Autophagy is a very complicated process when it comes to cancer. In general, autophagy isn’t complicated at all. It is a highly conserved process in which damaged or long-lived proteins and organelles can be removed from cells. Functioning through lysosomal machinery, this process ensures cellular survival during starvation by maintaining cellular energy levels. Think of it as a waste removal/renewable energy source system; bad or unnecessary stuff gets broken down in order to sustain the rest of the cell. This happens in nearly all cells and it works wonderfully.
In cancer, however, the role of autophagy is a bit murkier. Sometimes, autophagy is working with the doctors in the suppression of tumor cells; isolating damaged organelles, allowing cell differentiation or promoting cell death of the cancerous cells. But other times, autophagy is working against the doctors; allowing stressed tumor cells to undergo dormancy and resistance to chemotherapeutic drugs. Such a dichotomy in roles can be very frustrating to the doctors and ultimately deadly to a patient if the therapy is compromised due to the lack of effective autophagy or if the cancer comes back due to effective autophagy. Knowing which cancers use autophagy for survival and which cancers are susceptible to autophagy is key to corrective treatment.
None of this is particularly new, however. The role of autophagy in cancer cells is quite known (there is a dedicated Autophagy Journal, after all). There are also a number of clinical studies on various cancer types which are looking into the use of anti-autophagy drugs in conjunction with chemotherapy drugs. Autophagy-inhibitory drugs can come in one of two types: there are the early-stage inhibitors which can target class III P13K and interfere with its membrane recruitment, and late-stage inhibitors (such as chloroquine, hydrochloroquine and monensin) which prevent the acidification of lysosomes (Yang, 2011). Below is a table of various ongoing (c. 2011) clinical trials utilizing some of these late-stage, autophagy inhibitors.
More recently, a group in South Korea headed by Cheol Hyeon Kim investigated the effect of monensin on two anticancer drugs (erlotinib and rapamycin) in the treatment of lung cancer cells. Erlotinib is an Epidermal Growth Factor Receptor (EGFR) inhibitor which binds to the ATP binding site on the EGFR, which prevents the formation of an EGFR homodimer and its ensuing signaling cascade. Rapamycin is a macrocyclic triene, antibacterial drug which also has immunosuppressant and anticancer activities. The major target of rapamycin in mammalian cells is the mTOR pathway, which is a major regulator of autophagy, and which is downstream of the P13K-AKT pathway.
Kim’s group saw an increase in apoptosis in the cells treated with both the anticancer drug as well as nanomolar concentrations of monensin, with a 40% reduction in cells compared to the control and around ~20% reduction compared to the anticancer drug alone (P <0.01). Perhaps this isn’t really that surprisingly, after all. Hydrochloroquine in conjunction with erlotinib is already in a phase 2 trials for lung cancer (see table above). But their published record further assists in the elucidation of how autophagy functions in the realm of cancer cell tumorigenesis and ultimately, that is most important thing right now.
Choi, H. S., Jeong, E. H., Lee, T. G., Kim, S. Y., Kim, H. R., & Kim, C. H. (2013). Autophagy Inhibition with Monensin Enhances Cell Cycle Arrest and Apoptosis Induced by mTOR or Epidermal Growth Factor Receptor Inhibitors in Lung Cancer Cells. Tuberculosis and Respiratory Diseases, 75(1), 9-17.
Yang, Z. J., Chee, C. E., Huang, S., & Sinicrope, F. A. (2011). The role of autophagy in cancer: therapeutic implications. Molecular cancer therapeutics, 10(9), 1533-1541.
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