Vacuolization as a Novel Approach to Cancer Therapy

A wide variety of cellular functions are performed by vacuoles, including storing nutrients and degrading waste. In cancer cells, some compounds can induce vacuole formation, frequently producing cell death. Interestingly, vacuole-induced death usually involves nonapoptotic mechanisms, such as oncosis, paraptosis and methuosis. Oncosis is characterized by rapid cellular swelling and impaired membrane transporters, affecting ion balance and causing cell rupture. In paraptosis, endoplasmic reticulum and mitochondria swell, large vacuoles form within the cells, resulting in cell lysis through specific signaling pathways. Cellular constituents are recycled and degraded during autophagy, but cells can also die from vacuoles and autophagosomes. In autophagy, damaged organelles and non-functioning proteins are encapsulated in autophagosomes, which are then digested by hydrolases within the lysosome/vacuole. Conversely, methuosis induces the formation of macropinosomes which acquire the characteristics of late endosomes, but do not fuse with lysosomes. The process of methuosis differs from apoptosis and autophagy in that it may involve specific signaling pathways. These types of nonapoptotic cell death are all triggered by the formation of vacuoles in cancer cells, and they are all potentially targets for cancer treatment. There is a need to discover and develop compounds that induce nonapoptotic cell death with vacuolization, because many types of cancer cells acquire resistance to therapies that induce apoptosis. This review will discuss compounds that induce vacuoles for various types of cells, particularly cancer cells. Our goal is to categorize and group compounds, according to their efficacy to induce vacuoles during specific types of cell death.