Non-Toxic Drug Combination Induces Stress that Kills Cancer Cells

Fenofibrate is a drug of the fibrate class that is mainly used to reduce cholesterol levels in patients at risk of cardiovascular disease. Like other fibrates, it reduces low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL) levels, as well as increasing high-density lipoprotein (HDL) levels and reducing triglyceride levels. It is used alone or with statins in the treatment of hypercholesterolemia and hypertriglyceridemia.

Unregulated growth and replication as well as an abnormal microenvironment, leads to elevated levels of stress, which is a common trait of cancer. By inducing both energy and endoplasmic reticulum (ER) stress, 2-DG is particularly well suited to take advantage of the therapeutic window that heightened stress in tumors provides. Under hypoxia, blocking glycolysis with 2-DG leads to significant lowering of ATP, which results in energy stress and cell death in numerous carcinoma cell types. In contrast, at normal levels of oxygen, 2-DG at a low-concentration is not toxic in most carcinomas tested, but induces growth inhibition, which is primarily due to ER stress.

Investigators at the University of Miami School of Medicine (FL, USA) reported in the May 10, 2016, online edition of the journal Oncotarget that they had identified a synergistic toxic effect in several tumor cell lines in vitro by combining 2-DG with fenofibrate. This combination induced much greater energy stress than either agent alone, as measured by ATP reduction, increased p-AMPK, and downregulation of mTOR.

Mammalian target of rapamycin (mTOR) is a master regulator of protein synthesis that under ordinary conditions induces cells to grow and divide. In situations of severe nutrient deprivation mTOR prevents protein synthesis so that the cell can conserve energy. However, in cancer cells the mTOR pathway does not function correctly and signals tumor cells to grow, divide, undergo metastasis, and invade new, healthy tissues.

Inhibition of mTOR resulted in blockage of GRP78 (Binding immunoglobulin protein), a critical component of the unfolded protein response. This probably led to greater ER stress.

"We believe our findings effectively pave the way for using this combination to provide non-toxic treatments for a wide variety of cancers," said senior author Dr. Theodore Lampidis, professor of cell biology at the University of Miami School of Medicine. "We found that the unique combination of 2-DG and fenofibrate simultaneously provoked two types of stress, known as energy and ER stress, which most cancer types cannot overcome."

"Cancer cells found in the inner core of all solid tumors - due to the abnormally low levels of oxygen they are in - must rely on the process of glycolysis, the breakdown of glucose for energy, to survive," said Dr. Lampidis. "These cells, by nature of their slow growth, have been found to be the most resistant to conventional cancer treatments such as radiation and chemotherapy. In this study, we showed that a false sugar such as 2-DG, which blocks glycolysis, selectively starves these slow-growing cancer cells while sparing normal cells, which can use other sources of energy, such as fats and proteins because they are fully oxygenated."

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