Targeting glucose metabolism to suppress cancer progression: prospective of anti-glycolytic cancer therapy.

Most solid tumor cells adapt to their heterogeneous microenvironment by depending largely on aerobic glycolysis for energy production, a phenomenon called the Warburg effect, which is a hallmark of cancer. The altered energy metabolism not only provides cancer cell with ATP for cellular energy, but also generate essential metabolic intermediates that play a pivotal role in the biosynthesis of macromolecules, to support cell proliferation, invasiveness, and chemoresistance. The cellular metabolic reprogramming in cancer is regulated by several oncogenic proteins and tumor suppressors such as hypoxia-inducible factor (HIF-1), Myc, p53, and PI3K/Akt/mTOR pathway. A better understanding of the mechanisms involved in the regulation of aerobic glycolysis can help in developing glycolytic inhibitors as anticancer agents. These metabolic antiglycolytic agents could be more effective if used in drug combinations to combat cancer. Several preclinical and early clinical studies have shown the effectiveness of targeting the glycolytic pathway as a therapeutic approach to suppress cancer progression. This review aimed to present the most recent data on the emerging drug candidate targeting enzymes and intermediates involved in glucose metabolism to provide therapeutic opportunities and challenges for antiglycolytic cancer therapy.

Abdel-Wahab AF ，Mahmoud W ，Al-Harizy RM 《-》

Anticancer strategies based on the metabolic profile of tumor cells: therapeutic targeting of the Warburg effect.

Chen XS ，Li LY ，Guan YD ，Yang JM ，Cheng Y ... -  《-》

The Warburg effect: essential part of metabolic reprogramming and central contributor to cancer progression.

Vaupel P ，Schmidberger H ，Mayer A 《-》

p53 and glucose metabolism: an orchestra to be directed in cancer therapy.

Metabolic reprogramming is a hallmark of cancer with a strong impact on tumor cell survival, proliferation, dissemination, and resistance to therapy. As such, it has represented a promising therapeutic target for cancer. Although cancer cells may exhibit a wide range of metabolic profiles, the enhancement of aerobic glycolysis to generate lactate and ATP (Warburg effect) is a cancer-associated trait, which is under regulation of both oncogenes and tumor suppressor genes. Particularly, the tumor suppressor protein p53 was shown to revert the Warburg effect, and to negatively influence the oncogenic metabolic adaption of cancer cells. This review provides a systematization of the p53 influence on glycolysis and oxidative phosphorylation (OXPHOS), giving attention to the interplay of p53 with key signaling pathways, including c-Myc, HIF-1, LKB1/AMPK, and PI3K/Akt, as well as to mutant p53 gain-of-function. It also contributes to a better understanding of distinct metabolic profiles in heterogeneous tumor cell populations, and of its impact on cancer therapeutic resistance. Additionally, a reflection on current strategies adopted in clinical trials to overcome therapeutic resistance is presented, highlighting the main limitations and future therapeutic perspectives based on metabolic reprogramming. In particular, this review emphasizes the p53 activation as a promising therapeutic strategy to reprogram tumor glucose metabolism, conducting to cell death. Moreover, potential synergisms between p53-activating agents and metabolic inhibitors are discussed, fostering the improvement of cancer therapy.

Gomes AS ，Ramos H ，Soares J ，Saraiva L ... -  《-》

UP12, a novel ursolic acid derivative with potential for targeting multiple signaling pathways in hepatocellular carcinoma.

Targeting cancer cell glucose metabolism is a promising strategy for cancer therapy. In past approaches to cancer drug discovery, ursolic acid (UA) has been chemically modified to improve its antitumor activities and bioavailability. Here, a novel ursolic acid (UA) derivative UP12 was developed via computer-aided drug design to explore potent anti-cancer agents and to examine possible mechanisms. The structural docking analyses suggested that UP12 could bind to the active sites of glucokinase (GK), glucose transporter 1 (GLUT1) and ATPase, which are the main enzymes involved in cancer glucose metabolism. We further investigated the synergistic effect between UP12 and glycolysis inhibitor 2-deoxy-d-glucose (2-DG) in inhibiting glucose metabolism of cancer cells. The pharmacological results showed that the combination enhanced depletion of intracellular ATP and decrease in lactate production, and pushed more cancer cells arrested in the S and G2/M cycle phases. The combination selectively down-regulated the expression of Bcl-2 and HKII proteins, up-regulated the expression of Bax and p53, and collectively resulted in enhanced apoptosis related to caspase-3, -8, and -9 activities, in addition to inhibition on the cell mitochondrial membrane potential. The animal studies further demonstrated that the combination exhibited significant antitumor activity without obvious toxicity. In summary, UP12 can interfere cancer cell metabolism pathway and further enhance the therapeutic effects of 2-DG likely through synergistic suppression of cancer cell glucose metabolism, making UP12 a likely new candidate for anti-cancer drug development.

Dong H ，Yang X ，Xie J ，Xiang L ，Li Y ，Ou M ，Chi T ，Liu Z ，Yu S ，Gao Y ，Chen J ，Shao J ，Jia L ... -  《-》