Combination of an Autophagy Inducer and an Autophagy Inhibitor: A Smarter Strategy Emerging in Cancer Therapy

Abstract

Autophagy is considered a cytoprotective function in cancer therapy under certain conditions and is a drug resistance mechanism that represents a clinical obstacle to successful cancer treatment and leads to poor prognosis in cancer patients. Because certain clinical drugs and agents in development have cytoprotective autophagy effects, targeting autophagic pathways has emerged as a potential smarter strategy for cancer therapy. Multiple preclinical and clinical studies have demonstrated that autophagy inhibition augments the efficacy of anticancer agents in various cancers. Autophagy inhibitors, such as chloroquine and hydroxychloroquine, have already been clinically approved, promoting drug combination treatment by targeting autophagic pathways as a means of discovering and developing more novel and more effective cancer therapeutic approaches. We summarize current studies that focus on the antitumor efficiency of agents that induce cytoprotective autophagy combined with autophagy inhibitors. Furthermore, we discuss the challenge and development of targeting cytoprotective autophagy as a cancer therapeutic approach in clinical application. Thus, we need to facilitate the exploitation of appropriate autophagy inhibitors and coadministration delivery system to cooperate with anticancer drugs. This review aims to note optimal combination strategies by modulating autophagy for therapeutic advantage to overcome drug resistance and enhance the effect of antitumor therapies on cancer patients.

Simvastatin Induces Unfolded Protein Response and Enhances Temozolomide-Induced Cell Death in Glioblastoma Cells

“…Confirming findings from previous studies, we showed that Simva–TMZ inhibited autophagy flux [ 41 , 62 , 63 ]; we demonstrate here for the first time that this is dependent on the IRE1–XBP-1s axis (as MKC-8866 inhibited the Simva–TMZ effect). To our surprise, the cytotoxic effect of Simva–TMZ was not affected by MKC8866.…”

Repurposing of host-based therapeutic agents for the treatment of coronavirus disease 2019 (COVID-19): a link between antiviral and anticancer mechanisms?

“…The antimalarials hydroxychloroquine and chloroquine are known to inhibit autophagic pathways in aggressive metastatic cells and potentiate the efficacy of chemotherapy in various types of cancer. Autophagy is considered a cytoprotective mechanism that confers drug resistance, representing a key obstacle to effective cancer treatment [2] . Likewise, the antiparasitic drug nitazoxanide induces cancer cell cytotoxicity under hypoxic conditions and could be an excellent candidate to target dormant cancer cells in hypoxic regions of tumours in combination with chemotherapeutic agents [3] .…”

Effect of Calomelanone, a Dihydrochalcone Analogue, on Human Cancer Apoptosis/Regulated Cell Death in an In Vitro Model

“…Notably, it inhibits autophagy via PI3K class III suppression, a survival signaling pathway. A combination of 3-MA with natural product(s) could induce cytotoxicity and apoptosis/regulated cell death in various cancer cell types [ 64 ]. In this study, after combining calomelanone with 3-MA, it was found that 3-MA could significantly ameliorate cell viability at high doses (IC 20 and IC 50 ).…”