2‐Deoxy‐D‐glucose has distinct and cell line‐specific effects on the survival of different cancer cells upon antitumor drug treatment

Abstract

The dependence of tumors on glycolysis for ATP generation offers a rationale for therapeutic strategies aimed at selective inhibition of the glycolytic pathway. Analysis of tumor cell responses to anticancer drugs revealed that inhibition of glycolysis by 2‐deoxy‐D‐glucose (2‐DG) generally augmented the apoptotic response; however, in HCT116 human colon carcinoma cells, apoptosis was suppressed. A comparison of neuroblastoma SK‐N‐BE(2) and HCT116 cells revealed, that in contrast to HCT116, in SK‐N‐BE(2) cells 2‐DG alone was able to induce cell death. In SK‐N‐BE(2) cells the decrease in ATP levels upon treatment with 2‐DG was more prominent because in HCT116 cells mitochondria compensated for the loss of ATP caused by glycolysis suppression. In both cells lines 2‐DG triggered endoplasmic reticulum (ER) stress, assessed by the accumulation of the marker protein GRP78/BiP. Suppression of ER stress by mannose attenuated the 2‐DG‐induced apoptotic response in SK‐N‐BE(2) cells, implying that apoptosis in these cells is a consequence of ER stress induction. In HCT116 cells, ER stress stimulated autophagy, assessed by the accumulation of the lipidated form of LC3. The inhibitor of ER stress mannose attenuated autophagy and reversed 2‐DG‐mediated suppression of cisplatin‐induced apoptosis. When autophagy in HCT116 cells was suppressed by bafilomycin, cisplatin‐induced apoptosis was decreased. At the same time, stimulation of autophagy in SK‐N‐BE(2) cells suppressed cell death. Thus, successful treatment of tumors with conventionally used anticancer drugs should be combined with targeting metabolic pathways involved in the regulation of apoptosis, autophagy, and cellular bioenergetics.

Crizotinib changes the metabolic pattern and inhibits ATP production in A549 non‑small cell lung cancer cells

“…It has been reported that 2-DG decreases the migration of triple-negative breast cancer cells, supporting a link between metabolic dysfunction and decreased migration (32). A previous study demonstrated that 2-DG attenuates ATP production, and also inhibits mitochondrial bioenergetics (33). 2-DG combined with other antitumor drugs, such as metformin, propranolol or docetaxel, effectively prevents cell proliferation and induces apoptosis in prostate cancer cells and other solid tumors, for example NSCLC and adenoid-cystic carcinoma (34,35).…”

Autophagy modulating agents as chemosensitizers for cisplatin therapy in cancer

“…2-DG additively enhanced apoptosis in CPT-treated SK-N-BE(2) which was diminished by ER-stress inhibition or autophagy induction by rapamycin. In contrast, 2-DG rescued HCT116 from CPT-induced apoptosis which was even more visible after the addition of rapamycin and attenuated by ERstress inhibition [80].…”

“…This widely studied metabolic shift, often considered as one of cancer hallmarks, is called Warburg effect. Energetic imbalance with alerted ATP:ADP ratio leads to changes in autophagy and cell death which may potentialize antineoplastic efficacy of chemotherapeutics [80].…”

2‑Deoxy‑D‑glucose enhances the anti‑cancer effects of idarubicin on idarubicin‑resistant P388 leukemia cells

“…However, clinical studies on the application 2-DG in cancers have reported that 2-DG administration induces several side effects, such as fatigue and dizziness, among others (22,23). Additionally, the effective concentration of 2-DG on cancer cells has been found to vary across different cancer cells (11,19,24,25). The underlying mechanism of such differences is poorly understood and the administration of high concentrations of 2-DG increases the risk of side effects.…”