Table of Contents
Introduction
Cancer cells undergo metabolic programming or alterations to fulfill the increased requirement of energy and metabolites, which also facilitates cancer cell progression. In healthy cells, the food is usually converted into energy and other chemical compounds by a complex metabolic pathway. Cancer cells thus alter the efficient energy-producing pathways of healthy cells and shift them to alternative strategies to produce more material needed for their proliferation. However, these alternative metabolic pathways followed by cancer cells offer growth advantages to these cells, and with rapid progression, cancer cells often become dependent on these alternative pathways. Thus, interfering with these pathways can be an effective way to prevent cancer growth.
What Are the Various Metabolic Pathways of Clinical Cancer Cells?
Metabolic pathways of clinical cancer cells are as follows:
-
Glycolysis - This process involves the conversion of glucose to pyruvate (in the presence of oxygen). Cancer cells often undergo a glycolysis process to produce adenosine triphosphate (ATP) and other metabolites essential for biosynthesis. The upregulation of glycolytic enzymes, such as phosphofructokinase, hexokinase, and lactate dehydrogenase, also facilitates this metabolic pathway.
-
Warburg Effects: Warburg effects is a phenomenon where cancer cells utilize glycolysis from adenosine triphosphate (ATP) production in the presence of oxygen and do not rely on OXPHOs (oxidative phosphorylation) in the mitochondria. This switch in the metabolic pathway of cancer cells is the hallmark feature that plays a crucial role in rapid cancer cell proliferation and survival.
-
-
Pentose Phosphate Pathway (PPP) - Cancer cells often upregulate this metabolic pathway to facilitate their growth, progression, or proliferation. The pentose phosphate pathway branches off the glycolysis pathway to generate NADPH (nicotinamide adenine dinucleotide phosphate) for redox reduction and biosynthetic reactions and ribose-5-phosphate for nucleotide synthesis.
-
Oxidative Phosphorylation (OXPHOS) - Most cancer cells usually opt for the glycolysis metabolism pathway; some may retain functional mitochondria and produce ATP by utilizing oxidative phosphorylation during metastasis (cancer spreading to other parts of the body) or nutrient-rich conditions. However, mitochondrial DNA (deoxyribonucleic acid) mutations can alter the functioning of mitochondria in cancer cells and, thus, affect the chain complexes of electron transport.
-
Tricarboxylic Acid (TCA) Cycle - This pathway is usually downregulated in most cancer cells but may be active in some cells. It provides an intermediate for generating reducing equivalents, such as NADH (nicotinamide adenine dinucleotide) and FADH2 (flavin adenine dinucleotide) for oxidative phosphorylation, biosynthesis, or other processes.
-
Glutamine Metabolism - Glutamine is also considered an essential nutrient for cancer cells as it serves as a nitrogen and carbon source for biosynthesis and fuel for the tricarboxylic acid (TCA) cycle. Many cancer cells show addiction to glutamine, and therefore, targeting glutamine metabolism is considered an essential therapeutic strategy in cancer treatment.
-
Fatty Acid Metabolism - Fatty acid synthesis often increases in cancer cells for energy production and membrane biogenesis.
-
One-Carbon Metabolism -This metabolic pathway is often upregulated in cancer cells. It provides one-carbon units for amino acid and nucleotide synthesis to support rapid cell proliferation.
What Are the Targeted Therapies Specific to Cancer Cell Metabolic Pathways?
Targeted cancer cell therapies involve therapeutic agents or drugs that mainly target the metabolic pathways or molecules essential for cancer cell growth and proliferation.
These targeted cancer cell therapies include:
-
Small Molecule Inhibitors: These drugs mainly target specific proteins involved in the signaling pathways of cancer cells. Small molecule inhibitors block enzymes (mainly kinases) crucial for cell growth, proliferation, and survival. The drugs used in this therapy include Vemurafenib (targets BARF-kinase) for melanoma and Imatinib (targets BCR-ABL kinase) for chronic myeloid leukemia.
-
Monoclonal Antibodies (mAbs): These are engineered antibodies that recognize and bind to specific proteins on the surface of cancer cells. Monoclonal antibodies targeted to bind to these proteins can block the cancer cell’s signaling pathways that facilitate cell growth, survival, delivery of cytotoxic agents, and immune-mediated destruction of these malignant cells. The drugs used in this therapy include Rituximab for lymphomas of some types and Trastuzumab for HER2-positive breast cancer.
-
Hormone Therapy: Hormone-sensitive cancers, including prostate and breast cancers, are usually treated with hormone therapy, as it works by blocking the activity or production of hormones that support cancer growth. The therapy involves the use of androgen deprivation therapy for prostate cancer to suppress testosterone levels and the use of drugs, such as Aromatase and Tamoxifen inhibitors, to block estrogen signaling in breast cancers that are estrogen receptor-positive.
-
Targeted Immunotherapy: This therapy identifies and eliminates cancer cells by controlling the power of the immune system. Targeted immunotherapy involves drugs, such as Nivolumab and Prembolizumab, that block the cancer cell’s inhibitory signals that evade immune detection, thus helping the immune system show an anti-tumor response.
-
PARP Inhibitors: These inhibitors inhibit the activity of enzymes involved in deoxyribonucleic acid (DNA) repair, such as poly (ADP-ribose) polymerase (PARP). This therapy thus, prevents the repair of DNA damage by the cancer cells, leading to their death. Therefore, PARP inhibitors are primarily effective against cancer cells with defects in DNA repair pathways. The drugs used in this therapy include Rucaparib and Olaparib used in BRCA-mutated ovarian and breast cancer.
-
Angiogenesis Inhibitors: These mainly target the formation of new blood vessels or angiogenesis, supplying oxygen and nutrients to the cancer cells for growth, thereby preventing their proliferation by depriving them of resources. The drugs used in this targeted therapy include Avastin or Bevacizumab, which inhibit the activity of a protein, and VEGF (vascular endothelial growth factor), which promotes angiogenesis. The therapy treats various cancers, such as lung, colorectal, and kidney.
Conclusion
To conclude, metabolic pathways play an important role in the healthy functioning of the cells in the body, providing energy for growth and survival. However, any dysfunction in the metabolic pathway of the cells can lead to various metabolic disorders or diseases, such as cancer, through clinical cancer cell formation. Thus, metabolic pathways also play a significant role in establishing targeted therapies used in therapeutic interventions to treat cancers by targeting their metabolic pathways.
