Thursday, April 14, 2011

Chloroquine and Cancer Treatment !

Strange as it may sound, but it is true. Yes, this is what a group of researchers from Harvard Medical School recently reported in a reputed journal.  I believe most of us especially those living in India and Africa, are well aware of Chloroquine, which is known as one of the most widely and successfully used first generation anti-malarial drug.  It is very famous (for its effectiveness) rather infamous (for its characteristic bitter taste), I still remember during my childhood back in India, elders used to threaten kids that if they won’t sleep in bed equipped with mosquito nets, they would have to eat chloroquine, and all kids out of fear for chloroquine rather malaria itself, would immediately agree to go to bed under the net (which they otherwise did not like normally). Anyways, in last few decades because of emerging chloroquine-resistant malaria parasites, chloroquine was almost forgotten and researchers started to look for other more effective and less toxic drugs to treat and prevent malaria. It is only last couple of years that chloroquine got sudden attention especially among biologists when cancer biologists noticed its role as an inhibitor of autophagy.

Autophagy (from Greek auto-oneself, phagy-to eat) is a process of self-cannibalization which is dependent on the presence of autophagosomes, autolysosomes, as well as an intact nucleus in the cell. Autophagy was first described in the 1960s but many questions about the actual processes and mechanisms involved still remain to be elucidated. Cells capture their own cytoplasm and organelles and consume them in lysosomes. The resulting breakdown products are inputs to cellular metabolism, through which they are used to generate energy and to build new proteins and membranes. Autophagy preserves the health of cells and tissues by replacing outdated and damaged cellular components with fresh ones. In starvation, it provides an internal source of nutrients for energy generation and, thus, survival. A powerful promoter of metabolic homeostasis at both the cellular and whole-animal level, autophagy prevents degenerative diseases. It does have a downside, however--cancer cells exploit it to survive in nutrient-poor tumors. However, the role of autophagy in cancer is complex and may differ depending on tumor type or context.

Pancreatic cancer is highly lethal disease. It is estimated that in 2010 more than 43,000 individuals in the United States have been diagnosed with this condition, and 36,800 have died from the disease. Most of these tumors tend to be therapeutically resistant against cytotoxic chemotherapies, targeted agents, and radiotherapy. Most common form of pancreatic cancer is pancreatic ductal adenocarcinoma (PDAC), which contains activating KRAS mutations in the great majority of cases, making this an ideal target for therapeutic intervention. Unfortunately, effective KRAS inhibitors have yet to be developed. The inhibition of pathways downstream from KRAS is a potentially viable approach to circumventing the difficulties in KRAS inhibition. However, KRAS has a multitude of effectors, many of which are poorly characterized, making it a significant challenge to completely shut off the KRAS pathway.

In their study Dr. Alec Kimmelman, MD, PhD, a radiation oncologist at Harvard Medical School, and his group demonstrated that pancreatic tumor derived cell lines and tumors isolated from patients with pancreatic cancers had activated autophagy. Cleaved form of LC3, a protein which associates with autophagosome membranes, widely used as a marker protein for autophagy in the field, was found to be over-expressed in these cells lines and primary tumors. Realizing that profuse activation of autophagy may contribute to pancreatic tumor growth, researchers designed an experiment in which they planned to treat the pancreatic cancer cell lines with Chloroquine, already known as inhibitor of autophagy. As a control, chloroquine was also used to treat normal cell lines with low expression of autophagy. Lo and behold, these researchers found that cell lines derived from pancreatic cancers which had higher level of autophagy were highly sensitive to autophagy inhibition by Chloroquine but this drug had minimal effects on those non cancerous cell lines which had lower levels of autophagy. In many other supporting experiments, researchers confirmed that in keeping with their elevated basal autophagy, pancreatic cancer derived cell lines exhibited a marked sensitivity to chloroquine.

However, apart from having a translational implication, this study must be taken as an indicator of levels of complexities of ongoing cellular processes inside a growing tumor. It is important to re-emphasize that autophagy may act to promote tumorigenesis in other types of cancer, but it may not be as prevalent or as pronounced as in pancreatic cancer, in which the overwhelming majority of tumors are dependent on this process. This study also warrants for further work to be performed to determine the specific roles of autophagy in other tumor types as it should not be forgotten that the positive role for autophagy in the maintenance of advanced pancreatic cancers stands in contrast to a number of other malignancies, in which genetic evidence from human specimens and mouse models shows that inactivation of autophagy can promote tumorigenesis.

The most important aspect of this study is that chloroquine and its derivatives which effectively inhibit autophagy, and in this study, inhibit pancreatic tumor growth—have been safely used in patients for many years as anti-malarial therapies. Given all these factors, we all should hope to see clinical trials to begin soon in pancreatic cancers using these drugs targeting autophagy.


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