Sorafenib and 2-Deoxyglucose Synergistically Inhibit Proliferation of Both Sorafenib-Sensitive and -Resistant HCC Cells by Inhibiting ATP Production

Abstract

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths globally1,2. Sorafenib is the only first-line systemic drug for advanced HCC, but it has very limited survival benefits because patients treated with sorafenib either suffer from side effects or show disease progression after initial response. Thus, there is an urgent need to develop novel strategies for first-line and second-line therapy. The association between sorafenib resistance and glycolysis prompted us to screen several drugs with known anti-glycolytic activity to identify those that will sensitize cells to sorafenib. We demonstrate that the combination of glycolytic inhibitor 2-deoxy-D-glucose (2DG) and sorafenib drastically inhibits viability of sorafenib sensitive and resistant cells. However, the combination of other anti-glycolytic drugs like lonidamine, gossypol, 3-bromopyruvate and imatinib with sorafenib does not show synergistic effect. Cell cycle analysis revealed that the combination of 2DG and sorafenib induced cell cycle arrest at G0/G1. Mechanistic investigation suggests that the cell-cycle arrest is due to depletion of cellular ATP that activates AMP-activated protein kinase (AMPK), which, in turn, inhibits mammalian target of rapamycin (mTOR) to induce cell cycle arrest. This study provides strong evidence for the therapeutic potential of the combination of sorafenib and 2-deoxyglucose for HCC.

Simvastatin re-sensitizes hepatocellular carcinoma cells to sorafenib by inhibiting HIF-1α/PPAR-γ/PKM2-mediated glycolysis

“…Fiume et al found that Sora treatment could damage OXPHOS and promote aerobic glycolysis in cells grown in a glucose rich environment [45]. Reyes et al found that Sora and 2-Deoxyglucose (2-DG) co-treatment could synergistically inhibit the proliferation of Sora resistant HCC cells by inhibiting ATP production [34]. It was also shown by Wong et al that 2-DG can reverse Sora resistance in HCC [44].…”

“…The mechanisms of Sora resistance remain obscure, but new insights include a higher EGFR, c-Jun and Akt activation in HCC cells, as well as increased EMT, cancer stem cells, hypoxic environment, autophagy, and exosomes [2,5,34,41,42]. Recently, several studies reported that aerobic glycolysis may also contribute to Sora resistance.…”

“…Since the IC50 of LM3 was the lowest among the five liver cancer cell lines, which meant that LM3 was the most sensitive to Sora. Therefore, LM3 cells were chosen as Sora-sensitive cells, and we then established the Sora-resistant LM3 cells line (LM3-SR) as control to explore the underlying mechanism in Sora resistance [9,33,34]. The IC50 of LM3-SR was 16.33 μM ( Fig.…”

The microenvironmental and metabolic aspects of sorafenib resistance in hepatocellular carcinoma

“…Metabolic processes are demonstrated to exhibit consistent prognostic patterns, and they are associated with the sensitivity of drugs in clinical use. 2-deoxy-D-glucose, a common glycolytic inhibitor, could drastically inhibit the growth of sorafenib-resistant cells [41]. Glucose uptake and lactate export have also been enhanced in response to sorafenib [42].…”

Chemotherapy for hepatocellular carcinoma: The present and the future

“…On the other hand, elaboration of sorafenib was targeted to add molecules which could acts as biological enhancers in a synergistic way. Two examples of molecules used with this intent are C2-ceramide[ 97 ], a potent inducer of apoptosis in human neoplastic cells, and 2-Deoxyglucose[ 98 ], an inhibitor of glycolysis that leads to depletion of ATP.…”