Title:How Antimalarials and Antineoplastic Drugs can Interact in Combination Therapies: A Perspective on the Role of PPT1 Enzyme
Volume: 22
Issue: 13
Author(s): Diana Duarte and Nuno Vale*
Affiliation:
- OncoPharma Research Group, Center for Health Technology and Services Research (CINTESIS), Rua Dr. Plácido da Costa, 4200-450 Porto,Portugal
Keywords:
PPT1, antimalarial drugs, antineoplastic drugs, mTOR, autophagy, drug combination.
Abstract: Antimalarial drugs from different classes have demonstrated anticancer effects in different types of cancer
cells, but their complete mode of action in cancer remains unknown. Recently, several studies reported the important
role of palmitoyl-protein thioesterase 1 (PPT1), a lysosomal enzyme, as the molecular target of chloroquine and its
derivates in cancer. It was also found that PPT1 is overexpressed in different types of cancer, such as breast, colon,
etc. Our group has found a synergistic interaction between antimalarial drugs, such as mefloquine, artesunate and
chloroquine and antineoplastic drugs in breast cancer cells, but the mechanism of action was not determined. Here,
we describe the importance of autophagy and lysosomal inhibitors in tumorigenesis and hypothesize that other antimalarial
agents besides chloroquine could also interact with PPT1 and inhibit the mechanistic target of rapamycin
(mTOR) signalling, an important pathway in cancer progression. We believe that PPT1 inhibition results in changes
in the lysosomal metabolism that result in less accumulation of antineoplastic drugs in lysosomes, which increases
the bioavailability of the antineoplastic agents. Taken together, these mechanisms help to explain the synergism of
antimalarial and antineoplastic agents in cancer cells.
