Cancerous Cells Should Be Urged To Suicide

When fighting cancerous growths, it is very important to use internal cellular mechanisms on top of various external impacts on the tumor. Among internal mechanisms is cells’ ability for “suicide” – programmed cell death, which is called apoptosis. The cells resort to apoptosis when something is irreparably broken in them and the cells need to perform self-destruction to avoid causing damage to the entire organism. Apoptosis is executed by intracellular protease enzymes (they are called caspases). Caspases destroy target proteins located in the cytoplasm and the cell’s nucleus. Cellular genome is also the target of caspases’ action. Caspases’ activation occurs as a result of a complicated chain of biochemical reactions which are launched specifically by special receptors on the cellular membrane. Specialists call them dreadly – “receptors of death”.

Unfortunately, cancerous cells, on top of their ability for uncontrolled reproduction, also possess a striking capability for survival. As the contents of caspases’ predecessors – procaspases – and accordingly that of caspases may be reduced in the cancerous cells, induction of apoptosis in these cells is difficult. If the content could be increased, physicians would get an efficient instrument to fight this fatal disease. Solution of this problem is addressed by the joint project of Russian and American researchers from the Center for Theoretical Problems of Physicochemical Pharmacology (project manager – Mikhail Khanin, Doctor of Science (Engineering), Professor, the Lenin prize laureate) and Mayo Clinic, Rochester, Minnesota, USA (project manager – Scott Harold Kaufmann, prominent researcher of apoptosis, Professor, Doctor of Philosophy and Medicine).

The project has been sponsored by the international foundation CRDF and the Federal Agency for Science and Innovations (Rosnauka). The researchers are planning to solve the task by a combination of mathematical modelling and biochemical methods. “Mathematical models are increasingly recognized in recent years as an efficient method for investigation of execution behaviour of complicated biochemical systems, points out Mikhail Khanin. These systems are nonlinear, and their behavior has typical properties; for example, threshold effects. All these dynamic properties can be predicted and described with the help of mathematical modelling and subsequent computer simulation.”

Apoptosis – is a cellular suicide, but the decision about it is made not only by the cell itself but also the immune system, which “gives an order” having discovered fatal injuries in a certain cell. And the cell is at constant alert to fulfill the order. This can be compared to a person who, leaving home, takes a rope and a bar of soap just in case. Thus, any cell carries the mechanism of death inside. The “receptors of death” on the cellular membrane stick out by one end, a molecule released by the immune system cells comes up to this end and forms a complex with the receptor. After that, the receptor transmits a signal inside the cell to activate caspases. This is how apoptosis is launched.

To build the mathematical model for caspases’ activation, researchers should know numerical values of all kinetic constants of apoptosis biochenical reactions. Kinetic constants determine the enzymatic reactions’ rate. The point is that only a small part of necessary kinetic constants is determined by biochemical methods. The rest can be calculated with the help of optimization mathematical models. In this case, the basic principle of physiological (and biochemical) systems’ organization – principle of optimality – helps the researchers. This means, for example, that the system spends minimal energy to perform its functions in the organism. The same is applicable to apoptosis – it is necessary to destroy proteins and the genome quickly enough and at minimal expense.

So, at first phase, the researchers need to calculate kinetic constants of reactions and then to build mathematical model of caspases’ activation dynamics, i.e., in fact, the apoptosis induction model. The model’s accuracy will be appreciated by coincidence of modelling and biochemical research results.

Having the mathematical model of apoptosis dynamics available, the researchers will be able to apply it to find the ways of apoptosis induction reinforcement in various types of malignant cells.