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Updated: Jan 19, 2026
Evaluating the Effectiveness of Cancer Drug Sensitization In Vitro and In Vivo
Published on: February 6, 2015
The TRAIL to cancer therapy: Hindrances and potential solutions
Sonia How Ming Wong1, Wei Yang Kong1, Chee-Mun Fang2
1School of Biosciences, Faculty of Science and Engineering, University of Nottingham Malaysia, 43500, Semenyih, Selangor, Malaysia.
Abstract:
Apoptosis is an ordered and orchestrated cellular process that occurs in physiological and pathological conditions. Resistance to apoptosis is a hallmark of virtually all malignancies. Despite being a cause of pathological conditions, apoptosis could be a promising target in cancer treatment. Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), also known as Apo-2 ligand (Apo2L), is a member of TNF cytokine superfamily. It is a potent anti-cancer agent owing to its specific targeting towards cancerous cells, while sparing normal cells, to induce apoptosis. However, resistance occurs either intrinsically or after multiple treatments which may explain why cancer therapy fails. This review summarizes the apoptotic mechanisms via extrinsic and intrinsic apoptotic pathways, as well as the apoptotic resistance mechanisms. It also reviews the current clinically tested recombinant human TRAIL (rhTRAIL) and TRAIL receptor agonists (TRAs) against TRAIL-Receptors, TRAIL-R1 and TRAIL-R2, in which the outcomes of the clinical trials have not been satisfactory. Finally, this review discusses the current strategies in overcoming resistance to TRAIL-induced apoptosis in pre-clinical and clinical settings.
Insights
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) shows promise for cancer treatment by inducing apoptosis. However, resistance to TRAIL therapy is a significant challenge that requires new strategies for effective cancer treatment.
Area of Science:
- Cellular biology
- Molecular oncology
- Cancer therapeutics
Background:
- Apoptosis, or programmed cell death, is crucial in physiological and pathological states.
- Resistance to apoptosis is a key characteristic of most cancers.
- Targeting apoptosis pathways presents a potential strategy for cancer treatment.
Purpose of the Study:
- To review mechanisms of apoptosis, including extrinsic and intrinsic pathways.
- To summarize mechanisms of apoptosis resistance in cancer.
- To discuss strategies for overcoming resistance to TRAIL-induced apoptosis.
Main Methods:
- Literature review of apoptotic mechanisms and resistance.
- Analysis of clinical trial data for recombinant human TRAIL (rhTRAIL) and TRAIL receptor agonists (TRAs).
- Discussion of pre-clinical and clinical strategies to overcome TRAIL resistance.
Main Results:
- TRAIL targets cancer cells to induce apoptosis, sparing normal cells.
- Intrinsic and acquired resistance to TRAIL limits its therapeutic efficacy.
- Clinical trials with rhTRAIL and TRAs have yielded unsatisfactory outcomes.
Conclusions:
- TRAIL-based therapies hold potential for cancer treatment but face significant resistance challenges.
- Understanding apoptotic and resistance mechanisms is vital for developing effective cancer therapies.
- Novel strategies are needed to overcome TRAIL resistance in clinical and pre-clinical settings.
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