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Glycolytic enzyme inhibitors effectively kill cancer cells – Part 1

September 9, 2012, Featured in Cancer and Natural Medicines, 0 Comments

The Warburg effect describes a pro-oncogenic metabolism switch such that cancer cells take up more glucose than normal tissue and favor incomplete oxidation of glucose even in the presence of oxygen. Most cancer cells exhibit increased glycolysis (the Warburg effect) and use this metabolic pathway for generation of ATP as a main source of their energy supply. A number of studies suggest several possible mechanisms by which this metabolic alteration may evolve during cancer development. These mechanisms include mitochondrial defects and malfunction, adaptation to hypoxic tumor microenvironment, oncogenic signaling, and abnormal expression of metabolic enzymes.

The glycolytic switch occupies a privileged position in the aggressive agenda of most solid tumors. As such, switching to a glycolytic metabolism may precede the evolution of tumors toward the more aggressive angiogenic and metastatic phenotypes. Glycolysis also exerts a pervasive influence throughout tumor growth, making of cancer a metabolic disease and suggesting necessary crosstalks between metabolism, angiogenesis, and metastasis.

The development of cancer-specific therapeutics has been limited because most healthy cells and cancer cells depend on common pathways. Importantly, inhibition of glycolysis can effectively kill cancer cells. The glycolytic inhibitors are particularly effective against cancer cells with mitochondrial defects or under hypoxic conditions, which are frequently associated with cellular resistance to conventional anticancer drugs and radiation therapy. Persistence of high-rate glycolysis is under the master command of the transcription factor HIF-1 which, in collaboration with other oncogenic signaling pathways including c-Myc, AMPK, and mTOR, promotes the expression of most glycolytic enzymes and transporters.

Cancer metabolism: current perspectives and future directions.

Dysregulation of glucose transport, glycolysis, TCA cycle and glutaminolysis by oncogenes and tumor suppressors in cancer cells.

Anticancer targets in the glycolytic metabolism of tumors: a comprehensive review.

Effects of hypoxia and HIFs on cancer metabolism.

Pyruvate kinase (PK) is a key enzyme that regulates aerobic glycolysis in tumor cells. The M2 isoenzyme of pyruvate kinase (PKM2) is specifically expressed at high levels in tumor cells, including breast cancer and colon cancer. PKM1 and PKM2 originate from the same gene submitted to alternative splicing. Whereas PKM1 is constitutively active with a rapid substrate turnover, PKM2 can switch from high to low-activity states depending on the cellular needs.

Low activity of PKM2 is useful for cancer cells because it promotes the use of glycolytic intermediates for biosynthetic pathways. mTOR upregulates PKM2, and this effect was described as mediated though Hypoxia-Inducible Factor (HIF)-1α, a transcription factor that reprograms cancer cell metabolism, as we will discuss later. Conversely, PKM2 was shown to promote transcriptional activity of HIF-1 through direct binding. PKM2 is a master switch orienting glycolysis to ATP synthesis or to the production of biosynthetic blocks, making it an attractive target for anticancer treatments.

The reverse Warburg effect: glycolysis inhibitors prevent the tumor promoting effects of caveolin-1 deficient cancer associated fibroblasts.

Pyruvate kinase type M2: a key regulator of the metabolic budget system in tumor cells.

Pyruvate kinase M2 promotes de novo serine synthesis to sustain mTORC1 activity and cell proliferation.

Pyruvate kinase M2-specific siRNA induces apoptosis and tumor regression.

Pyruvate kinase type M2 is upregulated in colorectal cancer and promotes proliferation and migration of colon cancer cells.

Silencing of pkm2 increases the efficacy of docetaxel in human lung cancer xenografts in mice.

HIF-1alpha modulates energy metabolism in cancer cells by inducing over-expression of specific glycolytic isoforms.

Glycolytic enzyme inhibitors in cancer treatment.

Shikonin is a natural anthraquinone derivative isolated from the dried roots of zicao (Lithospermum erythrorhizon ), a Chinese herbal medicine with various biological activities, including inhibition of human immunodeficiency virus (HIV) type 1 (HIV-1). Shikonin exerts anti-tumor effects mainly by inhibiting cell growth and inducing apoptosis. Recently, shikonin and its enantiomeric isomer alkannin have been shown to inhibit PKM2 at concentrations that resulted in over 50% inhibition of PKM2 without affecting the activities of PKM1 and pyruvate kinase-L. Shikonin and alkannin significantly inhibited the glycolytic rate, as manifested by cellular lactate production and glucose consumption in drug-sensitive and resistant cancer cell lines that primarily express PKM2.

Shikonin, a component of chinese herbal medicine, inhibits chemokine receptor function and suppresses human immunodeficiency virus type 1.

Shikonin and its analogs inhibit cancer cell glycolysis by targeting tumor pyruvate kinase-M2.

mTOR upregulates PKM2. Resveratrol, a compound found largely in the skins of red grapes, down-regulates PKM2 expression by inhibiting mTOR signaling and suppresses cancer metabolism. 

The chemopreventive agent butyrate in human colon cells also reduces PKM2 expression. The mechanism by which butyrate is acting on PKM2 expression is currently unknown.

Mammalian target of rapamycin up-regulation of pyruvate kinase isoenzyme type M2 is critical for aerobic glycolysis and tumor growth.

Resveratrol inhibits cancer cell metabolism by down regulating pyruvate kinase M2 via inhibition of mammalian target of rapamycin.

Impact of butyrate on PKM2 and HSP90β expression in human colon tissues of different transformation stages: a comparison of gene and protein data.

Shikonin also induces apoptosis via several different mechanisms. These mechanisms contribute to the anti-cancer activities of shikonin. Consequently, shikonin may directly or indirectly inhibit or modulate disease-related cellular targets in cancer. Herbalzym Vinegar contains the purest, most highly bioavailable Shikonin. Herbalzym Vinegar modulates energy metabolism in cancer cells.

Shikonin induces apoptosis through reactive oxygen species/extracellular signal-regulated kinase pathway in osteosarcoma cells.

Induction of apoptosis by shikonin through a ROS/JNK-mediated process in Bcr/Abl-positive chronic myelogenous leukemia (CML) cells.

Shikonin induces immunogenic cell death in tumor cells and enhances dendritic cell-based cancer vaccine.

Shikonin enhances efficacy of a gene-based cancer vaccine via induction of RANTES.

Novel multiple apoptotic mechanism of shikonin in human glioma cells.

Glutathione-S-transferase enhances proliferation-migration and protects against shikonin-induced cell death in breast cancer cells.

Shikonin exerts antitumor activity via proteasome inhibition and cell death induction in vitro and in vivo.

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