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Implementation of In Vitro Drug Resistance Assays: Maximizing the Potential for Uncovering Clinically Relevant Resistance Mechanisms
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Role of genomics-based strategies in overcoming chemotherapeutic resistance

M Vijay Kumar1, Robert Shirley, Yulin Ma

  • 1Department of Urology, Medical College of Georgia, Augusta, GA 30912, USA. vkumar@mail.mcg.edu

Current Pharmaceutical Biotechnology
|November 17, 2004
PubMed

Insights

Targeting apoptosis pathways, including caspases and inhibitors of apoptosis (IAPs), offers strategies against cancer. Manipulating proteins like Smac/DIABLO and inhibiting survival pathways such as NFkappaB and Akt can enhance cancer cell apoptosis and therapeutic outcomes.

Area of Science:

  • Cancer Biology
  • Molecular Oncology
  • Cell Death Pathways

Background:

  • Cancer is increasingly viewed as a failure of apoptosis, prompting the development of apoptosis-based therapeutic strategies.
  • Caspases are crucial for apoptosis induction; their reduced expression correlates with higher cancer grade, while increased expression sensitizes cells to chemotherapy.
  • Inhibitors of Apoptosis (IAPs) counteract caspases, and blocking IAPs can induce apoptosis in chemo-resistant cancer cells.

Purpose of the Study:

  • To review the complex interactions between cell survival and death pathways in cancer.
  • To highlight methods for manipulating these pathways to achieve therapeutic advantages in cancer treatment.
  • To explore the role of caspases, IAPs, Smac/DIABLO, TRAIL, NFkappaB, and Akt in apoptosis and cancer resistance.

Main Methods:

  • Discussing the mechanism of action of caspases and their regulation by IAPs.
  • Examining the role of Second Mitochondria-Derived Activator Of Caspase (Smac)/Direct IAP Binding Protein With Low Pi (DIABLO) in IAP inhibition.
  • Analyzing the involvement of TNFalpha-Related Apoptosis-Inducing Ligand (TRAIL) pathway and its resistance mechanisms.
  • Investigating the impact of NFkappaB and Akt signaling pathways on apoptosis and cell survival.

Main Results:

  • Smac/DIABLO release from mitochondria upon apoptotic stimulus inhibits IAPs, thereby promoting apoptosis.
  • Overexpression of Smac/DIABLO sensitizes neuroblastoma cells to TRAIL-induced apoptosis.
  • Cytotoxic drugs can sensitize TRAIL-resistant cancer cells to TRAIL-mediated apoptosis.
  • NFkappaB interferes with TNFalpha/TRAIL signaling and activates antiapoptotic proteins; Akt promotes cell survival by regulating survival proteins and phosphorylating proapoptotic proteins like Bad.

Conclusions:

  • Understanding the intricate interplay of cell survival and death pathways is essential for cancer therapy.
  • Targeting IAPs with agents like Smac/DIABLO can overcome chemoresistance.
  • Combination therapies involving TRAIL agonists and cytotoxic drugs show promise.
  • Inhibiting pro-survival pathways (NFkappaB, Akt) alongside apoptosis induction is a viable strategy for enhancing anti-cancer effects.

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