Enhancing Anti-Cancer Therapy with Selective Autophagy Inhibitors by Targeting Protective Autophagy

Abstract

Autophagy is a process of eliminating damaged or unnecessary proteins and organelles, thereby maintaining intracellular homeostasis. Deregulation of autophagy is associated with several diseases including cancer. Contradictory dual roles of autophagy have been well established in cancer. Cytoprotective mechanism of autophagy has been extensively investigated for overcoming resistance to cancer therapies including radiotherapy, targeted therapy, immunotherapy, and chemotherapy. Selective autophagy inhibitors that directly target autophagic process have been developed for cancer treatment. Efficacies of autophagy inhibitors have been tested in various pre-clinical cancer animal models. Combination therapies of autophagy inhibitors with chemotherapeutics are being evaluated in clinal trials. In this review, we will focus on genetical and pharmacological perturbations of autophagy-related proteins in different steps of autophagic process and their therapeutic benefits. We will also summarize combination therapies of autophagy inhibitors with chemotherapies and their outcomes in pre-clinical and clinical studies. Understanding of current knowledge of development, progress, and application of cytoprotective autophagy inhibitors in combination therapies will open new possibilities for overcoming drug resistance and improving clinical outcomes.

Challenges of Regulated Cell Death: Implications for Therapy Resistance in Cancer

“…In particular, chronic use of CQ has shown promise in preventing drug resistance, particularly in highly autophagy-addicted tumors such as most aggressive BCs. These findings highlight the potential of combining low doses of CQ with PI3K inhibitors and chemotherapy [56,61].…”

Targeting autophagy with natural products as a potential therapeutic approach for diabetic microangiopathy

“…Non-selective autophagy mainly refers to autophagy that is induced in most cases, such as autophagy induced by mammalian target of rapamycin (mTOR) ( Glick et al, 2010 ). In selective autophagy, specific autophagy adapter proteins like SQSTM1/p62, interact with microtubule-associated protein light chain 3 (Lc3) located in the phagolysosome membrane, delivering substrates directly to autophagosomes for degradation ( Lee et al, 2023 ). Identified types of selective autophagy are mitophagy, ribosomal autophagy, endoplasmic reticulum (ER) autophagy, and peroxisome autophagy ( Adriaenssens et al, 2022 ).…”

Chinese herbal medicine and its active compounds in attenuating renal injury via regulating autophagy in diabetic kidney disease

“…Non-selective autophagy degradation substrates are relatively non-selective, such as rapamycin induced autophagy, nitrogen source starvation induced autophagy, serum starvation induced autophagy, etc (60). Selective autophagy refers to the direct binding of selective autophagy receptors with LC3 (Atg8 in yeast and plant cells) to deliver specific degradation substrates to autophagosomes for degradation (61). The selective autophagy types found so far include mitochondrial autophagy, ribosomal autophagy, endoplasmic reticulum autophagy, peroxisome autophagy, etc (62).…”