on the cancer stem-like phenotype via inhibition of autophagy (14,15). However, it has recently been suggested that chloroquine may also function as an inhibitor of CXCR4 signaling (16).…”