2-Deoxy-d-Glucose Sensitizes Human Ovarian Cancer Cells to Cisplatin by Increasing ER Stress and Decreasing ATP Stores in Acidic Vesicles

Abstract

Cisplatin is a commonly used chemotherapeutic agent; however, the development of acquired resistance limits its application. Here, we demonstrate that 2-deoxy-d-glucose (2-DG) enhanced the antitumor effects of cisplatin in SKOV3 cells, which include inhibition of proliferation and promotion of apoptosis. Additionally, either cisplatin or 2-DG alone could upregulate the endoplasmic reticulum (ER) stress-associated protein glucose-regulated protein-78 (GRP78). Moreover, exposure to 2-DG increased the expression of GRP78 induced by cisplatin. Cisplatin also upregulated ER stress-associated apoptotic protein 153/C/EBP homology protein (CHOP) in SKOV3 cells. While treatment with 2-DG alone could not upregulate the CHOP expression, a combination of both 2-DG and cisplatin increased the protein levels of CHOP above those induced by Cisplatin alone. Finally, cisplatin mediated an increase in ATP stores within acidic vesicles, whereas 2-DG decreased this effect. These data demonstrate that 2-DG sensitizes SKOV3 cells to cisplatin by increasing ER stress and decreasing ATP stores in acidic vesicles.

SIRT3 participates in glucose metabolism interruption and apoptosis induced by BH3 mimetic S1 in ovarian cancer cells

“…Tumor glycolysis is regarded as a target for cancer therapy (38), and experimental data show that the inhibition of glycolysis enhances cisplatin-induced apoptosis in ovarian cancer cells (39). Because our findings showed that earlier exposure to S1 mainly reduces mitochondrial respiration and that the upregulation of glycolysis seemed to be a compensatory effect, we speculated that the glycolysis inhibitor 2-DG would further aggravate the apoptosis induced by S1.…”

Cell Metabolism and DNA Repair Pathways: Implications for Cancer Therapy

“…The intracellular accumulation of this metabolite inhibits hexokinase activity and therefore ATP production via glycolysis. Significantly, the anti-proliferative effects of 2-DG have been demonstrated in numerous preclinical studies (Giammarioli et al, 2012;Zhang et al, 2015). 2-DG has also been shown to be an effective sensitizer in several tumor types, including gliomas and lung carcinomas (Dwarkanath et al, 2001;Singh et al, 2019).…”

“…Additionally, combining 2-DG with chemotherapy has already shown promising results in its ability to restore the sensitivity of chemo-resistance cells. A recent study analyzed the effect of combination treatment with 2-DG and carboplatin chemotherapy in high stage and recurrent ovarian clear cell carcinoma (OCC), and found that 2-DG in combination with carboplatin and cisplatin chemotherapy increased efficacy in chemo-resistant ovarian tumor cell lines and patient-derived xenograft models (Zhang et al, 2015;Khan et al, 2020). Thus, the combination of 2-DG with both radio-and chemotherapy drugs improves tumor cell sensitivity; however, the underlying mechanism for the restoration of sensitivity to therapy remains largely unknown.…”

Golgi apparatus dis- and reorganizations studied with the aid of 2-deoxy-d-glucose and visualized by 3D-electron tomography

“…The present work aims to improve the insight into Golgi apparatus dynamics and unravel processes of Golgi apparatus disorganizations and reorganizations. For this, we used 2-deoxy- d -glucose (2DG), a nonmetabolizable glucose analogue, which causes a reversible decrease of the cellular levels of adenosine triphosphate (ATP) and which is used in both experimental cell biology and medicine (e.g., Aft et al 2002; Dwarakanath 2009; Kavaliauskiene et al 2015; Zhang et al 2015). Since the Golgi apparatus changes its architecture under the influence of 2DG, this drug was found to be of great value in the context of Golgi apparatus research (del Valle et al 1999; Meisslitzer-Ruppitsch et al 2011; Ranftler et al 2015).…”

“…Moreover, 2DG has been found to enhance autophagy, or have discriminating effects on autophagy regulation (Wu et al 2009; Wang et al 2011; Xi et al 2011; Jeon et al 2015), another fact that is of particular interest in anti-tumor-application. The combined use of 2DG and cytostatic drugs and other substances offers promising new possibilities in tumor therapies (Estañ et al 2012; Huang et al 2013; Mustafa et al 2015; Oladghaffari et al 2015; Li et al 2015; Jangamreddy et al 2015; Zhang et al 2015). 2DG might also help in the treatment of systemic lupus erythematodes by normalizing the T cell metabolism (Yin et al 2015) and has been recognized as a caloric restriction mimetic (Ingram and Roth 2015).…”