How Antimalarials and Antineoplastic Drugs can Interact in Combination Therapies: A Perspective on the Role of PPT1 Enzyme.

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.

• Authors: Diana Duarte, Nuno Vale
• Journal: Current drug metabolism (Curr Drug Metab) Vol. 22 Issue 13 Pg. 1009-1016 ( 2021) ISSN: 1875-5453 [Electronic] Netherlands
• PMID: 34791996 (Publication Type: Journal Article)
• Copyright: Copyright© Bentham Science Publishers; For any queries, please email at [email protected].

Chemical References

• Antimalarials
• Antineoplastic Agents
• Membrane Proteins
• MTOR protein, human
• TOR Serine-Threonine Kinases
• Thiolester Hydrolases
• PPT1 protein, human

Topics

• Antimalarials (pharmacology)
• Antineoplastic Agents (pharmacology)
• Autophagy (drug effects)
• Biological Availability
• Carcinogenesis (drug effects, metabolism)
• Drug Interactions
• Drug Synergism
• Drug Therapy, Combination
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Lysosomes (drug effects, enzymology)
• Membrane Proteins (metabolism)
• Molecular Targeted Therapy (methods)
• Neoplasms (drug therapy, metabolism)
• Signal Transduction (drug effects)
• TOR Serine-Threonine Kinases (metabolism)
• Thiolester Hydrolases (metabolism)