The majority of current cancer treatments is limited, as tumors are able to develop drug resistance. In particular, anti-metabolic drugs, which aim to mimic starvation in cancerous cells, have been observed to induce autophagy – a cellular defense mechanism, which helps the tumor escape cell death, thus gaining resistance to the drug.
Autophagy is a self-digestion process, usually activated under nutrient deprivation. A cell degrades non-essential components under these conditions to provide molecules for energy production and other metabolic reactions critical for survival. Essentially, this state is associated with halted proliferation, and a number of anti-metabolic drugs have been related to decreased cancerous growth in vitro and in vivo. However, since autophagy generally protects the cells from undergoing apoptosis, the growth of a tumor cannot be completely suppressed.
A new research published in Cancer & Metabolism suggests a traditional antimalarial drug – chloroquine, is able to inhibit autophagy, and, used in combination with anti-metabolites, can boost their cytotoxic effect significantly.
In the beginning cancerous cells are “tricked” into a state of starvation by inhibiting enzymes of the glycolytic pathway – the main energetic pathway in the cell. Nutrient deficiency response leads to lower glucose uptake and reduced cell proliferation, survival pathways are activated through autophagy. However, the administration of chloroquine leads to halted autophagic response, as such leaving the cells “stranded”. The cells eventually go through apoptosis, degrading the tumor from within, as they are unable to recover.
Chloroquine, which has been used as an anti-malarial agent since 1940s, has only recently been observed to induce cancer cell death, as is currently being used in combination with a number of chemotherapeutic drugs in human cancer clinical trials.
The research shows that use of chloroquine with anti-metabolites in fact leads to significantly smaller tumors in an animal model, as compared to either therapy applied on its own. By increasing the rate of apoptosis, chloroquine improves the anti-growth effect of the primary drug, and should be explored as a potent supplement to different anti-cancer treatment options.
Uncovering the autophagy-driven tumor survival mechanism is a major milestone in the fight against cancer, and could lead to better cancer-specific therapeutics, potentially reducing the global burden of the disease.