Risk factors of using late-autophagy inhibitors: Aspects to consider when combined with anticancer therapies

Area of Science:

• Oncology
• Cellular Biology
• Pharmacology

Background:

• Cancer therapy resistance is a major clinical challenge.
• Cellular senescence, including therapy-induced senescence (TIS), is a newly recognized hallmark of cancer that can promote resistance.
• Macroautophagy inhibition is explored as a strategy to overcome TIS-mediated resistance.

Purpose of the Study:

• To review late-stage autophagy inhibitors, focusing on 4-aminoquinoline derivatives like chloroquine/hydroxychloroquine (CQ/HCQ).
• To examine the role of these inhibitors in regulating autophagy and senescent cell phenotypes.
• To assess their impact on cancer treatment response in preclinical models and clinical trials.

Main Methods:

• Literature review of studies on late-stage autophagy inhibitors.
• Analysis of in vitro and in vivo models of cancer.
• Examination of clinical trial data for oncological patients.

Main Results:

• Late-stage autophagy inhibitors, such as CQ/HCQ, disrupt autophagolysosome function and lysosomal pH, impairing cargo degradation.
• These inhibitors have shown potential in sensitizing cancer cells to therapy-induced senescence in preclinical studies.
• Clinical trials indicate that CQ/HCQ can enhance treatment effectiveness in some cancer patients.

Conclusions:

• Inhibition of late-stage autophagy presents a promising strategy to overcome therapy-induced senescence and enhance anticancer efficacy.
• However, practical application of autophagy inhibitors like CQ/HCQ may be limited by systemic toxicity, dose/time-dependent effects, and potential escape from TIS.
• Further research is needed to optimize the use of autophagy inhibitors in cancer therapy, balancing efficacy with safety concerns.