Scientists in the CDER Office of Pharmaceutical Quality1 are studying the biochemical reactions of cancer cells to certain drugs that are designed to penetrate into subcellular structures known as mitochondria. Mitochondria are commonly called the “powerhouses” of the cell, because like tiny biochemically powered furnaces, they use oxygen to extract and convert the energy contained in food-derived nutrients into a form that drives cell growth and metabolism.
Drugs that selectively enter and damage the mitochondria of cancer cells are of interest to many drug developers and biomedical scientists, but the OPQ investigators point out that cancer cells may thwart this strategy by employing a multi-step process, called mitophagy, through which they isolate and destroy such damaged mitochondria in order to survive. CDER scientists want to understand mitophagy in cancer cells and determine how the removal of damaged mitochondria by mitophagy contributes to drug resistance during chemotherapy.
The Rationale for Designing Drugs to Penetrate and Affect Mitochondria
Mitochondria can be likened to tiny furnaces within each cell. If we think about a malfunctioning furnace in the home that is producing little heat but is producing lots of a dangerous “oxidant” byproduct (like carbon monoxide, for example), then we can envision instances where we might turn to medicine to optimize the energy-generating function of mitochondria and therefore improve health. For instance, the current nutritional emphasis on antioxidants in certain marketed products aspires to neutralize the reactive and toxic byproducts (oxidants) of energy production within our mitochondria.
In addition to the antioxidants provided in certain foods, specialized drugs called “mitochondria-targeted agents” have been designed to squelch potentially dangerous byproducts that occur within energy-generating mitochondria. But intriguingly, cancer cells are in certain instances harmed, rather than aided, by some of these mitochondrial drugs.
This key observation likely reflects fundamental ways that cancer cells differ from normal cells in terms of mitochondrial function and cell growth. For example, scientists have learned that the electrochemical “potential” of the mitochondrial membrane, a property that is directly linked to the energy-generating apparatus of mitochondria, is exaggerated in cancer cells. This property has been the basis for the development of several new classes of drugs for indications where the mitochondria are involved, including cardiovascular and neurological disorders, as well as cancer.
Understanding How Cancer Cells May Use Mitophagy to Resist Mitochondrial Targeted Agents
Before mitochondrial drugs can effectively fight cancer or other diseases, we need to know what elements of drug design could target and damage the mitochondria of cancer cells without triggering the process of mitophagy. Drug developers must keep in mind that the transformation of normal cells into cancer cells entails metabolic changes that affect properties related to mitochondrial function and mitophagy, even in the absence of treatment with mitochondrial drugs. The analytical tools and methods used in such investigations must allow scientists to differentiate changes associated with the transformation of normal cells into cancer cells from changes that relate to the treatment of cancer cells with mitochondrial drugs.
The work from CDER scientists1 reflects the careful methodological approach necessary to appreciate the details of mitophagy and mitochondrial damage in cancer cells. For example, the group found that drugs targeting mitochondria selectively affect cancer cells by triggering mechanisms related to the isolation and potential destruction of mitochondria (mitophagy). This finding suggests that cancer cells can use mitophagy to develop a resistance to and protect themselves against such drugs.
The results of the FDA research provide new and interesting insights into the sequence of events that transpire when cancer cells undergo mitochondrial damage and mitophagy. For example, cancer cells may actually be less prepared than normal cells to induce early steps in mitophagy. This observation may seem counterintuitive, given that the overall goal is to prevent cancer cells from using mitophagy to escape treatment. But the research suggests that we might achieve this goal if we could trick cancer cells into remaining unprepared, compared to normal cells, to enter into the early steps leading to mitophagy.
The research also confirms that mitochondrial damage precedes discrete biochemical events that are well-implicated in cancer cell sensitivity to mitochondrial drugs and that specific proteins associated with mitophagy function are activated in cancer cells following treatment with mitochondrial drugs. These observations are important because they identify potential mitophagy-related targets for drug development in effective anti-cancer strategies.
Mitophagy is complex, and very few analytical methods currently are available to evaluate the interplay between mitophagy and FDA-regulated drugs. FDA research into the effects of mitochondrial drugs on cancer cells establishes a quantitative and reliable new analytical test for measuring the effects of drugs on mitophagy. This new methodology offers drug developers the opportunity to explore and target mitochondrial functions in cancer and a variety of other diseases.
The Spotlight series presents generalized perspectives on ongoing research- and science-based activities within CDER. Spotlight articles should not be construed to represent FDA’s views or policies.
1Biel TG and Rao VA. Mitochondrial dysfunction activates lysosome-dependent mitophagy selectively in cancer cells. Oncotarget 2017; 9(1):955-1011.