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Bortezomib in cancer therapy: Mechanisms, side effects, and future proteasome inhibitors
Olusola Sogbein1, Pradipta Paul2, Meenakshi Umar1
1Department of Medicine, Tulane University School of Medicine, New Orleans, LA 70112, USA.
Abstract:
The ubiquitin-proteasome pathway (UPP) regulates protein stability and normal cellular functions with the help of autocatalytic proteasome complex. Studies have linked aberrant proteasome activity to malignant cells and found that proteasome inhibitors play a significant role as therapeutic drugs for various types of cancer, specifically multiple myeloma and mantle cell lymphoma. Bortezomib, the first FDA-approved proteasome inhibitor for treating different stages of multiple myeloma, acts on cancer cells by inhibiting the 26S proteasome, modulating NF-κB, phosphorylating Bcl-2, upregulating of NOXA, blocking p53 degradation, activating caspase, generating reactive oxygen species (ROS), and inhibiting angiogenesis. However, its efficacy is limited due to side effects such as peripheral neuropathy (PN), thrombotic microangiopathy (TMA), and acute interstitial nephritis (AIN). Therefore, a better understanding of its precise mechanism of action may help mitigate these side effects. In this review, we have discussed the proposed mechanisms of action and off target effects of Bortezomib, along with the prospects of next generation potential proteasome inhibitor drugs in the treatment of cancer.
Insights
Proteasome inhibitors like Bortezomib treat cancer by targeting protein degradation. Understanding Bortezomib
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- The ubiquitin-proteasome pathway (UPP) is crucial for protein stability and cellular function.
- Aberrant proteasome activity is linked to cancer development.
- Proteasome inhibitors are established cancer therapeutics, particularly for multiple myeloma and mantle cell lymphoma.
Purpose of the Study:
- To review the proposed mechanisms of action of Bortezomib.
- To discuss the off-target effects and limitations of Bortezomib therapy.
- To explore the potential of next-generation proteasome inhibitors for cancer treatment.
Main Methods:
- Literature review of Bortezomib's mechanism of action.
- Analysis of Bortezomib's impact on cellular pathways (NF-κB, p53, caspases).
- Examination of Bortezomib-associated side effects (peripheral neuropathy, TMA, AIN).
Main Results:
- Bortezomib inhibits the 26S proteasome, affecting multiple downstream cellular processes.
- Key mechanisms include NF-κB modulation, Bcl-2 phosphorylation, NOXA upregulation, p53 stabilization, caspase activation, ROS generation, and anti-angiogenesis.
- Significant side effects limit Bortezomib's clinical utility.
Conclusions:
- Further understanding of Bortezomib's action is needed to mitigate side effects.
- Next-generation proteasome inhibitors offer potential for improved cancer therapy.
- Targeted inhibition of the proteasome remains a promising strategy in oncology.
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