For years, scientists all around the world have been trying to conquer cancer. Different approaches have been taken to treat different types of cancer, including surgery, hormone therapy, radiation therapy, and many others. However, there exists a different procedure. It involves the organelle in our cells, mitochondria. 

What is a Mitochondrium?

Mitochondrium is an organelle in our cells that is responsible for providing them with energy. It provides the cell with chemical energy by generating adenosine triphosphate, or ATP in short. Therefore, it’s been named “the powerhouse of a cell”. 

What Does Targeting Mean?

Targeting is a term used in cancer therapy, specifically drug therapy. To explain it, we firstly need to take a look at the fundamentals of drug therapy itself.

At the lowest molecular level, drug therapy relies on an interaction between two molecules. One molecule, distributed in the patient’s body by drugs, interacts with another molecule in the patient’s body. This interaction is supposed to induce a physiological response, which, in result, improves the patient’s health.

Targeting In Drug Therapy

In the field of drug discovery, targeting describes the ability of a drug to interact only with the intended molecules. To put it simply, the less healthy molecules the drug interacts with, the better. Finding such selective molecules has been relatively easy, up to a point. Nowadays, however, it’s getting progressively harder to recognize the diseased molecules from the healthy ones. The topic of upgrading the drugs’ ability of selectively targeting the intended molecules is a major area of concern in drug therapy.

The Role Of Mitochondria In Cancer

As it turns out, mitochondria play a much bigger role in cancer than expected. The ATP it produces is necessary to the tumor’s growth, and it plays a key role in oncogenesis and macromolecular synthesis. Cancerous mitochondria have the ability to adapt to the cell’s increased energy needs. Therefore, targeting mitochondria is a promising strategy against cancer development. 

How Are Mitochondria Targeted For Cancer Therapy

There exist multiple strategies for targeting mitochondria for cancer therapy. 

Targeting the cell’s mitochondrial metabolism. This approach uses the following ways of targeting the mitochondrial metabolism: The electron transport chain, or ETC, is pivotal for the respiration of mitochondria. The functional Electron Transport Chain supports ATP generation and OXPHOS activity. ETC inhibitors, such as tamoxifen, metformin, 3-bromopyruvate, and a-tocopheryl succinate act to disrupt the functioning of the respiratory chain complexes within the ETC while also inducing an increased ROS level to destroy cancerous cells. A new approach tags a cationic triphenylphosphonium group to various anticancer compounds for selectively targeting cancer mitochondria. This mitochondrial-targeted therapy preferentially delivers drugs into mitochondria of the cancer cells based on the high transmembrane potential they have for triggering mitochondrial-dependent apoptosis through rapid ROS generation. This type of tagging has been used to prepare both MitoVES and MitoTAM to efficiently kill colorectal, breast, and lung cancer cells while also inhibiting the growth of tumors. 

Targeting glycolysis and OXPHOS: Glycolysis is a metabolic pathway that has a direct effect on the function of mitochondria. It supports mitochondrial metabolism by providing it with important metabolic intermediates like pyruvate. Furthermore, the malignant cells are able to freely switch between OXPHOS and glycolysis, and this proves to be crucial in multiple resistance modes to oncogenic inhibition. So, agents that are able to target both OXPHOS and glycolysis functions are viewed as the ideal approach to anticancer therapy. Combining mitochondria-targeted therapeutics and glycolytic inhibitors results in synergistically suppressing the proliferation of tumor cells. 

Targeting TCA cycle: TCA cycle provides the ETC with a stream of electrons in order to generate ATP through electrochemical proton gradient. Isocitrate dehydrogenases 1, 2 serve as a catalyst when isocitrate converts to α-ketoglutarate, and this is of critical importance in tumorigenesis. The mutations of IDH1 as well as IDH2 are found in various human cancers, rendering them as prime targets in anticancer therapy. Inhibitors of these substances like AGI-5198, AGI-6780 and 3BP have great anticancer potential and can play their part in cancer therapy for many types of cancer.

Targeting ROS Homeostasis and Apoptotic Pathways. In this approach, the following ways of targeting ROS homeostasis and apoptotic pathways are used. 

Targeting Bcl-2 family proteins. The proteins from the Bcl-2 family – like  Bcl-2, Bax, Bak, and Bcl-xL – are crucial in the apoptotic pathway. Venetoclax and navitoclax are examples of Bcl-2 or Bcl-xL inhibitors that exhibit anticancer ability.

Targeting redox-regulating enzymes and the production of ROS. The ROS, when released in large quantities as a result of interference with ECT complexes, can lead to cellular damage. Oxymatrone was observed to be effective in killing melanoma cells in humans by producing large quantities of ROS. Substances such as capsaicin, myricetin, and casticin show anticancer activity as they increase the rate of ROS production. This increased ROS production results in disrupting the potential of mitochondrial transmembrane in cancer cells. If this method to produce mitochondrial ROS is promoted in order to induce the death of cancerous cells, it may result in the improved chemotherapy activity. 

Challenges Of Targeting Mitochondria For Cancer Therapy

There are three main challenges when it comes to developing drugs which can selectively target mitochondria for cancer therapy:

• To come up with a drug that targets mitochondrial metabolism; the normal cell’s toxicity needs to be established
• The drug has to not only go through the cell’s membrane but also the two mitochondrial membranes
• More research is needed about the fundamental biology of how tumorigenesis is regulated

The Future Of Anticancer Treatment

As many studies show, targeting mitochondria for cancer therapy is a very promising approach. It may be the solution to the huge problem i.e. cancer. Unfortunately, mitochondria’s importance in the progression of cancer has been discovered only recently. As a result, this field of study is still relatively new, and there is a lot more to explore. Hopefully, it’s only a matter of time before targeting mitochondria proves to be the ultimate cure to cancer. 

Dr. Paul Zhang at the Institute of Integrative BioOncology in Houston provides evidence-based treatments for a wide range of cancers. Call today for more information.