Bortezomib, marketed under names like Velcade, is a medication used in the treatment of certain cancers, including multiple myeloma and mantle cell lymphoma. It represents a class of drugs known as targeted therapies, designed to interfere with specific molecules involved in tumor growth and survival. This approach allows for more precise intervention compared to traditional chemotherapy. Bortezomib was approved for medical use in the United States in 2003.
Understanding the Cell’s Protein Recycling System
Cells continuously produce and break down proteins to maintain their health and proper function. This process, known as protein homeostasis, is primarily managed by the ubiquitin-proteasome system (UPS). At the core of this system is the proteasome, a large protein complex found within the cytoplasm and nucleus of all eukaryotic cells. The 26S proteasome, the primary site for protein degradation, consists of a 20S catalytic core and one or two 19S regulatory particles.
Proteasomes act as cellular recycling centers, responsible for degrading old, damaged, or unneeded proteins into smaller peptides and amino acids. Proteins destined for degradation are first tagged with a small protein called ubiquitin, which acts as a signal for the proteasome. This ubiquitin tag directs the marked protein to the 26S proteasome, where the 19S regulatory particle recognizes the tag and feeds the protein into the 20S core for breakdown.
This controlled breakdown of proteins is fundamental for many cellular activities. It regulates cell cycle progression, gene expression, and responses to cellular stress. By managing protein turnover, the proteasome prevents the accumulation of toxic protein aggregates and ensures that protein levels are balanced for normal cell operation. This system is vital for cell survival, as its impairment can lead to various health issues.
Bortezomib’s Specific Action
Bortezomib is the first medication in a class of drugs known as proteasome inhibitors. Its mechanism of action involves selectively and reversibly blocking the activity of the 26S proteasome. The boron atom within the bortezomib molecule binds to the active sites of the proteasome’s beta-5 (β5) subunit. This subunit mediates the chymotrypsin-like activity, one of the three main proteolytic functions of the proteasome.
By binding to the β5 subunit, bortezomib inhibits the proteasome’s ability to break down ubiquitinated proteins, leading to an accumulation of various cellular proteins. Among these are regulatory proteins that control cell cycle progression, signal transduction, and programmed cell death. Bortezomib primarily targets the β5 subunit, but can also inhibit the β1 (caspase-like) and β2 (trypsin-like) subunits.
The reversible nature of bortezomib’s binding means its inhibitory effect is not permanent; proteasome activity can recover after approximately 72 hours. This sustained disruption of proteasome function is sufficient to alter cellular protein regulation. The consequence of this inhibition is an overload of the cell’s protein management system, leading to a buildup of poly-ubiquitinated proteins and other substrates within the cell, disrupting normal cellular processes.
Consequences for Cancer Cells
The inhibition of proteasome function by bortezomib damages cancer cells. Malignant cells exhibit higher rates of protein synthesis and rapid proliferation compared to healthy cells. This increased protein turnover makes them more dependent on the proteasome for maintaining protein balance. When the proteasome is inhibited, cancer cells are more susceptible to the resulting cellular stress.
One consequence is the accumulation of misfolded proteins within the endoplasmic reticulum (ER). This protein buildup triggers ER stress, activating stress response pathways. If the stress is prolonged, these pathways can lead to programmed cell death, or apoptosis. Bortezomib induces apoptosis by preventing the degradation of pro-apoptotic factors.
Proteasome inhibition also impacts pathways overactive in cancer, such as the NF-kB pathway. NF-kB promotes cell survival and proliferation. By preventing the degradation of NF-kB’s inhibitor, IκB, bortezomib can suppress NF-kB activity, reducing the expression of anti-apoptotic genes and sensitizing cancer cells to death. The accumulation of cell cycle regulatory proteins like p21 and p27 can lead to cell cycle arrest.
Clinical Use and Importance
Bortezomib has impacted the treatment landscape for certain blood cancers. It is approved for multiple myeloma, a cancer of plasma cells, and mantle cell lymphoma, a type of non-Hodgkin lymphoma. For multiple myeloma, bortezomib is used in newly diagnosed patients and those with relapsed or refractory disease.
In mantle cell lymphoma, bortezomib has demonstrated clinical efficacy in patients with relapsed and refractory disease, and also in upfront treatment regimens. Its ability to induce responses in these aggressive cancers has improved outcomes for many patients.