Niclosamide in prostate cancer: An inhibitor of AR-V7, a mitochondrial uncoupler, or more?
A recent phase Ib study investigating the use of reformulated niclosamide in combination with abiraterone and prednisone in patients with castration-resistant prostate cancer (CRPC) demonstrated encouraging preliminary efficacy with low toxicity. Preclinical studies have reported that niclosamide at...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-01-01
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| Series: | Cancer Treatment and Research Communications |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2468294223000060 |
| _version_ | 1797828127871729664 |
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| author | Minas Sakellakis |
| author_facet | Minas Sakellakis |
| author_sort | Minas Sakellakis |
| collection | DOAJ |
| description | A recent phase Ib study investigating the use of reformulated niclosamide in combination with abiraterone and prednisone in patients with castration-resistant prostate cancer (CRPC) demonstrated encouraging preliminary efficacy with low toxicity. Preclinical studies have reported that niclosamide at clinically relevant concentrations inhibits androgen receptor splice variant 7 (AR-V7), a known tumor driver in CRPC. However, the magnitude of anti-tumor effects of niclosamide either used alone or in combination with abiraterone in these experimental models, far exceeded what could have been explained as a simple AR-V7 inhibition. Niclosamide at clinically relevant concentrations also acts as an oxidative phosphorylation (OxPhos) uncoupler in mitochondria. This raises the question whether the observed effects of niclosamide were partly mediated by OxPhos inhibition. Most OxPhos inhibitors did not demonstrate selectivity towards cancer cells and failed to enter clinical practice due to unacceptable toxicity. However, some mitochondrial uncouplers have greater cytotoxicity against cancerous cells compared to non-cancerous. Hyperpolarization of cancer cell mitochondria, or the more alkaline mitochondrial matrix of cancer cells could be potential reasons for this. Niclosamide can also alter Wnt/β-catenin, mTOR, Notch, NF-kB and STAT3 signaling pathways. Hence, the mechanism of action of reformulated niclosamide in CRPC patients requires further investigation. This will potentially lead to new opportunities to develop and investigate even more selective and effective treatments against prostate cancer. |
| first_indexed | 2024-04-09T12:59:47Z |
| format | Article |
| id | doaj.art-88f4de814d4e4112832e8eab6336f2ee |
| institution | Directory Open Access Journal |
| issn | 2468-2942 |
| language | English |
| last_indexed | 2024-04-09T12:59:47Z |
| publishDate | 2023-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cancer Treatment and Research Communications |
| spelling | doaj.art-88f4de814d4e4112832e8eab6336f2ee2023-05-13T04:25:27ZengElsevierCancer Treatment and Research Communications2468-29422023-01-0135100685Niclosamide in prostate cancer: An inhibitor of AR-V7, a mitochondrial uncoupler, or more?Minas Sakellakis0Hellenic GU Cancer Group, Athens, Greece; Department of Medical Oncology, Metropolitan Hospital, Athens, 18547, Greece; Corresponding author at: Department of Medical Oncology, Metropolitan Hospital, 9 Ethnarchou Makariou, Athens,18547, Greece.A recent phase Ib study investigating the use of reformulated niclosamide in combination with abiraterone and prednisone in patients with castration-resistant prostate cancer (CRPC) demonstrated encouraging preliminary efficacy with low toxicity. Preclinical studies have reported that niclosamide at clinically relevant concentrations inhibits androgen receptor splice variant 7 (AR-V7), a known tumor driver in CRPC. However, the magnitude of anti-tumor effects of niclosamide either used alone or in combination with abiraterone in these experimental models, far exceeded what could have been explained as a simple AR-V7 inhibition. Niclosamide at clinically relevant concentrations also acts as an oxidative phosphorylation (OxPhos) uncoupler in mitochondria. This raises the question whether the observed effects of niclosamide were partly mediated by OxPhos inhibition. Most OxPhos inhibitors did not demonstrate selectivity towards cancer cells and failed to enter clinical practice due to unacceptable toxicity. However, some mitochondrial uncouplers have greater cytotoxicity against cancerous cells compared to non-cancerous. Hyperpolarization of cancer cell mitochondria, or the more alkaline mitochondrial matrix of cancer cells could be potential reasons for this. Niclosamide can also alter Wnt/β-catenin, mTOR, Notch, NF-kB and STAT3 signaling pathways. Hence, the mechanism of action of reformulated niclosamide in CRPC patients requires further investigation. This will potentially lead to new opportunities to develop and investigate even more selective and effective treatments against prostate cancer.http://www.sciencedirect.com/science/article/pii/S2468294223000060NiclosamideProstate cancerUncouplersAR-V7Inhibitor |
| spellingShingle | Minas Sakellakis Niclosamide in prostate cancer: An inhibitor of AR-V7, a mitochondrial uncoupler, or more? Cancer Treatment and Research Communications Niclosamide Prostate cancer Uncouplers AR-V7 Inhibitor |
| title | Niclosamide in prostate cancer: An inhibitor of AR-V7, a mitochondrial uncoupler, or more? |
| title_full | Niclosamide in prostate cancer: An inhibitor of AR-V7, a mitochondrial uncoupler, or more? |
| title_fullStr | Niclosamide in prostate cancer: An inhibitor of AR-V7, a mitochondrial uncoupler, or more? |
| title_full_unstemmed | Niclosamide in prostate cancer: An inhibitor of AR-V7, a mitochondrial uncoupler, or more? |
| title_short | Niclosamide in prostate cancer: An inhibitor of AR-V7, a mitochondrial uncoupler, or more? |
| title_sort | niclosamide in prostate cancer an inhibitor of ar v7 a mitochondrial uncoupler or more |
| topic | Niclosamide Prostate cancer Uncouplers AR-V7 Inhibitor |
| url | http://www.sciencedirect.com/science/article/pii/S2468294223000060 |
| work_keys_str_mv | AT minassakellakis niclosamideinprostatecanceraninhibitorofarv7amitochondrialuncouplerormore |