How 2-Deoxy-D-Glucose (2DG) Works?

Cancer is a daunting disease that continues to increase worldwide and by the year 2040, cancer could be diagnosed in more than 29.4 million people per year¹.

Most cancer-related deaths are attributed to cancer metastasis, which occurs when the cancer cells move from the original tumor site to other tissues and organs. Cancer metastasis is a multistep process which is in large part facilitated by alterations in cell metabolism.

Metabolic Reprogramming: A Prominent Hallmark of Cancer and Key Reason Why Existing Cancer Therapies Fail

Cancer cells often multiply at a faster rate than normal, non-cancerous cells, requiring a continuous enormous supply of energy. To meet their high energy demand, cancer cells, unlike normal cells, switch their usual energy metabolism from oxidative phosphorylation in the mitochondria (powerhouses of our cells) to aerobic glycolysis in the cytosol (fluid matrix inside the cell).

Glucose is the primary source of energy for majority of cells. Since aerobic glycolysis is less efficient for generating ATP, therefore, a high rate of glucose uptake is required to meet the increased tumor energy needs. To drive aerobic glycolysis, cancer cells acquire this altered state of augmented upregulation of glucose uptake and exceeds the normal rate more than 200-fold; a phenomenon known as the Warburg effect².

This altered metabolic reprogramming is a prominent hallmark of cancer because it facilitates rapid multiplication³. Furthermore, aerobic glycolysis results in the production of excess lactate (acid). When expelled from cancer cells, this lactate accumulates in the tumor microenvironment (TME), making the TME acidic. This in turn promotes immune evasion, resistance to cancer fighting treatments, propels tumor progression and stimulates metastasis of cancer cells.

The metastasis and proliferation of cancer cells can be managed by depriving them of essential nutrients, which can be achieved by regulating their altered sugar metabolism. To control glucose metabolism in cancer cells, we need to suppress the glycolytic pathway and decrease energy production in the cancer cells using drugs like 2-Deoxy-D-glucose or 2DG. Therefore, when used in combination with other treatments, 2DG is a safer therapeutic strategy to combat cancer compared to using chemotherapeutic or other agents used alone⁴.

Hypoxia and Cancer: Why is it important to Target Hypoxic Core of Tumor?

Within most solid tumors, inside the tumor core, there are populations of cells residing under low oxygen (hypoxia) environments due to poor vascularization (blood supply). The cancer cells in such hypoxic core divide slowly and are consequently intrinsically resistant to chemotherapy and radiation treatment induced damages⁵.

Furthermore, these quiescent and plastic cancer cells of the hypoxic core that manage to escape the onslaught of chemotherapy and radiation therapy, are primarily responsible for the resurgence of cancer after a brief remission. These cells which have acquired plasticity change their phenotype by undergoing epithelial-to-mesenchymal transition (EMT), acquire cancer cell mobility and drive further invasion and metastasis⁶. Such cells are also often termed cancer stem cells, and are known to be resistant to standard therapies. This is one reason why tumors regrow after therapy – larger and tougher than before. Cancer is often not curable via this single approach.

Conventional cancer therapy, including chemotherapy and radiation therapy are primarily effective against actively multiplying tumor cells (fast growing cancer cells that constitute most of the tumor).  Hence to eradicate cancer completely, the treatment paradigm should ideally include therapeutic modalities that can enter the hypoxic core and target the resting cancer stem cells in addition to eradicating the rapidly proliferating cancer.

2-Deoxy-D-Glucose: The Wonder Molecule That Selectively Reaches the Hypoxic Core of Solid Tumors

2-Deoxy-D-glucose (2DG) is a natural, non-metabolizable glucose analog in which the 2-hydroxyl group is replaced by hydrogen. To meet the increased demand for glycolysis, cancer cells increase the number of glucose transporters (GLUTs) to allow more sugar to enter.

Glucose transporting enzyme (GLUT1) transports both glucose and 2DG inside the tumor as they do not differentiate between sugar and 2DG when they transport these molecules inside cancer cells. Hence 2DG is selectively taken by the cancer cells along with glucose.

Furthermore, when 2DG binds to the transporter protein (GLUTs), it does not allow excess sugar molecules to bind and enter the cell⁴. As a result, glucose molecules are deprived from the cancer cells (which then die due to energy starvation), while normal cells still receive vital nutrients. In this way, cancer cells can be starved without depriving our normal cells.

2DG: A Glucose Mimic That Blocks Key Cancer Enzymes

Once inside the cell, 2DG, the glucose mimic, derails the energy generating glycolytic pathway. 2DG is converted to 2-deoxyglucose-6-phosphate (2DG-6P) by hexokinase, 2DG-6P cannot be metabolized further by glucose-6-phosphate isomerase in the next enzymatic step of glycolysis unlike glucose-6-phosphate and accumulates as a metabolic dead end. Cancer cells start to slow down as they receive less energy.

Accumulation of 2DG-6P also inhibits hexokinase, disrupting sugar metabolism in tumor cells. This total energy depletion ultimately leads to selective cancer cell death⁴.

2-DG: Acts as a Mannose Mimic That Triggers Endoplasmic Reticulum (ER) Stress and Unfolded Protein Response in Cancer Cells

2DG, as a mannose analog, interferes with a process known as N-linked glycosylation. This process is crucial for tumor cells and is associated with immune evasion, cancer growth and progression, metastasis, andeven resistance to treatment.

In the process of N-linked glycosylation, it has been shown that 2DG competes with mannose for assembly of lipid-linked oligosaccharides that are precursors of the sugar moiety in glycoproteins⁹.

Interference with N-linked glycosylation results in accumulation of unfolded proteins and consequently leads to endoplasmic reticulum (ER) stress which ultimately results in cancer cell death.

2DG Induces Apoptotic Cell Death by Targeting GFAT1 and Disrupting Glycosylation in Cancer Cells

The glutamine amidotransferase 1 (GFAT1) gene plays a key role in protein glycosylation and in the metabolism of cancer cells. By reducing GFAT1 activity, 2DG inhibits cancer cell survival pathways and bypasses mechanisms of drug resistance. This eventually leads to tumors undergoing programmed cell death (apoptosis).

Administration of 2DG leads to a dose-dependent decrease in GFAT1 activity, which is a key enzyme in the hexosamine biosynthetic pathway responsible for protein N-glycosylation.

Because of this glycosylation disruption, cancer cells experience severe ER stress, and they are unable to handle it properly. This stress ultimately triggers a cascade of cellular events that culminates in apoptosis, or programmed cell death, specifically targeting the cancer cells while sparing normal cells.

2-DG – Induces Selective Cancer Cell Death by Inducing TXNIP

Further, 2DG increases the production of thioredoxin interacting protein (TXNIP), which is a tumor suppressor protein. TXNIP limits cellular glucose uptake by downregulating glucose transporter 1 (GLUT1) localization at the plasma membrane¹¹.

Less sugar intake by cancer cells leads to inhibition of glycolysis and glucose metabolism, it induces energy deprivation, which eventually triggers the death of cancer cells.

2DG – Increases the Chemosensitivity of Cancer Cells to Chemotherapy, Immunotherapy and Targeted Therapy and Enhances Their Radiosensitivity

When administered prior to conventional anti-cancer therapy, 2DG starves cancer cells, rendering them slower, weaker, and more susceptible to radiotherapy and cancer-fighting drugs.

After radiation and chemotherapy kills the rapidly dividing cancer cells, the radiation and chemotherapy resistant slow-dividing cancer cells of the hypoxic core of the tumor cannot derive nutrition from sugar when 2DG is administered.

The cancer cells are not able to metabolize 2DG which leads to depletion of energy and tumor cell death in the hypoxic cancer core.

2DG – Enhancing Gemcitabine Efficacy in Pancreatic Cancer: Insights from a Pre-Clinical Study

Previous studies have shown that elevated glycolysis – the cellular process by which sugar becomes energy – is linked to the development of drug resistance in some cancers, meaning that cancer cells that have heightened glycolytic activity might be less responsive to chemotherapy and other treatment options overall¹².

This can, in turn, make the disease harder to manage, and possibly lead to poorer outcomes for patients.

The efficacy of 2DG was evaluated by Dai and colleagues in pancreatic cancer cell lines. They demonstrated that 2DG-associated inhibition of glycolysis led to a significant reduction in pancreatic cancer cell survival and resistance to the chemotherapeutic drug Gemcitabine.

This suggests that 2DG combined with Gemcitabine might be an effective therapy for pancreatic cancer¹³. 

2DG Enhances Glioblastoma Sensitivity to Chemotherapy (Temozolomide): A Case Study

The positive effects of 2DG were also observed in a middle-aged male with Glioblastoma multiforme¹⁴. The patient was diagnosed with this aggressive brain tumor in 2020. He underwent surgery and received radiation therapy in combination with chemotherapy (temozolomide).

Initially, the patient responded well to the therapeutic interventions. However, by 2022, the patient’s initial response proved to be short-lived, and he showed signs of disease recurrence. The patient began experiencing significant fatigue, weakness on the right side, and seizures.

Follow-up scans revealed a 7 cm lesion with a necrotic center and adjacent high perfusion area (which indicates an active tumor). 2DG was prescribed alongside temozolomide and vitamin C. After few months’ the patient’s seizures stopped, central necrosis decreased and clinical symptoms improved. The patient showed increased motor strength.

Post-treatment brain imaging showed a decrease in brain edema and a reduction in FLAIR signals, which are typically associated with abnormal fluid accumulation in the brain, indicating an improvement in the surrounding tissue inflammation. The patient resumed walking.

After a year and a half, the disease had not returned, even though the patient had stopped taking temozolomide and continued only with 2DG and natural supplements.

2-Deoxy-Glucose (2DG): A Promising Breakthrough in Cancer Treatment

2DG is a novel compound that selectively starves cancer cells to prevent their growth, progression, metastases eventually destroying them. 2DG complements both conventional and alternative cancer therapies, restores the body’s immune response against occult cancer cells, and helps to prevent recurrences of cancer.

With a good safety profile if used according to established protocols, 2DG can be used as a single agent or in combination with other therapies for cancer prevention, eradication of active cancer and prevention of cancer relapse. It also targets both fast-growing and slow treatment-resistant cancer cells.

For patients who have exhausted conventional options or are searching for alternative ways to deal with cancer, 2DG can be considered as an integrative treatment. In the future, using 2DG alone or combining it with standard care could potentially reduce disease recurrence, improve survival, and even achieve a cure.

It seems 2DG could be a game-changer in cancer treatment.

References:

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