….written by Science Writer Heather Schmidt
Cancer is a disease of the cell. Cancerous cells are abnormally functioning cells that produce energy much differently than healthy cells. They use an entirely different pathway, one that enables them to divide much more rapidly than healthy cells.
Most cancer treatments are unable to specifically target only abnormally functioning cells. Instead, chemotherapies target rapidly dividing cells, which is why hair loss, loss of appetite and nausea are common amongst chemotherapy patients. Like cancerous cells, both hair cells and the cells that line the gut are rapidly dividing cells. Almost all cancer treatments are so destructive to the body and to a patient’s overall health because healthy cells are effected just as much as cancer cells are effected.
But, what if cancer treatments could target the way cancer sustains itself, at some part along its energy production pathway, leaving healthy cells alone?
Healthy cells produce energy utilizing Adenosine triphosphate, better known as the ATP pathway. It is the molecule responsible for energizing our cells. Cancerous cells exhibit an irregular pathway of energy production referred to as The Warburg Effect. The Warburg Effect explains how cancer cells become so malignant. Malignant cells learn not only how to survive under near-constant attack, they learn how to thrive, how to manipulate cellular metabolism as they divide and then invade their surrounding tissues.
If we can better understand how malignant cells produce energy and then identify steps that are unique to the formation of malignant cancer cells; can we target their specific metabolism when designing drugs to combat cancer?
Over half a century ago scientists learned that malignant cells were undergoing glycolysis at a rate of almost two hundred times higher than that of healthy cells. Glycolysis is the breakdown of sugar (glucose) to extract energy for cellular metabolism.
Scientists further realized that malignant cells were foregoing the Krebs Cycle (aka TCA cycle) instead resorting to the fermentation of lactic acid within the cell’s cytosol. Healthy cells produce energy via glucose oxidation. Glucose oxidation occurs as three distinct but linked processes; glycolysis, the Krebs Cycle and oxidative phosphorylation; together these processes net a total of 38 molecules of ATP.
Glycolysis occurs within the cytosol of the cell. This beginning process is essential for creating the big player of the Krebs cycle; pyruvate. Under normal circumstances 2 molecules of pyruvate are formed for every molecule of glucose.
Once produced it travels into the mitochondria, the workhorse of the cell, where it is then converted to Acetyl CoA. Acetyl CoA goes on to create a total of ten reduced (electron carrying) coenzymes (per glucose molecule) that will fuel the last step of glucose oxidation, oxidative phosphorylation. This end process is responsible for generating the bulk of ATP and is comprised of two steps; the electron transport chain and chemiosmotic coupling.
Electrons are released by the coenzymes previously produced and travel through the chain, ultimately releasing energy. This released energy transports hydrogen ions into the mitochondrial membrane. The movement of these hydrogen ions into the mitochondrial membrane creates a concentration gradient that stores some of the energy released during electron transport. This energy is then released, ultimately flowing through ATP synthase, creating ATP.
It’s important to note that the body is beautifully adaptive, and even in the absence of oxygen we can still create ATP. We accomplish this through the conversion of pyruvate to lactic acid. This reaction provides an alternative way for the body to still utilize glycolysis eventually forming ATP. However, a mere 2 molecules of ATP are produced compared to a total of 38 produced under normoxic conditions.
Thanks to scientist Otto Warburg, we now know that malignant cells undergo glycolytic rates up to two hundred times higher than that of healthy cells. Furthermore, these cells go on to ferment lactate, even in the presence of oxygen.
Warburg postulated that this was the root of cancer, he went on to form the Warburg hypothesis in 1924 that essentially described a malfunctioning mitochondria unable to successfully undergo the Kreb’s cycle and oxidative phosphorylation. He postulated that it was this altered state of metabolism that produced malignant cells. “Whether the Warburg phenomenon is the consequence of genetic dysregulation in cancer or the cause of cancer remains unknown. Moreover, the exact reasons and physiological values of this peculiar metabolism in cancer remain unclear.”1
The Warburg Effect is found to be true in almost all forms of cancer and is considered one of the hallmarks of cancer cells. “Moreover, glycolytic cancer cells are often invasive and impervious to therapeutic intervention. Thus, altered energy metabolism is now appreciated as a hallmark of cancer and a promising target for cancer treatment. A better understanding of the biology and the regulatory mechanisms of aerobic glycolysis has the potential to facilitate the development of glycolysis-based therapeutic interventions for cancer.”2 Targeting the enzymes involved in glycolysis has become a focus, numerous drugs have been developed based on this theory including, “Ritonavir, fasentin, genistein, STF-31 and WZB117 are anticancer drugs designed to target glucose transporter GLUT1 and exert anti-tumor effects by inhibiting glucose uptake in tumor cells, thus leading to cell death through glucose deprivation.”2
Future cancer treatments should exploit the Warburg Effect characteristic of cancer cells. This metabolic approach to cancer would include targeted treatments that interfere with only cancer’s metabolism, interfering with its ability to proliferate, to survive and to maintain itself. And it would do so without the toxicity of chemotherapies that target healthy cells along with cancerous ones.
Quangdon Tran, Hyunji Lee, Jisoo Park, Seon-Hwan Kim, Jongsun Park. 2016. Targeting cancer metabolism – revisiting the Warburg effect. Toxicol Res. 32(3):177-193.
Xi-sha Chen, Lan-ya Li, Yi-di Guan, Jin-ming Yang, Yan Cheng. 2016. Anticancer strategies based on the metabolic profile of tumor cells: therapeutic targeting of the Warburg effect. Acta Pharmacol Sin. 37(8): 1013–1019.