RETRACTED: Targeting the Warburg effect with a novel glucose transporter inhibitor to overcome gemcitabine resistance in pancreatic cancer cells

Abstract

Gemcitabine resistance remains a significant clinical challenge. Here, we used a novel glucose transporter (Glut) inhibitor, CG-5, as a proof-of-concept compound to investigate the therapeutic utility of targeting the Warburg effect to overcome gemcitabine resistance in pancreatic cancer. The effects of gemcitabine and/or CG-5 on viability, survival, glucose uptake and DNA damage were evaluated in gemcitabine-sensitive and gemcitabine-resistant pancreatic cancer cell lines. Mechanistic studies were conducted to determine the molecular basis of gemcitabine resistance and the mechanism of CG-5-induced sensitization to gemcitabine. The effects of CG-5 on gemcitabine sensitivity were investigated in a xenograft tumor model of gemcitabine-resistant pancreatic cancer. In contrast to gemcitabine-sensitive pancreatic cancer cells, the resistant Panc-1 and Panc-1(GemR) cells responded to gemcitabine by increasing the expression of ribonucleotide reductase M2 catalytic subunit (RRM2) through E2F1-mediated transcriptional activation. Acting as a pan-Glut inhibitor, CG-5 abrogated this gemcitabine-induced upregulation of RRM2 through decreased E2F1 expression, thereby enhancing gemcitabine-induced DNA damage and inhibition of cell survival. This CG-5-induced inhibition of E2F1 expression was mediated by the induction of a previously unreported E2F1-targeted microRNA, miR-520f. The addition of oral CG-5 to gemcitabine therapy caused greater suppression of Panc-1(GemR) xenograft tumor growth in vivo than either drug alone. Glut inhibition may be an effective strategy to enhance gemcitabine activity for the treatment of pancreatic cancer.

BRCA1-regulated RRM2 expression protects glioblastoma cells from endogenous replication stress and promotes tumorigenicity

“…4b,c). Consistent with previously published reports293034, ChIP analysis confirmed the binding of E2F1 to RRM2 promoter (Fig. 4d) and its knockdown significantly reduced BRCA1 recruitment to promoter regions amplified by both primer sets (P1 and P2), thereby indicating that BRCA1 binding and transcriptional activation of RRM2 occurs in E2F1-dependent manner (Fig.…”

“…3a and Table 1). To test the involvement of BRCA1 in the recovery of stalled replication forks, we monitored the stability of nascent replication tracts29 post exposure to exogenous RS (2 mM hydroxyurea (HU) for 4 h). Specifically, nascent replication tracts were CldU-labelled after replication stalling with HU.…”

Increased Expression of the Glucose Transporter Type 1 Gene Is Associated With Worse Overall Survival in Resected Pancreatic Adenocarcinoma

“…Apigenin, a flavonoid drug, exhibits antiproliferative properties in pancreatic cancer by decreasing glucose uptake and downregulating GLUT-1 in human pancreatic cancer cells [42]. Given that gemcitabine is the mainstay of treatment in pancreatic cancer and its resistance remains a serious clinical challenge to treatment, a recent study showed that targeting the Warburg effect with a novel GLUT inhibitor, CG-5, in combination with gemcitabine caused greater suppression of Panc-1 xenograft tumor growth in vivo than either drug alone [43]. This occurs via CG-5 restoring the sensitivity of drug-resistant Panc-1 cells to gemcitabine by abrogating the effect of gemcitabine by targeting the upregulation of gemcitabine-induced expression of ribonucleotide reductase M2 catalytic subunits to overcome drug resistance.…”

Anticancer agents interacting with membrane glucose transporters

“…The synergism with gemcitabine was demonstrated also in vivo : the co-administration of the two drugs reduced tumour growth to a greater extent than the treatment with the two compounds alone, without any evident signs of toxicity in treated mice. 67 …”