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Pentamidine is an inhibitor of PRL phosphatases with anticancer activity
Manas K Pathak1, Deepika Dhawan, Daniel J Lindner
1Department of Cancer Biology, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.
Abstract:
The PRL family oncogenic phosphatases are attractive targets for developing inhibitors as anticancer therapeutics given their potentially pathogenic role in human malignancies. Herein we demonstrate that pentamidine, an anti-protozoa drug with an unknown mechanism of action, is an inhibitor of PRLs with anticancer potential. Pentamidine at its therapeutic doses inhibited recombinant PRL phosphatases in vitro and inactivated ectopically expressed PRLs in NIH3T3 transfectants with an effective duration more than 24 h after a pulse cell treatment. The drug had in vitro growth-inhibitory activity against human cancer cell lines that express the endogenous PRLs. Pentamidine at a tolerable dose markedly inhibited the growth of WM9 human melanoma tumors in nude mice coincident with the induction of tumor cell necrosis and is capable of inactivating ectopically expressed PRL-2 in the cancer cells. These observations suggest the potential of pentamidine in anticancer therapies and may provide a basis for developing novel PTPase-targeted therapeutics.
Insights
Pentamidine, an anti-protozoa drug, inhibits PRL phosphatases, which are implicated in cancer. This discovery suggests pentamidine
Area of Science:
- Biochemistry
- Oncology
- Pharmacology
Background:
- PRL phosphatases are implicated in human malignancies.
- Developing inhibitors for PRLs is a promising anticancer therapeutic strategy.
Purpose of the Study:
- To investigate pentamidine as a potential inhibitor of PRL phosphatases.
- To evaluate the anticancer potential of pentamidine.
Main Methods:
- In vitro inhibition assays of recombinant PRL phosphatases.
- Inactivation of ectopically expressed PRLs in NIH3T3 cells.
- In vitro growth inhibition assays against human cancer cell lines.
- In vivo studies using WM9 human melanoma xenografts in nude mice.
Main Results:
- Pentamidine inhibited recombinant and ectopically expressed PRL phosphatases.
- Pentamidine demonstrated in vitro growth-inhibitory activity against PRL-expressing cancer cell lines.
- Pentamidine significantly inhibited melanoma tumor growth in vivo, inducing tumor cell necrosis.
Conclusions:
- Pentamidine exhibits inhibitory activity against PRL phosphatases.
- Pentamidine shows significant anticancer potential, warranting further investigation for novel PTPase-targeted therapies.