Mitochondria play important roles in tumor cell physiology and survival by providing energy and metabolites for growth and proliferation. As part of their oncogenic status, cancer cells frequently produce increased levels of mitochondrial-generated reactive oxygen species (ROS). However, extensive stimulation of ROS generation in mitochondria can induce cancer cell death, and is one of the major mechanisms of action of many anticancer agents.
Mitochondria control many growth and survival pathways in eukaryotic cells, not only as the major energy-producing organelle and a regulator of apoptosis and autophagy, but also as a source of steroids, hemes, amino acids, neurotransmitters, and organic acids. One side product of ATP production in the electron transfer chain (ETC) is the generation of up to 90% of total intracellular reactive oxygen species (ROS), including superoxide radical anion, hydroxyl radical, and reactive nitrogen species (RNS). ROS bursts can cause oxidative stress levels associated with acute and chronic damage to cellular components, including mitochondrial membrane lipids such as cardiolipin and mitochondrial DNA (mtDNA). Cumulative oxidative damage will result in functional aberrations of cellular metabolism and signaling pathways and various pathological disorders. However, rather than just representing a chemical nuisance and dangerous progenitor of lipid, protein, and DNA oxidation products, leading to apoptosis, ROS also mediate a diverse range of cellular processes such as signaling cascades, cell cycle control, and autophagy. In fact, controlled ROS release can serve as a modulator of redox-homeostasis and cell signaling pathways. Therefore, rather than complete abolition of ROS, controlled inflection of ROS levels may offer treatment options for a large number of diseases such as cancer, diabetes, cardiovascular and neurodegenerative disorders, where mitochondria have emerged as a key contributing factor.
Cancer cells apparently increase their ROS production relative to normal cells, which is believed to be essential for maintaining oncogenic signaling. Furthermore, disrupting redox homeostasis by either suppressing antioxidant enzymes or enhancing the ROS production in cancer cells has been shown to be able to induce cancer cell death and thus offers an effective strategy for cancer therapy. Directly or indirectly, ROS are also known to play important roles in the anticancer activities of many chemotherapeutic drugs. Unfortunately, these agents often fail to induce cell death in cancer cells due to alterations in their endogenous cell death signaling, such as the p53 pathway. Heat shock proteins compensating for oxidative stress are also frequently upregulated in cancer tissue. Therefore, agents that directly target mitochondria to induce mitochondria-initiated cell death are thought to have greater potential in circumventing tumor cell resistance compared to standard chemotherapeutic drugs. Furthermore, in addition to ROS production, other aspects of mitochondrial metabolism are also required for the function of many types of tumors, including melanoma. Induction of mitochondrial dysfunction is thus considered to be a promising strategy for cancer treatment.