Chloroquine Suppresses Pancreatic Cancer Growth in Culture and in Mouse Models

The antimalaria drug chloroquine, a potent inhibitor of the cellular process known as autophagy, blocks growth of pancreatic cancer cells in culture and in several mouse models of the disease.

Autophagy is a regulated catabolic pathway that degrades cellular organelles and macromolecules. The role of autophagy in cancer is complex and may differ depending on tumor type or context. In a recent study investigators at the Harvard Medical School's Dana-Farber Cancer Institute (Boston, MA, USA) found that pancreatic cancers have a distinct dependence on autophagy.

To study the effect of blocking autophagy on pancreatic cancer cells the investigators administered chloroquine to several different pancreatic cancer cell cultures, and tested its effects in three types of mouse models. The mouse models included xenografts, where human pancreatic cancer cells were placed under the rodents' skin; orthotopic transplants where human cells were injected into the animals' pancreases; and a genetic model where mice were genetically engineered to develop native pancreatic tumors.

Results published in the March 15, 2011, online edition of the journal Genes & Development revealed that chloroquine markedly suppressed the growth of the cancer cell cultures, showing that the cells were heavily dependent on autophagy for continued growth. Chloroquine treatment of eight xenograft recipient mice extended their life spans by 40 days as compared to a control group that did not receive the drug. In the other two model systems, the effect of chloroquine treatment was less pronounced but still significant.

At the molecular level inhibition of autophagy led to increased formation of reactive oxygen species, elevated DNA damage, and a metabolic defect leading to decreased mitochondrial oxidative phosphorylation. Together, these flaws caused significant growth suppression of pancreatic cancer cells both in culture and in the animal models.

"We are seeing robust and impressive responses in pancreatic cancer mouse models,” said senior author Dr. Alec Kimmelman, assistant professor of radiation oncology at Harvard Medical School. "The oral drug, hydroxychloroquine, is inexpensive, widely available, and causes relatively mild side effects. A planned clinical trial will combine the drug with radiation treatment.”

Related Links:
Dana-Farber Cancer Institute