E-Book

E-Book 3rd Congress

  • Modulating Glycolysis to Improve Cancer Therapy
  • Issa Layali,1,* Negar Jafari,2 Fatemeh Shahbazi,3
    1. Department of Biochemistery and Biophysics,Faculty of Advanced Sciences and Technology,Tehran Medical Sciences Branch, Islamic Azad University
    2. Faculty of Advanced Sciences and Technology,Tehran Medical Sciences Branch, Islamic Azad University
    3. Faculty of Advanced Sciences and Technology,Tehran Medical Sciences Branch, Islamic Azad University


  • Introduction: Altered metabolism in cancer cells provides a way to develop therapeutic targets for cancer cells and anti-cancer agents. cancer cells reprogram their metabolism to increase growth, metastasis and survival. Increasing glycolysis is not only important for meeting the energy needs of cells, but also for the production of metabolic mediators necessary for the synthesis of macromolecules in cancer cells. This phenomenon is often known as the Warburg effect. Glycolytic inhibition alone is not effective in a clinical setting. Targeted metabolism, especially in combination with chemotherapy, is expected to improve therapeutic responses and may help to overcome drug resistance. Increased glycolysis in cancer cells and latic acidosis caused by that stroma. modifies the tumor into a tumorigenic microenvironment. In this review, we examine glycolytic modification in cancer cells and how it can help as a therapeutic strategy in combination therapies with hormonal therapy.
  • Methods: Targeting Glycolysis to Enhance Hormonal Therapy: Hormone therapy has shown significant progress as a therapeutic strategy for hormone-dependent cancers, especially in breast, prostate and other gynecologic diseases. Cancers are aromatase inhibitors (Al), estrogen receptor antagonists (ER), ER-modulators, anti-estrogens and GnRH antagonists are effective therapeutic drugs and have shown high success rates in patients with recurrent or metastatic gynecologic malignancies sensitive to hormone. Hormone therapy interferes with the restricting of hormone production in the body by reliance on cancer cells, while hormone therapy improves survival and reduces recurrence in various types of cancer. New or acquired resistance to hormone therapy is a major clinical problem that requires the development of innovative strategies. Resistance to hormone therapy always occurs in most patients with ER+ metastatic BC and castration-resistant PC (CRPC). Metabolic reprogramming is an intrinsic feature of endocrine resistant cancer cells, suggesting that combined therapy with metabolic regulators and conventional hormone therapy may be helpful in overcoming resistance, but it is unclear whether metabolic rewiring is the cause or consequence of endocrine resistance, and several studies are investigating the interplay between hormonal signaling and cancer cell metabolism.
  • Results: Somatic mutations in estrogen receptors have been linked to the clinical development of resistance to hormone therapy. The Y537S mutation in ER-a increased mitochondrial and glycolysis metabolism in BC cells, suggesting that increased glucose metabolism is a highly protected mechanism of endocrine resistance. Pharmacological inhibition of glycolysis has been investigated with PFK-158, a PFKFB3 inhibitor, with tamoxifen or folusterant as a potential therapeutic intervention to overcome endocrine resistance. Involved PFKFB3, with high expression of the mRNA base of the PFKFB3 gene, is found in endocrine treatment-resistant BC cells and is associated with undesirable non-recurrence survival in BC patients. The anti-tumor effect of PFK-158 is exacerbated when combined with tamoxifen and folusterant therapy. PFKFB3 inhibited necroptosis markers that are activated by the synthetic lineage kinase pseudodomain kinase receptor (MLKL) and the pseudodomain kinase receptor (MLKL), implicating the possible mechanism of cell death caused by PFK-158. In a long-term estrogen deprivation (LTED) model of artificial intelligence resistance, cancer cells increased glycolysis dependence. Inhibition of glycolysis by HK2 inhibitors, along with Al and Letrozole, reduced cell viability. Targeting glucose metabolism with established glycolytic inhibitors has been shown to increase sensitivity to endocrine treatment in breast and PC models. The interaction between glucose metabolism and androgen receptor/ER signaling suggests that combined endocrine therapy approaches with metabolic modulators can be a standard care for overcoming resistance. Also, dietary interventions targeting metabolic rewiring and modulating glucose metabolism have also shown to improve the effectiveness of endocrine treatment in metastatic patients of BC liver.
  • Conclusion: The metabolic signatures of tumor cells are different from normal cells, which allows the tumor cells to adapt to the increased energy and metabolite demands.Though the inhibition of glycolysis might inhibit cancer cell proliferation, cancer cells may adapt by upregulating or glutaminolysis, which could result in the development of resistance to therapy, in addition to co-morbidities such as cachexia in patients. This rewiring of metabolic pathways poses challenges to precision therapies. In-depth analytical and extensive pre-clinical studies should identify targetable metabolic enzymes/enzyme isoforms that are efficacious in different tumor types with minimal toxicity to normal cells. Another major challenge in the clinical development of cancer therapeutics is the need to identify patient groups that would benefit from the therapy.
  • Keywords: Glycolysis, Combination theraphy, Hormonal Therapy