Chloroquine, a drug currently used to treat malaria, may be useful in treating patients with metastatic cancers, a new study by University of Kentucky Markey Cancer Center researchers shows.
The study found that chloroquine induced the secretion of the tumor suppressor protein Par-4 in both mouse models and in cancer patients in a clinical trial. Secreted Par-4 is essential for tumor cell death and the inhibition of tumor metastasis.
Chloroquine induces Par-4 secretion via the classical secretory pathway that requires activation of p53 (a mutation of the p53 protein, or disturbances in the pathways that signal to p53, is common in many cancers).
Mechanistically, p53 directly induces Rab8b, a GTPase essential for vesicle transport of Par-4 to the plasma membrane prior to secretion. The study’s findings indicate that the antimalarial induces p53- and Rab8b-dependent Par-4 secretion from normal cells for Par-4-dependent inhibition of metastatic tumor growth.
Chloroquine Cell Empowerment
The study was led by the lab of Vivek M. Rangnekar.
UK Researchers Ravshan Burikhanov and Nikhil Hebbar in Rangnekar’s group were co-first authors in the study.
“Because p53 is often mutated in tumors, it makes the tumors resistant to treatment. However, this study shows that the relatively safe, FDA-approved drug chloroquine empowered normal cells – which express wild type p53 – to secrete Par-4 and stop metastasis in p53-deficient tumors.”
said Rangnekar, also the co-leader of the Cancer Cell Biology and Signaling research program and associate director at Markey.
Chloroquine was discovered in 1934 by Hans Andersag and coworkers at the Bayer laboratories, who named it Resochin. It was ignored for a decade because it was considered too toxic for human use.
During World War II, United States government-sponsored clinical trials for antimalarial drug development showed unequivocally that chloroquine has a significant therapeutic value as an antimalarial drug. It was introduced into clinical practice in 1947 for the prophylactic treatment of malaria.
At the UK Markey Cancer Center, one clinical trial using chloroquine for Par-4 induction in a variety of cancer patients is ongoing. Researchers are now planning a second clinical trial that would involve giving a maintenance dose of chloroquine to patients who are in remission, with the hopes of preventing cancer relapse.
The work was supported by NIH/NCI.
Burikhanov, Ravshan et al.
Chloroquine-Inducible Par-4 Secretion Is Essential for Tumor Cell Apoptosis and Inhibition of Metastasis
Cell Reports , Volume 18 , Issue 2 , 508 – 519
Top Image: Wellcome Photo Library, Wellcome Images