Modulation of Endoplasmic Reticulum Stress in Experimental Anti-Cancer Therapy

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Tumor growth involves increased endoplasmic reticulum stress (ERS) and unfolded protein response (UPR) activation.
• UPR normally restores ER proteostasis, but prolonged ERS induces cell death, presenting a therapeutic vulnerability.
• ERS/UPR machinery components are dysregulated in various cancers, suggesting targeting them as a strategy.

Purpose of the Study:

• To review natural and synthetic compounds targeting ERS/UPR pathways for cancer therapy.
• To explore therapeutic strategies involving induction of excessive ERS or suppression of UPR.
• To discuss the molecular mechanisms and clinical potential of ERS/UPR inhibitors.

Main Methods:

• Narrative review of literature on ERS/UPR modulating agents.
• Analysis of compounds targeting ER Ca2+ pumps (SERCA) and UPR sensors (GRP78, PERK, IRE1α, ATF6).
• Examination of molecular alterations induced by ERS/UPR inhibitors.

Main Results:

• Several agents demonstrated promising preclinical combination therapy effects.
• Inhibitors can disrupt ER Ca2+ homeostasis or impair protein degradation signaling.
• Clinical trial data is limited and inconsistent, with significant side effects and bioavailability issues.

Conclusions:

• Pharmacological modulation of ERS/UPR is a viable approach to sensitize cancer cells to chemotherapy.
• Development of more selective, stable, and less toxic agents is crucial.
• Improved delivery systems are needed to enhance therapeutic specificity and clinical application.