Combination of an Autophagy Inducer and an Autophagy Inhibitor

Autophagy, a cellular process responsible for degrading unnecessary or damaged cellular components, has a complex role in cancer development and treatment. Under normal conditions, autophagy helps maintain cellular homeostasis by recycling cellular waste. However, in cancer, autophagy can function as a double-edged sword. While it can suppress tumor initiation by removing oncogenic substances, cancer cells often exploit autophagy to survive under stressful conditions, such as nutrient deprivation and anticancer treatments.

In cancer therapy, autophagy serves two primary functions: cytotoxic autophagy and cytoprotective autophagy. Cytotoxic autophagy, also known as autophagic cell death, can be triggered by overactivation of the autophagic process, leading to cancer cell death. This type of autophagy is often a desired outcome in cancer treatment, as it can enhance the therapeutic efficacy of anticancer agents. However, the more common response observed in cancer cells is cytoprotective autophagy. In this scenario, cancer cells use autophagy as a survival mechanism to resist therapy-induced stress, including chemotherapy and radiation, thereby promoting tumor progression and drug resistance.

The ability of cancer cells to leverage autophagy for survival has spurred interest in targeting autophagy as a therapeutic strategy. Inhibiting cytoprotective autophagy has become a promising approach to sensitizing cancer cells to treatment. Preclinical and clinical studies have demonstrated that combining autophagy inhibitors with standard anticancer therapies can enhance the effectiveness of treatment. For instance, drugs like chloroquine (CQ) and hydroxychloroquine (HCQ), which block the fusion of autophagosomes with lysosomes, have shown potential in clinical trials when used alongside chemotherapy or radiation. These inhibitors can disrupt the protective autophagic response in cancer cells, making them more susceptible to cell death.

Several autophagy inhibitors have been identified, including pharmacological agents such as 3-MA, BafA1, and resveratrol. These compounds target different stages of the autophagic process, preventing autophagy initiation or blocking autophagic flux. For example, resveratrol, a natural polyphenol, has been found to enhance the efficacy of chemotherapy drugs by inhibiting therapy-induced autophagy. Other inhibitors, such as the Bcl-2 family protein inhibitors, have shown similar potential in overcoming drug resistance.

Despite the promising results, there are challenges in the clinical application of autophagy modulation. One major hurdle is the need for more potent and specific autophagy inhibitors. Current inhibitors, such as CQ and HCQ, are not fully effective at inhibiting autophagy in vivo, and their toxicity profiles must be carefully managed. Additionally, the success of autophagy-targeting therapies may depend on developing optimized drug delivery systems to ensure that both autophagy inducers and inhibitors are delivered efficiently to the tumor site.

Targeting autophagy presents a novel and potentially powerful approach to enhance cancer treatment by overcoming drug resistance. However, further research is needed to refine this strategy, including discovering more potent inhibitors and developing effective combination therapies.​

References

Liu T, Zhang J, Li K, Deng L, Wang H. Combination of an Autophagy Inducer and an Autophagy Inhibitor: A Smarter Strategy Emerging in Cancer Therapy. Front Pharmacol. 2020 Apr 8;11:408. doi: 10.3389/fphar.2020.00408. PMID: 32322202; PMCID: PMC7156970.