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- Title
CONSIDERING CANCER AS A METABOLIC DISEASE: BEYOND WARBURG EFFECT.
- Authors
Guzel, Mustafa
- Abstract
Cancer now surpasses heart disease as leading cause of death in many countries of the world. Clinical validations prove that protein kinases are an attractive class of therapeutic drug targets for cancer as demonstrated with the recent approval of six protein kinase inhibitors. The Warburg effect describes the particular reliance of cancer cells on glycolysis for energy. Increased glycolysis and acid resistance have been postulated to be an essential part of carcinogenesis, conferring a significant growth advantage as well as promoting typical tumor progression. Warburg hypothesized that the energy consumption of cancer cells is different than the normal cells. When compared to normal conditions, cancer cells do not undergo tricarboxylic acid (TCA) cycle therefore resulting in more lactate in the cells. Glycolysis pathway is a way of cancer cells to provide energy. Targeting accelerated glycolysis in cancer cells is a new promising modality for treatment of cancer. Inhibition of glycolysis can be done without significant side effects, and such treatment will be additive to most known cancer therapies. The first step in glycolysis is the phosphorylation of glucose to glucose-6-phosphate. This reaction is catalyzed by the hexokinase-II enzyme (HK-II) which is known to be overexpressed in tumor cells. The feeding of cancer cells can be prevented by inhibiting the hexokinase-II enzyme in the first step of aerobic glycolysis. In literature, Methyl Jasmonate (MJ) is known as a Hexokinase-II inhibitor since it disposes VDAC and HK-II interaction on mitochondrial membrane. In our study, we aimed to increase the activity by synthesizing the novel MJ analogues with appropriate modifications. Recent studies show that Methyl Jasmonate reveals promising results for treatment of cancer as a HK-2 inhibitor. Cis-jasmone, Jasmonic acid and Methyl jasmonate are cyclopentanones that are fatty acid derivatives. Jasmonates are plant stress hormones which exhibit abnormal anticancer activity [1]. Jasmonates induced suppression of cell proliferation and death in a variety of cancer cell lines and cytotoxicity to cervical cancer cells with almost no effect on normal primary human keratinocytes [2]. As a result of our research, although methyl jasmonate is long-known natural product, it has not well-studied as an anti cancer agent. Based on the three different cancer cell lines we investigated, our novel MJ analogues proved to be more potent than the original molecule. Thus this research may provide more efficacious/novel HK-II inhibitors and may shed light to develop new anti-cancer agents. In our research laboratory, we designed and synthesized handfull of novel methyl jasmonate analogs. We will highlight the biological activity of those novel analogs as anti-cancer agents. This project (215S890) is funded by TUBITAK. We kindly appreciate for their support.
- Publication
Turkish Journal of Biochemistry / Turk Biyokimya Dergisi, 2019, Vol 44, p5
- ISSN
0250-4685
- Publication type
Academic Journal