Nelfinavir and other protease inhibitors in cancer: mechanisms involved in anticancer activity

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Quantitative Structure-Activity Relationship, Activity Prediction, and Molecular Dynamics of Non-nucleotide Reverse Transcriptase Inhibitors

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Tomas Koltai1

  • 1Centro de Diagnostico y Tratamiento de la Obra Social del Personal de la Alimentación, Talar de Pacheco, Buenos Aires, 1618, Argentina.

F1000Research
|June 23, 2015
PubMed
Abstract

Insights

Protease inhibitors (PIs), including nelfinavir, show anti-cancer effects through endoplasmic reticulum stress and Akt inhibition. Further clinical trials are needed to establish their role in cancer treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Protease inhibitors (PIs) are primarily used as antiretroviral agents.
  • Emerging evidence suggests anti-cancer properties for PIs, particularly nelfinavir (NFV).
  • Understanding the precise mechanisms of PI anti-cancer activity is crucial for therapeutic development.

Purpose of the Study:

  • To review the anti-cancer mechanisms of nelfinavir and other PIs.
  • To classify PIs based on their anti-cancer modes of action.
  • To address controversies surrounding nelfinavir's molecular mechanisms.

Main Methods:

  • Extensive literature review on nelfinavir and other PIs as anti-cancer agents.
  • Classification of PIs by their anti-cancer activity.
  • Analysis of published evidence on molecular targets and pathways.

Main Results:

  • The two primary anti-cancer mechanisms identified are endoplasmic reticulum (ER) stress-unfolded protein response (UPR) pathway and Akt inhibition.
  • Numerous other effects contribute to anti-cancer activity, including inhibition of MMP-2/9, down-regulation of various growth factors and signaling molecules (e.g., VEGF, NF-kB, STAT-3), and modulation of apoptosis-related proteins (e.g., Bax, DR5).
  • PIs can also decrease cellular ATP, inhibit proteasome and fatty acid synthase, increase radiosensitivity, and induce autophagy.

Conclusions:

  • Nelfinavir and other PIs exhibit multifaceted anti-cancer effects, leading to reduced proliferation, decreased angiogenesis and invasion, and increased cancer cell death.
  • PIs can be classified as AKT inhibitors, ER stressors, or combined AKT inhibitors/ER stressors based on their activity at clinically relevant doses.
  • Further well-designed clinical trials, including combination studies with other anti-cancer drugs, are necessary to determine the optimal role of PIs like nelfinavir in cancer therapy, considering potential differences in mechanisms between tumor cells and normal tissues.
Keywords:
AktNelfinavircancerendoplasmic reticulum stressprotease inhibitorunfolded protein response

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