Autophagy inhibition in combination cancer treatment

The effective elimination of cancer cells is compromised by mechanisms of resistance. Such mechanisms have been variably ascribed to drug export transporters, more effective DNA repair mechanisms compared with healthy cells, singularly resistant stem cells, resistance to apoptosis, self-sufficiency for growth factor signaling and an angiogenic switch, as well as immunological pathways associated with T-regulatory cells, myeloid-derived suppressor cells or plasmacytoid dendritic cells. In this review, the critically important process of autophagy, which is a mechanism of cell survival in the presence of genomic injury, endoplasmic reticulum stress, oxidant stress, nutrient insufficiency and viral/bacterial infection, is explored in the setting of cancer treatment. Autophagy has recently been demonstrated as important for conferring resistance to chemotherapy, radiation therapy and immunotherapy. Compounds are now available that can reverse autophagy, including the antimalarial compounds chloroquine and hydroxychloroquine, as well as the antidepressant agent clomipramine. Other strategies for the reversal of autophagy are based on the recent observation that the cytosolic location of the chromatin-binding protein HMGB1 (high-mobility group box-1) is associated with sustained autophagy. Targeting HMGB1 using platinum-containing compounds, ethyl pyruvate or glycyrrhizin has also been used to limit autophagy. Screening for new agents is ongoing, which, coupled with conventional chemotherapeutic compounds, may usher in a new generation of autophagy-inhibiting agents.